Delayed diagnosis of breast cancer: $15M award

A woman in her mid-50s had been seen by a breast surgeon for 16 years for regular mammograms and sonograms. In May 2009, the breast surgeon misinterpreted a mammogram as negative, as did a radiologist who re-read the mammogram weeks later. In December 2010, the patient returned to the breast surgeon with nipple discharge. No further testing was conducted. In October 2011, the patient was found to have Stage IIIA breast cancer involving 4 lymph nodes. She underwent left radical mastectomy, chemotherapy, radiation therapy, and breast reconstruction. At time of trial, the cancer had invaded her vertebrae, was Stage IV, and most likely incurable.

PATIENT'S CLAIM: Although the surgeon admittedly did not possess the qualifications required under the Mammography Quality Standards Act, he interpreted about 5,000 mammograms per year in his office. In this case, he failed to detect a small breast tumor in May 2009. He also failed to perform testing when the patient reported nipple discharge. A more timely diagnosis of breast cancer at Stage I would have provided a 90% chance of long-term survival.

DEFENDANTS' DEFENSE: The defense held the radiologist fully liable because the surgeon was not a qualified interpreter of mammography, therefore relying on the radiologist’s interpretation. The radiologist was legally responsible for the missed diagnosis.

VERDICT: A $15M New York verdict was reached, finding the breast surgeon 75% at fault and the radiologist 25%. The radiologist settled before the trial (the jury was not informed of this). The breast surgeon was responsible for $11.25M. The defense indicated intent to appeal.

Alleged failure to evacuate uterus after cesarean delivery

A 37-year-old woman underwent cesarean delivery (CD) performed by 2 ObGyns. After delivery, she began to hemorrhage and the uterus became atonic. Hysterectomy was performed but the bleeding did not stop. The ObGyns called in 3 other ObGyns. During exploratory laparotomy, the bleeding was halted.

PATIENT'S CLAIM: She and her husband had hoped to have more children but the hysterectomy precluded that. She sued all 5 ObGyns, alleging that the delivering ObGyns failed to properly perform the CD and that each physician failed to properly perform the laparotomy, causing a large scar. The claim was discontinued against the 3 surgical ObGyns; trial addressed the 2 delivering ObGyns.

The patient’s expert ObGyn remarked that the hemorrhage was caused by a small placental remnant that remained in the uterus as a result of inadequate evacuation following delivery. The presence of the remnant was indicated by the uterine atony and should have prompted immediate investigation. The physicians’ notes did not document exploration of the uterus prior to closure.

PHYSICIAN'S DEFENSE: The defense’s expert contended that atony would not be a result of a small remnant of placenta. The patient’s uterus was properly evacuated, the hemorrhage was an unforeseeable complication, and the ObGyns properly addressed the hemorrhage.

VERDICT: A New York defense verdict was returned.

Alleged bowel injury during hysterectomy

Two days after a woman underwent a hysterectomy performed by her ObGyn, she went to the emergency department with increasing pain. Her ObGyn admitted her to the hospital. A general surgeon performed an exploratory laparotomy the next day that revealed an abscess; a 1-cm perforation of the patient’s bowel was surgically repaired. The patient had a difficult recovery. She developed pneumonia and respiratory failure. She underwent multiple repair surgeries for recurrent abscesses and fistulas because the wound was slow to heal.

PATIENT'S CLAIM: The ObGyn’s surgical technique was negligent. He injured the bowel when inserting a trocar and did not identify the injury in a timely manner. The expert witness commented that such an injury can sometimes be a surgical complication, but not in this case: the ObGyn rushed the procedure because he had another patient waiting for CD at another hospital.

PHYSICIAN'S DEFENSE: The ObGyn denied negligence and contended that the trocar used in surgery was too blunt to have caused a perforation. It would have been obvious to the ObGyn during surgery if a perforation had occurred. The perforation developed days after surgery within an abscess.

VERDICT: A Mississippi defense verdict was returned.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

Delayed diagnosis of breast cancer: $15M award

A woman in her mid-50s had been seen by a breast surgeon for 16 years for regular mammograms and sonograms. In May 2009, the breast surgeon misinterpreted a mammogram as negative, as did a radiologist who re-read the mammogram weeks later. In December 2010, the patient returned to the breast surgeon with nipple discharge. No further testing was conducted. In October 2011, the patient was found to have Stage IIIA breast cancer involving 4 lymph nodes. She underwent left radical mastectomy, chemotherapy, radiation therapy, and breast reconstruction. At time of trial, the cancer had invaded her vertebrae, was Stage IV, and most likely incurable.

PATIENT'S CLAIM: Although the surgeon admittedly did not possess the qualifications required under the Mammography Quality Standards Act, he interpreted about 5,000 mammograms per year in his office. In this case, he failed to detect a small breast tumor in May 2009. He also failed to perform testing when the patient reported nipple discharge. A more timely diagnosis of breast cancer at Stage I would have provided a 90% chance of long-term survival.

DEFENDANTS' DEFENSE: The defense held the radiologist fully liable because the surgeon was not a qualified interpreter of mammography, therefore relying on the radiologist’s interpretation. The radiologist was legally responsible for the missed diagnosis.

VERDICT: A $15M New York verdict was reached, finding the breast surgeon 75% at fault and the radiologist 25%. The radiologist settled before the trial (the jury was not informed of this). The breast surgeon was responsible for $11.25M. The defense indicated intent to appeal.

Alleged failure to evacuate uterus after cesarean delivery

A 37-year-old woman underwent cesarean delivery (CD) performed by 2 ObGyns. After delivery, she began to hemorrhage and the uterus became atonic. Hysterectomy was performed but the bleeding did not stop. The ObGyns called in 3 other ObGyns. During exploratory laparotomy, the bleeding was halted.

PATIENT'S CLAIM: She and her husband had hoped to have more children but the hysterectomy precluded that. She sued all 5 ObGyns, alleging that the delivering ObGyns failed to properly perform the CD and that each physician failed to properly perform the laparotomy, causing a large scar. The claim was discontinued against the 3 surgical ObGyns; trial addressed the 2 delivering ObGyns.

The patient’s expert ObGyn remarked that the hemorrhage was caused by a small placental remnant that remained in the uterus as a result of inadequate evacuation following delivery. The presence of the remnant was indicated by the uterine atony and should have prompted immediate investigation. The physicians’ notes did not document exploration of the uterus prior to closure.

PHYSICIAN'S DEFENSE: The defense’s expert contended that atony would not be a result of a small remnant of placenta. The patient’s uterus was properly evacuated, the hemorrhage was an unforeseeable complication, and the ObGyns properly addressed the hemorrhage.

VERDICT: A New York defense verdict was returned.

Alleged bowel injury during hysterectomy

Two days after a woman underwent a hysterectomy performed by her ObGyn, she went to the emergency department with increasing pain. Her ObGyn admitted her to the hospital. A general surgeon performed an exploratory laparotomy the next day that revealed an abscess; a 1-cm perforation of the patient’s bowel was surgically repaired. The patient had a difficult recovery. She developed pneumonia and respiratory failure. She underwent multiple repair surgeries for recurrent abscesses and fistulas because the wound was slow to heal.

PATIENT'S CLAIM: The ObGyn’s surgical technique was negligent. He injured the bowel when inserting a trocar and did not identify the injury in a timely manner. The expert witness commented that such an injury can sometimes be a surgical complication, but not in this case: the ObGyn rushed the procedure because he had another patient waiting for CD at another hospital.

PHYSICIAN'S DEFENSE: The ObGyn denied negligence and contended that the trocar used in surgery was too blunt to have caused a perforation. It would have been obvious to the ObGyn during surgery if a perforation had occurred. The perforation developed days after surgery within an abscess.

VERDICT: A Mississippi defense verdict was returned.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

Delayed diagnosis of breast cancer: $15M award

A woman in her mid-50s had been seen by a breast surgeon for 16 years for regular mammograms and sonograms. In May 2009, the breast surgeon misinterpreted a mammogram as negative, as did a radiologist who re-read the mammogram weeks later. In December 2010, the patient returned to the breast surgeon with nipple discharge. No further testing was conducted. In October 2011, the patient was found to have Stage IIIA breast cancer involving 4 lymph nodes. She underwent left radical mastectomy, chemotherapy, radiation therapy, and breast reconstruction. At time of trial, the cancer had invaded her vertebrae, was Stage IV, and most likely incurable.

PATIENT'S CLAIM: Although the surgeon admittedly did not possess the qualifications required under the Mammography Quality Standards Act, he interpreted about 5,000 mammograms per year in his office. In this case, he failed to detect a small breast tumor in May 2009. He also failed to perform testing when the patient reported nipple discharge. A more timely diagnosis of breast cancer at Stage I would have provided a 90% chance of long-term survival.

DEFENDANTS' DEFENSE: The defense held the radiologist fully liable because the surgeon was not a qualified interpreter of mammography, therefore relying on the radiologist’s interpretation. The radiologist was legally responsible for the missed diagnosis.

VERDICT: A $15M New York verdict was reached, finding the breast surgeon 75% at fault and the radiologist 25%. The radiologist settled before the trial (the jury was not informed of this). The breast surgeon was responsible for $11.25M. The defense indicated intent to appeal.

Alleged failure to evacuate uterus after cesarean delivery

A 37-year-old woman underwent cesarean delivery (CD) performed by 2 ObGyns. After delivery, she began to hemorrhage and the uterus became atonic. Hysterectomy was performed but the bleeding did not stop. The ObGyns called in 3 other ObGyns. During exploratory laparotomy, the bleeding was halted.

PATIENT'S CLAIM: She and her husband had hoped to have more children but the hysterectomy precluded that. She sued all 5 ObGyns, alleging that the delivering ObGyns failed to properly perform the CD and that each physician failed to properly perform the laparotomy, causing a large scar. The claim was discontinued against the 3 surgical ObGyns; trial addressed the 2 delivering ObGyns.

The patient’s expert ObGyn remarked that the hemorrhage was caused by a small placental remnant that remained in the uterus as a result of inadequate evacuation following delivery. The presence of the remnant was indicated by the uterine atony and should have prompted immediate investigation. The physicians’ notes did not document exploration of the uterus prior to closure.

PHYSICIAN'S DEFENSE: The defense’s expert contended that atony would not be a result of a small remnant of placenta. The patient’s uterus was properly evacuated, the hemorrhage was an unforeseeable complication, and the ObGyns properly addressed the hemorrhage.

VERDICT: A New York defense verdict was returned.

Alleged bowel injury during hysterectomy

Two days after a woman underwent a hysterectomy performed by her ObGyn, she went to the emergency department with increasing pain. Her ObGyn admitted her to the hospital. A general surgeon performed an exploratory laparotomy the next day that revealed an abscess; a 1-cm perforation of the patient’s bowel was surgically repaired. The patient had a difficult recovery. She developed pneumonia and respiratory failure. She underwent multiple repair surgeries for recurrent abscesses and fistulas because the wound was slow to heal.

PATIENT'S CLAIM: The ObGyn’s surgical technique was negligent. He injured the bowel when inserting a trocar and did not identify the injury in a timely manner. The expert witness commented that such an injury can sometimes be a surgical complication, but not in this case: the ObGyn rushed the procedure because he had another patient waiting for CD at another hospital.

PHYSICIAN'S DEFENSE: The ObGyn denied negligence and contended that the trocar used in surgery was too blunt to have caused a perforation. It would have been obvious to the ObGyn during surgery if a perforation had occurred. The perforation developed days after surgery within an abscess.

VERDICT: A Mississippi defense verdict was returned.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

Martha Boxer (not her real name) had mentally prepared herself that this could happen, but the news still hit hard. Her doctors on the leukemia service broke the facts as gently as we could: The chemotherapy she had been suffering through for the last 2 weeks hadn’t worked. The results of her latest bone marrow biopsy showed it remained packed with cancer cells.

As Martha absorbed the news quietly, her son, sitting next to her bedside with his hand on hers, spoke first. “What now?”

I looked at my attending and nodded, as we were fully ready to answer this question. From the outset, we knew that Martha’s leukemia carried a genetic mutation that unfortunately put her in a high-risk category. The chances of her cancer responding to the first round of chemotherapy were low. When this happens, what we typically do next is reinduction, we explained. It’s a different combination of chemotherapy drugs, with a somewhat different side effect profile. But it would give her the best chance of response, we believed. We could start the new chemotherapy as early as today, we said.

Martha took this in. “Okay,” she said pensively. “I’ve been thinking. And I think maybe … I won’t do chemotherapy anymore.”

Her words caught me off guard because, frankly, they seemed premature. Her leukemia had not budged with the first round of treatment. But we still had an option B, and then an option C. It was usually at a later, more dire stage – when multiple lines of treatment had not worked, and instead had only caused harm – or, when the decision was forced by the medical system’s admission that we had nothing left to offer – that I’d heard patients express similar preferences. It was then that I’d seen patients and their loved ones flip a mental switch and choose to focus the time they had left on what really mattered to them.

It didn’t feel like we were at that point.

And so, as we debriefed outside her room, my first instinct was to convince her otherwise.

However, Martha had other priorities, as I would come to learn. Above all else, she hated the hospital. She hated feeling trapped in a strange room that wasn’t hers; she hated how the chemotherapy stole her energy and made her feel too weak to even shower. She wanted to be in her own home. She wanted to eat her own food, sleep in her own bed, and be surrounded by what she recognized.

But, she also wanted to live. Two paths lay ahead of her. It was a trade-off of more suffering with a small chance at remission, versus accepting no chance of cure but feeling well for as long as she could. She soon clarified that she wasn’t definitely against chemotherapy. She couldn’t decide. She needed more information from us to make this decision, the hardest of her life.

Over the next few days, I watched as our attending physician expertly provided just that. There were actually three options, she laid out. There was aggressive chemotherapy, entailing at least 3 more weeks in the hospital and coming with significant risk of infection, nausea, vomiting, and fatigue. The chances of inducing a remission were about one in three to one in two, and that remission would likely last between several months and 2 years before the leukemia would relapse. The second option was a chemotherapy pill she could take at home, an option with fewer side effects but no longer aimed at cure. The third option was home hospice support, focused on symptoms, without any anticancer medication.

I noticed a few things during those conversations. I noticed how my attending took a navigator role, not pushing Martha in one direction or another, but rather imparting all the relevant information to empower Martha to decide for herself. I noticed how she provided realistic estimates, not hedging away from numbers, but giving the honest, nitty-gritty facts, as best as she could predict. I noticed how she took the time and never rushed, even in spite of external pressures to discharge the patient from the hospital.

There was no right or wrong answer. I no longer felt that we had something in our grasp – a clear-cut, best decision – to persuade Martha toward. Is one in three good odds, or bad odds? Is 2 years a long period of time, or a short one? Of course, there is no actual answer to these questions; the answer is as elusive and personal as if we had asked Martha: What do you think?

What I learned from Martha is that, with a devastating diagnosis, there isn’t a right time to make this decision. There isn’t one defining moment where we flip a switch and change course. It isn’t only when we run out of treatment options that the choice to forgo it makes sense. That option is on a flexible line, different for every person and priority. As my attending later said, with Martha’s diagnosis and her values, it wouldn’t have been unreasonable to decide against chemotherapy from the start.

The language we use can sometimes mask that reality. As doctors, we may casually slip in words like “need” and “have to” in response to patients’ questions about what to do next. “You need more chemotherapy,” we might say. “We’d have to treat it.” We have “treatment,” after all, and so we go down the line of offering what’s next in the medical algorithm. That word, too, can be deceivingly tempting, enticing down a road that makes it seem like the obvious answer – or the only one. If the choices are treatment versus not, who wouldn’t want the treatment? But the details are where things get murky. What does that treatment involve? What are the chances it will work, and for how long?

Surreptitiously missing from this language is the fact that there’s a choice. There’s always a choice, and it’s on the table at any point. You can start chemotherapy without committing to stick it out until the end. You can go home, if that is what’s important to you. The best treatment option is the one the patient wants.

After 4 days, Martha decided to go home with palliative chemotherapy and a bridge to hospice. Each member of our team hugged her goodbye and wished her luck. She was nervous. But she packed her hospital room, and she left.

I recently pulled up her medical chart, bracing myself for bad news. But the interesting thing about hospice is that even though the focus is no longer on prolonging life, people sometimes live longer.

She felt well, the most recent palliative note said. She was spending her time writing, getting her finances in order, and finishing a legacy project for her grandchildren.

For Martha, it seemed to be the right choice.

Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.

Martha Boxer (not her real name) had mentally prepared herself that this could happen, but the news still hit hard. Her doctors on the leukemia service broke the facts as gently as we could: The chemotherapy she had been suffering through for the last 2 weeks hadn’t worked. The results of her latest bone marrow biopsy showed it remained packed with cancer cells.

As Martha absorbed the news quietly, her son, sitting next to her bedside with his hand on hers, spoke first. “What now?”

I looked at my attending and nodded, as we were fully ready to answer this question. From the outset, we knew that Martha’s leukemia carried a genetic mutation that unfortunately put her in a high-risk category. The chances of her cancer responding to the first round of chemotherapy were low. When this happens, what we typically do next is reinduction, we explained. It’s a different combination of chemotherapy drugs, with a somewhat different side effect profile. But it would give her the best chance of response, we believed. We could start the new chemotherapy as early as today, we said.

Martha took this in. “Okay,” she said pensively. “I’ve been thinking. And I think maybe … I won’t do chemotherapy anymore.”

Her words caught me off guard because, frankly, they seemed premature. Her leukemia had not budged with the first round of treatment. But we still had an option B, and then an option C. It was usually at a later, more dire stage – when multiple lines of treatment had not worked, and instead had only caused harm – or, when the decision was forced by the medical system’s admission that we had nothing left to offer – that I’d heard patients express similar preferences. It was then that I’d seen patients and their loved ones flip a mental switch and choose to focus the time they had left on what really mattered to them.

It didn’t feel like we were at that point.

And so, as we debriefed outside her room, my first instinct was to convince her otherwise.

However, Martha had other priorities, as I would come to learn. Above all else, she hated the hospital. She hated feeling trapped in a strange room that wasn’t hers; she hated how the chemotherapy stole her energy and made her feel too weak to even shower. She wanted to be in her own home. She wanted to eat her own food, sleep in her own bed, and be surrounded by what she recognized.

But, she also wanted to live. Two paths lay ahead of her. It was a trade-off of more suffering with a small chance at remission, versus accepting no chance of cure but feeling well for as long as she could. She soon clarified that she wasn’t definitely against chemotherapy. She couldn’t decide. She needed more information from us to make this decision, the hardest of her life.

Over the next few days, I watched as our attending physician expertly provided just that. There were actually three options, she laid out. There was aggressive chemotherapy, entailing at least 3 more weeks in the hospital and coming with significant risk of infection, nausea, vomiting, and fatigue. The chances of inducing a remission were about one in three to one in two, and that remission would likely last between several months and 2 years before the leukemia would relapse. The second option was a chemotherapy pill she could take at home, an option with fewer side effects but no longer aimed at cure. The third option was home hospice support, focused on symptoms, without any anticancer medication.

I noticed a few things during those conversations. I noticed how my attending took a navigator role, not pushing Martha in one direction or another, but rather imparting all the relevant information to empower Martha to decide for herself. I noticed how she provided realistic estimates, not hedging away from numbers, but giving the honest, nitty-gritty facts, as best as she could predict. I noticed how she took the time and never rushed, even in spite of external pressures to discharge the patient from the hospital.

There was no right or wrong answer. I no longer felt that we had something in our grasp – a clear-cut, best decision – to persuade Martha toward. Is one in three good odds, or bad odds? Is 2 years a long period of time, or a short one? Of course, there is no actual answer to these questions; the answer is as elusive and personal as if we had asked Martha: What do you think?

What I learned from Martha is that, with a devastating diagnosis, there isn’t a right time to make this decision. There isn’t one defining moment where we flip a switch and change course. It isn’t only when we run out of treatment options that the choice to forgo it makes sense. That option is on a flexible line, different for every person and priority. As my attending later said, with Martha’s diagnosis and her values, it wouldn’t have been unreasonable to decide against chemotherapy from the start.

The language we use can sometimes mask that reality. As doctors, we may casually slip in words like “need” and “have to” in response to patients’ questions about what to do next. “You need more chemotherapy,” we might say. “We’d have to treat it.” We have “treatment,” after all, and so we go down the line of offering what’s next in the medical algorithm. That word, too, can be deceivingly tempting, enticing down a road that makes it seem like the obvious answer – or the only one. If the choices are treatment versus not, who wouldn’t want the treatment? But the details are where things get murky. What does that treatment involve? What are the chances it will work, and for how long?

Surreptitiously missing from this language is the fact that there’s a choice. There’s always a choice, and it’s on the table at any point. You can start chemotherapy without committing to stick it out until the end. You can go home, if that is what’s important to you. The best treatment option is the one the patient wants.

After 4 days, Martha decided to go home with palliative chemotherapy and a bridge to hospice. Each member of our team hugged her goodbye and wished her luck. She was nervous. But she packed her hospital room, and she left.

I recently pulled up her medical chart, bracing myself for bad news. But the interesting thing about hospice is that even though the focus is no longer on prolonging life, people sometimes live longer.

She felt well, the most recent palliative note said. She was spending her time writing, getting her finances in order, and finishing a legacy project for her grandchildren.

For Martha, it seemed to be the right choice.

Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.

Martha Boxer (not her real name) had mentally prepared herself that this could happen, but the news still hit hard. Her doctors on the leukemia service broke the facts as gently as we could: The chemotherapy she had been suffering through for the last 2 weeks hadn’t worked. The results of her latest bone marrow biopsy showed it remained packed with cancer cells.

As Martha absorbed the news quietly, her son, sitting next to her bedside with his hand on hers, spoke first. “What now?”

I looked at my attending and nodded, as we were fully ready to answer this question. From the outset, we knew that Martha’s leukemia carried a genetic mutation that unfortunately put her in a high-risk category. The chances of her cancer responding to the first round of chemotherapy were low. When this happens, what we typically do next is reinduction, we explained. It’s a different combination of chemotherapy drugs, with a somewhat different side effect profile. But it would give her the best chance of response, we believed. We could start the new chemotherapy as early as today, we said.

Martha took this in. “Okay,” she said pensively. “I’ve been thinking. And I think maybe … I won’t do chemotherapy anymore.”

Her words caught me off guard because, frankly, they seemed premature. Her leukemia had not budged with the first round of treatment. But we still had an option B, and then an option C. It was usually at a later, more dire stage – when multiple lines of treatment had not worked, and instead had only caused harm – or, when the decision was forced by the medical system’s admission that we had nothing left to offer – that I’d heard patients express similar preferences. It was then that I’d seen patients and their loved ones flip a mental switch and choose to focus the time they had left on what really mattered to them.

It didn’t feel like we were at that point.

And so, as we debriefed outside her room, my first instinct was to convince her otherwise.

However, Martha had other priorities, as I would come to learn. Above all else, she hated the hospital. She hated feeling trapped in a strange room that wasn’t hers; she hated how the chemotherapy stole her energy and made her feel too weak to even shower. She wanted to be in her own home. She wanted to eat her own food, sleep in her own bed, and be surrounded by what she recognized.

But, she also wanted to live. Two paths lay ahead of her. It was a trade-off of more suffering with a small chance at remission, versus accepting no chance of cure but feeling well for as long as she could. She soon clarified that she wasn’t definitely against chemotherapy. She couldn’t decide. She needed more information from us to make this decision, the hardest of her life.

Over the next few days, I watched as our attending physician expertly provided just that. There were actually three options, she laid out. There was aggressive chemotherapy, entailing at least 3 more weeks in the hospital and coming with significant risk of infection, nausea, vomiting, and fatigue. The chances of inducing a remission were about one in three to one in two, and that remission would likely last between several months and 2 years before the leukemia would relapse. The second option was a chemotherapy pill she could take at home, an option with fewer side effects but no longer aimed at cure. The third option was home hospice support, focused on symptoms, without any anticancer medication.

I noticed a few things during those conversations. I noticed how my attending took a navigator role, not pushing Martha in one direction or another, but rather imparting all the relevant information to empower Martha to decide for herself. I noticed how she provided realistic estimates, not hedging away from numbers, but giving the honest, nitty-gritty facts, as best as she could predict. I noticed how she took the time and never rushed, even in spite of external pressures to discharge the patient from the hospital.

There was no right or wrong answer. I no longer felt that we had something in our grasp – a clear-cut, best decision – to persuade Martha toward. Is one in three good odds, or bad odds? Is 2 years a long period of time, or a short one? Of course, there is no actual answer to these questions; the answer is as elusive and personal as if we had asked Martha: What do you think?

What I learned from Martha is that, with a devastating diagnosis, there isn’t a right time to make this decision. There isn’t one defining moment where we flip a switch and change course. It isn’t only when we run out of treatment options that the choice to forgo it makes sense. That option is on a flexible line, different for every person and priority. As my attending later said, with Martha’s diagnosis and her values, it wouldn’t have been unreasonable to decide against chemotherapy from the start.

The language we use can sometimes mask that reality. As doctors, we may casually slip in words like “need” and “have to” in response to patients’ questions about what to do next. “You need more chemotherapy,” we might say. “We’d have to treat it.” We have “treatment,” after all, and so we go down the line of offering what’s next in the medical algorithm. That word, too, can be deceivingly tempting, enticing down a road that makes it seem like the obvious answer – or the only one. If the choices are treatment versus not, who wouldn’t want the treatment? But the details are where things get murky. What does that treatment involve? What are the chances it will work, and for how long?

Surreptitiously missing from this language is the fact that there’s a choice. There’s always a choice, and it’s on the table at any point. You can start chemotherapy without committing to stick it out until the end. You can go home, if that is what’s important to you. The best treatment option is the one the patient wants.

After 4 days, Martha decided to go home with palliative chemotherapy and a bridge to hospice. Each member of our team hugged her goodbye and wished her luck. She was nervous. But she packed her hospital room, and she left.

I recently pulled up her medical chart, bracing myself for bad news. But the interesting thing about hospice is that even though the focus is no longer on prolonging life, people sometimes live longer.

She felt well, the most recent palliative note said. She was spending her time writing, getting her finances in order, and finishing a legacy project for her grandchildren.

For Martha, it seemed to be the right choice.

Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.

Table of Contents

• Association of VA Hematology/Oncology 2018 Annual Meeting Schedule
• AVAHO 2018 Abstract Index
• Poster Abstracts

Table of Contents

• Association of VA Hematology/Oncology 2018 Annual Meeting Schedule
• AVAHO 2018 Abstract Index
• Poster Abstracts

Table of Contents

• Association of VA Hematology/Oncology 2018 Annual Meeting Schedule
• AVAHO 2018 Abstract Index
• Poster Abstracts

Rivaroxaban (Xarelto)

Both low-dose and full-dose rivaroxaban had superior benefit-risk profiles for extended venous thromboembolism (VTE) treatment when compared to aspirin, according to investigators.

The team found the combined outcome of recurrent VTE and major bleeding was less likely to occur in patients treated with rivaroxaban at 20 mg or 10 mg than in patients treated with aspirin.

Paolo Prandoni, MD, of the University of Padua in Italy, and his colleagues reported these results in Thrombosis Research.

The investigators analyzed data from the EINSTEIN-CHOICE trial, a double-blind, randomized study of 3,365 patients age 18 or older with deep vein thrombosis (DVT) or pulmonary embolism (PE) who had previously received anticoagulant treatment for 6 to 12 months.

Patients were given once-daily rivaroxaban at a low dose (10 mg), once-daily rivaroxaban at the full dose (20 mg), or once-daily aspirin at a dose of 100 mg.

The incidence of the combined outcome of recurrent VTE and major bleeding was 2.8% lower in the 20 mg rivaroxaban arm and 3.4% lower in the 10 mg rivaroxaban arm than in the aspirin arm.

The cumulative incidence of recurrent VTE was 1.9% in the 20 mg rivaroxaban arm, 1.6% in the 10 mg rivaroxaban arm, and 5.0% in the aspirin arm.

The cumulative incidence of major bleeding was 0.7%, 0.4%, and 0.5%, respectively.

Benefit-risk profile

Benefit and risk were calculated using “excess numbers of events,” or the difference in cumulative incidences in a hypothetical population of 10,000 VTE patients treated for 1 year.

Excess numbers of events were defined as the number of patients in this hypothetical population who would experience a particular event when treated with rivaroxaban (at either dose), minus that in the same population treated with aspirin.

In patients treated with 20 mg of rivaroxaban instead of aspirin, there would be 123 fewer episodes of PE (95% confidence interval [CI], 21-226) and 198 fewer episodes of DVT (95% CI, 62-333).

In patients given 10 mg of rivaroxaban instead of aspirin, there would be 121 fewer episodes of PE (95% CI, 4-238) and 217 fewer episodes of DVT (95% CI, 92-342).

Net clinical benefit was defined as the composite of symptomatic recurrent VTE and major bleeding events. It occurred in 23 patients in the 20 mg rivaroxaban arm, 17 patients in the 10 mg rivaroxaban arm, and 53 patients in the aspirin arm.

For 10,000 patients treated for 1 year with rivaroxaban instead of aspirin, there would be 284 fewer net clinical benefit outcomes for the 20 mg dose (95% CI, 106-462) and 339 fewer (95% CI, 165-512) for the 10 mg dose.

This means that one additional symptomatic recurrent VTE or major bleed would be avoided for every 36 patients treated with rivaroxaban at 20 mg or every 30 patients treated with rivaroxaban at 10 mg.

The investigators therefore concluded that rivaroxaban “provides a clinically important benefit in terms of reduction in recurrent VTE” and has a favorable benefit-risk profile relative to aspirin.

In fact, the team said there is “no longer a place” for extended VTE treatment with aspirin.

Bayer AG funded this study. Dr. Prandoni reported financial relationships with Bayer, Sanofi, Daiichi Sankyo, and Pfizer.

Rivaroxaban (Xarelto)

Both low-dose and full-dose rivaroxaban had superior benefit-risk profiles for extended venous thromboembolism (VTE) treatment when compared to aspirin, according to investigators.

The team found the combined outcome of recurrent VTE and major bleeding was less likely to occur in patients treated with rivaroxaban at 20 mg or 10 mg than in patients treated with aspirin.

Paolo Prandoni, MD, of the University of Padua in Italy, and his colleagues reported these results in Thrombosis Research.

The investigators analyzed data from the EINSTEIN-CHOICE trial, a double-blind, randomized study of 3,365 patients age 18 or older with deep vein thrombosis (DVT) or pulmonary embolism (PE) who had previously received anticoagulant treatment for 6 to 12 months.

Patients were given once-daily rivaroxaban at a low dose (10 mg), once-daily rivaroxaban at the full dose (20 mg), or once-daily aspirin at a dose of 100 mg.

The incidence of the combined outcome of recurrent VTE and major bleeding was 2.8% lower in the 20 mg rivaroxaban arm and 3.4% lower in the 10 mg rivaroxaban arm than in the aspirin arm.

The cumulative incidence of recurrent VTE was 1.9% in the 20 mg rivaroxaban arm, 1.6% in the 10 mg rivaroxaban arm, and 5.0% in the aspirin arm.

The cumulative incidence of major bleeding was 0.7%, 0.4%, and 0.5%, respectively.

Benefit-risk profile

Benefit and risk were calculated using “excess numbers of events,” or the difference in cumulative incidences in a hypothetical population of 10,000 VTE patients treated for 1 year.

Excess numbers of events were defined as the number of patients in this hypothetical population who would experience a particular event when treated with rivaroxaban (at either dose), minus that in the same population treated with aspirin.

In patients treated with 20 mg of rivaroxaban instead of aspirin, there would be 123 fewer episodes of PE (95% confidence interval [CI], 21-226) and 198 fewer episodes of DVT (95% CI, 62-333).

In patients given 10 mg of rivaroxaban instead of aspirin, there would be 121 fewer episodes of PE (95% CI, 4-238) and 217 fewer episodes of DVT (95% CI, 92-342).

Net clinical benefit was defined as the composite of symptomatic recurrent VTE and major bleeding events. It occurred in 23 patients in the 20 mg rivaroxaban arm, 17 patients in the 10 mg rivaroxaban arm, and 53 patients in the aspirin arm.

For 10,000 patients treated for 1 year with rivaroxaban instead of aspirin, there would be 284 fewer net clinical benefit outcomes for the 20 mg dose (95% CI, 106-462) and 339 fewer (95% CI, 165-512) for the 10 mg dose.

This means that one additional symptomatic recurrent VTE or major bleed would be avoided for every 36 patients treated with rivaroxaban at 20 mg or every 30 patients treated with rivaroxaban at 10 mg.

The investigators therefore concluded that rivaroxaban “provides a clinically important benefit in terms of reduction in recurrent VTE” and has a favorable benefit-risk profile relative to aspirin.

In fact, the team said there is “no longer a place” for extended VTE treatment with aspirin.

Bayer AG funded this study. Dr. Prandoni reported financial relationships with Bayer, Sanofi, Daiichi Sankyo, and Pfizer.

Rivaroxaban (Xarelto)

Both low-dose and full-dose rivaroxaban had superior benefit-risk profiles for extended venous thromboembolism (VTE) treatment when compared to aspirin, according to investigators.

The team found the combined outcome of recurrent VTE and major bleeding was less likely to occur in patients treated with rivaroxaban at 20 mg or 10 mg than in patients treated with aspirin.

Paolo Prandoni, MD, of the University of Padua in Italy, and his colleagues reported these results in Thrombosis Research.

The investigators analyzed data from the EINSTEIN-CHOICE trial, a double-blind, randomized study of 3,365 patients age 18 or older with deep vein thrombosis (DVT) or pulmonary embolism (PE) who had previously received anticoagulant treatment for 6 to 12 months.

Patients were given once-daily rivaroxaban at a low dose (10 mg), once-daily rivaroxaban at the full dose (20 mg), or once-daily aspirin at a dose of 100 mg.

The incidence of the combined outcome of recurrent VTE and major bleeding was 2.8% lower in the 20 mg rivaroxaban arm and 3.4% lower in the 10 mg rivaroxaban arm than in the aspirin arm.

The cumulative incidence of recurrent VTE was 1.9% in the 20 mg rivaroxaban arm, 1.6% in the 10 mg rivaroxaban arm, and 5.0% in the aspirin arm.

The cumulative incidence of major bleeding was 0.7%, 0.4%, and 0.5%, respectively.

Benefit-risk profile

Benefit and risk were calculated using “excess numbers of events,” or the difference in cumulative incidences in a hypothetical population of 10,000 VTE patients treated for 1 year.

Excess numbers of events were defined as the number of patients in this hypothetical population who would experience a particular event when treated with rivaroxaban (at either dose), minus that in the same population treated with aspirin.

In patients treated with 20 mg of rivaroxaban instead of aspirin, there would be 123 fewer episodes of PE (95% confidence interval [CI], 21-226) and 198 fewer episodes of DVT (95% CI, 62-333).

In patients given 10 mg of rivaroxaban instead of aspirin, there would be 121 fewer episodes of PE (95% CI, 4-238) and 217 fewer episodes of DVT (95% CI, 92-342).

Net clinical benefit was defined as the composite of symptomatic recurrent VTE and major bleeding events. It occurred in 23 patients in the 20 mg rivaroxaban arm, 17 patients in the 10 mg rivaroxaban arm, and 53 patients in the aspirin arm.

For 10,000 patients treated for 1 year with rivaroxaban instead of aspirin, there would be 284 fewer net clinical benefit outcomes for the 20 mg dose (95% CI, 106-462) and 339 fewer (95% CI, 165-512) for the 10 mg dose.

This means that one additional symptomatic recurrent VTE or major bleed would be avoided for every 36 patients treated with rivaroxaban at 20 mg or every 30 patients treated with rivaroxaban at 10 mg.

The investigators therefore concluded that rivaroxaban “provides a clinically important benefit in terms of reduction in recurrent VTE” and has a favorable benefit-risk profile relative to aspirin.

In fact, the team said there is “no longer a place” for extended VTE treatment with aspirin.

Bayer AG funded this study. Dr. Prandoni reported financial relationships with Bayer, Sanofi, Daiichi Sankyo, and Pfizer.

In the world of research, an “n of 1” is considered an insufficient sample size to make an inference about a population. While distinguishing significance in research is vital in the scientific world, this statistical view often feels invalid when the “n of 1” is you or someone you know. And when the statistic is a diagnosis of cancer, that “1” feels even more noteworthy.

We know that cancer is a devastating disease that results in an increasing number of diagnoses each day. Case in point, the American Cancer Society estimates that more than 4,700 new cancers will be diagnosed each day in 2018.¹ Most of us know that breast, colon, lung, and prostate cancer are the main contributors to those staggering numbers. But did you know that the incidence of oropharyngeal cancers (OPCs) is increasing? I didn’t.

It is estimated that 51,540 new cancer cases in 2018 will be of the oral cavity and pharynx and will cause approximately 10,000 deaths in the United States (US).¹ Included in this estimate is the increasing incidence of human papillomavirus–associated oropharyngeal cancers (HPV-OPCs). The “n of 1” that started this discussion? That was a colleague of mine, who received just such a diagnosis. And the causative factor was surprising to me.

Now, please don’t misunderstand me—I know that HPV, a group of more than 150 related viruses, is the most common sexually transmitted infection (STI) in the US.² I also know that HPV is implicated in genital warts and in cervical and anal cancers. The virus, which is transmitted through intimate skin-to-skin contact, is acquired by many during their adolescent and young adult years.² Currently, 84 million Americans have HPV, and 14 million new cases are diagnosed each year.³ And while many of these infections resolve on their own, others can cause serious health problems.

The most serious of those health problems, HPV-related cancers (which include cervical, vulvovaginal, anal, and oropharyngeal), are on the rise in the US.⁴ The prevalence of HPV in oropharyngeal tumors increased from 16.3% during the 1980s to 72.7% during the 2000s.⁵ Moreover, HPV has been implicated in 12% to 63% of all oropharyngeal cancers.⁶ Fifteen years ago, researchers concluded that HPV type 16 was the cause of 90% of cases of HPV-positive squamous cell carcinomas of the head and neck.^7,8 At any given time, 7% of the population between ages 14 and 69 are infected by the virus within the oral mucosa.⁹

For my colleague—and many of us—the ship of prevention has sailed. But what disconcerts me most about this rise in HPV-related cancers is that, as of 2006, we have a vaccine that protects against infection with the two most prevalent cancer-causing HPV types. And yet, our vaccination rates continue to fall short of the Office of Disease Prevention and Health Promotion’s goal of having 80% of females ages 13 to 15 fully vaccinated against HPV.¹⁰

Continue to: Research has shown that parents of young adolescents...

Research has shown that parents of young adolescents are often upset by the recommendation that their children receive the HPV vaccine.¹¹ Common beliefs are that the vaccine will give adolescents permission to become sexually active—or, conversely, that the adolescent isn’t sexually active, so the vaccine isn’t necessary. The reality of the situation: Adolescents don’t consider oral sex as having sexual relations, and oral sex is often the first sexual encounter for young people. Adolescents also regard oral sex as less risky than vaginal sex.¹² So, many have unknowingly put themselves at risk while thinking they are actually being “safe.”

There are ways to reduce cancer risk, but few interventions are more effective than HPV vaccination.¹³ Given the incidence of HPV-OPC, it’s time to debunk the misbeliefs about sexual activity and move on to a concerted effort to promote HPV vaccination. Recent advertising about the HPV vaccine has emphasized the consequence of cancer in its messages. I applaud this new direction—it could be key to reversing the persistently low rate of HPV vaccination and changing that “n of 1” to zero. Share your trials and triumphs in promoting HPV vaccination with me at NPeditor@mdedge.com.

In the world of research, an “n of 1” is considered an insufficient sample size to make an inference about a population. While distinguishing significance in research is vital in the scientific world, this statistical view often feels invalid when the “n of 1” is you or someone you know. And when the statistic is a diagnosis of cancer, that “1” feels even more noteworthy.

We know that cancer is a devastating disease that results in an increasing number of diagnoses each day. Case in point, the American Cancer Society estimates that more than 4,700 new cancers will be diagnosed each day in 2018.¹ Most of us know that breast, colon, lung, and prostate cancer are the main contributors to those staggering numbers. But did you know that the incidence of oropharyngeal cancers (OPCs) is increasing? I didn’t.

It is estimated that 51,540 new cancer cases in 2018 will be of the oral cavity and pharynx and will cause approximately 10,000 deaths in the United States (US).¹ Included in this estimate is the increasing incidence of human papillomavirus–associated oropharyngeal cancers (HPV-OPCs). The “n of 1” that started this discussion? That was a colleague of mine, who received just such a diagnosis. And the causative factor was surprising to me.

Now, please don’t misunderstand me—I know that HPV, a group of more than 150 related viruses, is the most common sexually transmitted infection (STI) in the US.² I also know that HPV is implicated in genital warts and in cervical and anal cancers. The virus, which is transmitted through intimate skin-to-skin contact, is acquired by many during their adolescent and young adult years.² Currently, 84 million Americans have HPV, and 14 million new cases are diagnosed each year.³ And while many of these infections resolve on their own, others can cause serious health problems.

The most serious of those health problems, HPV-related cancers (which include cervical, vulvovaginal, anal, and oropharyngeal), are on the rise in the US.⁴ The prevalence of HPV in oropharyngeal tumors increased from 16.3% during the 1980s to 72.7% during the 2000s.⁵ Moreover, HPV has been implicated in 12% to 63% of all oropharyngeal cancers.⁶ Fifteen years ago, researchers concluded that HPV type 16 was the cause of 90% of cases of HPV-positive squamous cell carcinomas of the head and neck.^7,8 At any given time, 7% of the population between ages 14 and 69 are infected by the virus within the oral mucosa.⁹

For my colleague—and many of us—the ship of prevention has sailed. But what disconcerts me most about this rise in HPV-related cancers is that, as of 2006, we have a vaccine that protects against infection with the two most prevalent cancer-causing HPV types. And yet, our vaccination rates continue to fall short of the Office of Disease Prevention and Health Promotion’s goal of having 80% of females ages 13 to 15 fully vaccinated against HPV.¹⁰

Continue to: Research has shown that parents of young adolescents...

Research has shown that parents of young adolescents are often upset by the recommendation that their children receive the HPV vaccine.¹¹ Common beliefs are that the vaccine will give adolescents permission to become sexually active—or, conversely, that the adolescent isn’t sexually active, so the vaccine isn’t necessary. The reality of the situation: Adolescents don’t consider oral sex as having sexual relations, and oral sex is often the first sexual encounter for young people. Adolescents also regard oral sex as less risky than vaginal sex.¹² So, many have unknowingly put themselves at risk while thinking they are actually being “safe.”

There are ways to reduce cancer risk, but few interventions are more effective than HPV vaccination.¹³ Given the incidence of HPV-OPC, it’s time to debunk the misbeliefs about sexual activity and move on to a concerted effort to promote HPV vaccination. Recent advertising about the HPV vaccine has emphasized the consequence of cancer in its messages. I applaud this new direction—it could be key to reversing the persistently low rate of HPV vaccination and changing that “n of 1” to zero. Share your trials and triumphs in promoting HPV vaccination with me at NPeditor@mdedge.com.

In the world of research, an “n of 1” is considered an insufficient sample size to make an inference about a population. While distinguishing significance in research is vital in the scientific world, this statistical view often feels invalid when the “n of 1” is you or someone you know. And when the statistic is a diagnosis of cancer, that “1” feels even more noteworthy.

We know that cancer is a devastating disease that results in an increasing number of diagnoses each day. Case in point, the American Cancer Society estimates that more than 4,700 new cancers will be diagnosed each day in 2018.¹ Most of us know that breast, colon, lung, and prostate cancer are the main contributors to those staggering numbers. But did you know that the incidence of oropharyngeal cancers (OPCs) is increasing? I didn’t.

It is estimated that 51,540 new cancer cases in 2018 will be of the oral cavity and pharynx and will cause approximately 10,000 deaths in the United States (US).¹ Included in this estimate is the increasing incidence of human papillomavirus–associated oropharyngeal cancers (HPV-OPCs). The “n of 1” that started this discussion? That was a colleague of mine, who received just such a diagnosis. And the causative factor was surprising to me.

Now, please don’t misunderstand me—I know that HPV, a group of more than 150 related viruses, is the most common sexually transmitted infection (STI) in the US.² I also know that HPV is implicated in genital warts and in cervical and anal cancers. The virus, which is transmitted through intimate skin-to-skin contact, is acquired by many during their adolescent and young adult years.² Currently, 84 million Americans have HPV, and 14 million new cases are diagnosed each year.³ And while many of these infections resolve on their own, others can cause serious health problems.

The most serious of those health problems, HPV-related cancers (which include cervical, vulvovaginal, anal, and oropharyngeal), are on the rise in the US.⁴ The prevalence of HPV in oropharyngeal tumors increased from 16.3% during the 1980s to 72.7% during the 2000s.⁵ Moreover, HPV has been implicated in 12% to 63% of all oropharyngeal cancers.⁶ Fifteen years ago, researchers concluded that HPV type 16 was the cause of 90% of cases of HPV-positive squamous cell carcinomas of the head and neck.^7,8 At any given time, 7% of the population between ages 14 and 69 are infected by the virus within the oral mucosa.⁹

For my colleague—and many of us—the ship of prevention has sailed. But what disconcerts me most about this rise in HPV-related cancers is that, as of 2006, we have a vaccine that protects against infection with the two most prevalent cancer-causing HPV types. And yet, our vaccination rates continue to fall short of the Office of Disease Prevention and Health Promotion’s goal of having 80% of females ages 13 to 15 fully vaccinated against HPV.¹⁰

Continue to: Research has shown that parents of young adolescents...

Research has shown that parents of young adolescents are often upset by the recommendation that their children receive the HPV vaccine.¹¹ Common beliefs are that the vaccine will give adolescents permission to become sexually active—or, conversely, that the adolescent isn’t sexually active, so the vaccine isn’t necessary. The reality of the situation: Adolescents don’t consider oral sex as having sexual relations, and oral sex is often the first sexual encounter for young people. Adolescents also regard oral sex as less risky than vaginal sex.¹² So, many have unknowingly put themselves at risk while thinking they are actually being “safe.”

There are ways to reduce cancer risk, but few interventions are more effective than HPV vaccination.¹³ Given the incidence of HPV-OPC, it’s time to debunk the misbeliefs about sexual activity and move on to a concerted effort to promote HPV vaccination. Recent advertising about the HPV vaccine has emphasized the consequence of cancer in its messages. I applaud this new direction—it could be key to reversing the persistently low rate of HPV vaccination and changing that “n of 1” to zero. Share your trials and triumphs in promoting HPV vaccination with me at NPeditor@mdedge.com.

A novel method for detection of translocations appears to be superior to conventional molecular assays in the evaluation of bone and soft tissue tumor samples, according to researchers.

The technique of anchored multiplex polymerase chain reaction (AMP)–based targeted next-generation sequencing (NGS) had a failure rate of 14% but, nonetheless, worked favorably when compared with conventional techniques, which were associated with several false positives in this study, the researchers reported in the Journal of Molecular Diagnostics.

Two new fusion partners for the USP6 gene were found using AMP-based targeted NGS in this study, which thus contributed to the “further unraveling of the molecular landscape” for these tumors, added corresponding author Judith V.M.G. Bovée, MD, PhD, of the department of pathology at Leiden (the Netherlands) University Medical Center and her colleagues.

While the genetics of bone and soft tissue tumors have diagnostic value in clinical practice, standard fluorescence in situ hybridization (FISH) and reverse transcriptase PCR are associated with several drawbacks, such as a high false negative rate in the case of FISH, Dr. Bovée and her coauthors wrote.

Accordingly, the researchers evaluated the applicability of a targeted sequencing assay (Archer FusionPlex Sarcoma kit, which was developed by ArcherDX) aimed at 26 genes relevant to bone and soft tissue tumor diagnostics.

Besides allowing for assessment of multiple target genes in a single assay, this technique circumvents the need to know both fusion partners for translocation detection, which opens up the possibility of identifying novel or rare fusion partners, investigators noted.

AMP-based targeted NGS was used to evaluate 81 bone and soft tissue tumor samples, and of those, 48 cases showed a fusion. For the remaining 33 cases in which no fusion was detected, 22 were considered truly negative because samples met all criteria for good quality, while the remaining 11 (14%) were considered not reliable because of insufficient quality, investigators reported.

The samples were also evaluated through use of FISH, reverse transcriptase PCR, or both in 58 cases and use of immunohistochemistry in 16 cases; for the remaining seven cases, no assay or immunohistochemistry could be applied because of a lack of availability, according to investigators.

Among the 48 entities that were fusion-positive according to AMP-based targeted NGS, 29 were validated using standard molecular assays, and of those, 25 had concordant results. Further analysis of the four discordant cases with a third independent technique confirmed the AMP-based targeted NGS findings, according to the published report.

Among the 22 fusion-negative high-quality samples, 19 were validated using FISH, and one case was found to be discordant; however, despite use of a third independent technique, this discrepancy could not be resolved, investigators said.

The AMP-based targeted NGS technique identified COL1A1 and SEC31A as novel fusion partners for USP6 in two cases of nodular fasciitis. Those fusion partners had been previously described in aneurysmal bone cysts, according to investigators.

Despite the promising results for the novel assay, conventional methods were sufficient in this study to confirm translocations in straightforward cases and ordinary rearrangements, according to the investigators.

“Both reverse transcription PCR and FISH are not only quick and easy to conduct but are also of low cost and high analytical validity and accuracy, which make them attractive methods,” they wrote.

The work by Dr. Bovée and her colleagues was supported by Leiden University Medical Center. The department of pathology and the department of cell and chemical biology at the medical center receive royalty payments from Kreatech/Leica, which provided a COL1A1/PDGFB fusion probe used in the research.

SOURCE: Lam SW et al. J Mol Diagn. 2018 Aug 20;20(5):653-63.

A novel method for detection of translocations appears to be superior to conventional molecular assays in the evaluation of bone and soft tissue tumor samples, according to researchers.

The technique of anchored multiplex polymerase chain reaction (AMP)–based targeted next-generation sequencing (NGS) had a failure rate of 14% but, nonetheless, worked favorably when compared with conventional techniques, which were associated with several false positives in this study, the researchers reported in the Journal of Molecular Diagnostics.

Two new fusion partners for the USP6 gene were found using AMP-based targeted NGS in this study, which thus contributed to the “further unraveling of the molecular landscape” for these tumors, added corresponding author Judith V.M.G. Bovée, MD, PhD, of the department of pathology at Leiden (the Netherlands) University Medical Center and her colleagues.

While the genetics of bone and soft tissue tumors have diagnostic value in clinical practice, standard fluorescence in situ hybridization (FISH) and reverse transcriptase PCR are associated with several drawbacks, such as a high false negative rate in the case of FISH, Dr. Bovée and her coauthors wrote.

Accordingly, the researchers evaluated the applicability of a targeted sequencing assay (Archer FusionPlex Sarcoma kit, which was developed by ArcherDX) aimed at 26 genes relevant to bone and soft tissue tumor diagnostics.

Besides allowing for assessment of multiple target genes in a single assay, this technique circumvents the need to know both fusion partners for translocation detection, which opens up the possibility of identifying novel or rare fusion partners, investigators noted.

AMP-based targeted NGS was used to evaluate 81 bone and soft tissue tumor samples, and of those, 48 cases showed a fusion. For the remaining 33 cases in which no fusion was detected, 22 were considered truly negative because samples met all criteria for good quality, while the remaining 11 (14%) were considered not reliable because of insufficient quality, investigators reported.

The samples were also evaluated through use of FISH, reverse transcriptase PCR, or both in 58 cases and use of immunohistochemistry in 16 cases; for the remaining seven cases, no assay or immunohistochemistry could be applied because of a lack of availability, according to investigators.

Among the 48 entities that were fusion-positive according to AMP-based targeted NGS, 29 were validated using standard molecular assays, and of those, 25 had concordant results. Further analysis of the four discordant cases with a third independent technique confirmed the AMP-based targeted NGS findings, according to the published report.

Among the 22 fusion-negative high-quality samples, 19 were validated using FISH, and one case was found to be discordant; however, despite use of a third independent technique, this discrepancy could not be resolved, investigators said.

The AMP-based targeted NGS technique identified COL1A1 and SEC31A as novel fusion partners for USP6 in two cases of nodular fasciitis. Those fusion partners had been previously described in aneurysmal bone cysts, according to investigators.

Despite the promising results for the novel assay, conventional methods were sufficient in this study to confirm translocations in straightforward cases and ordinary rearrangements, according to the investigators.

“Both reverse transcription PCR and FISH are not only quick and easy to conduct but are also of low cost and high analytical validity and accuracy, which make them attractive methods,” they wrote.

The work by Dr. Bovée and her colleagues was supported by Leiden University Medical Center. The department of pathology and the department of cell and chemical biology at the medical center receive royalty payments from Kreatech/Leica, which provided a COL1A1/PDGFB fusion probe used in the research.

SOURCE: Lam SW et al. J Mol Diagn. 2018 Aug 20;20(5):653-63.

A novel method for detection of translocations appears to be superior to conventional molecular assays in the evaluation of bone and soft tissue tumor samples, according to researchers.

The technique of anchored multiplex polymerase chain reaction (AMP)–based targeted next-generation sequencing (NGS) had a failure rate of 14% but, nonetheless, worked favorably when compared with conventional techniques, which were associated with several false positives in this study, the researchers reported in the Journal of Molecular Diagnostics.

Two new fusion partners for the USP6 gene were found using AMP-based targeted NGS in this study, which thus contributed to the “further unraveling of the molecular landscape” for these tumors, added corresponding author Judith V.M.G. Bovée, MD, PhD, of the department of pathology at Leiden (the Netherlands) University Medical Center and her colleagues.

While the genetics of bone and soft tissue tumors have diagnostic value in clinical practice, standard fluorescence in situ hybridization (FISH) and reverse transcriptase PCR are associated with several drawbacks, such as a high false negative rate in the case of FISH, Dr. Bovée and her coauthors wrote.

Accordingly, the researchers evaluated the applicability of a targeted sequencing assay (Archer FusionPlex Sarcoma kit, which was developed by ArcherDX) aimed at 26 genes relevant to bone and soft tissue tumor diagnostics.

Besides allowing for assessment of multiple target genes in a single assay, this technique circumvents the need to know both fusion partners for translocation detection, which opens up the possibility of identifying novel or rare fusion partners, investigators noted.

AMP-based targeted NGS was used to evaluate 81 bone and soft tissue tumor samples, and of those, 48 cases showed a fusion. For the remaining 33 cases in which no fusion was detected, 22 were considered truly negative because samples met all criteria for good quality, while the remaining 11 (14%) were considered not reliable because of insufficient quality, investigators reported.

The samples were also evaluated through use of FISH, reverse transcriptase PCR, or both in 58 cases and use of immunohistochemistry in 16 cases; for the remaining seven cases, no assay or immunohistochemistry could be applied because of a lack of availability, according to investigators.

Among the 48 entities that were fusion-positive according to AMP-based targeted NGS, 29 were validated using standard molecular assays, and of those, 25 had concordant results. Further analysis of the four discordant cases with a third independent technique confirmed the AMP-based targeted NGS findings, according to the published report.

Among the 22 fusion-negative high-quality samples, 19 were validated using FISH, and one case was found to be discordant; however, despite use of a third independent technique, this discrepancy could not be resolved, investigators said.

The AMP-based targeted NGS technique identified COL1A1 and SEC31A as novel fusion partners for USP6 in two cases of nodular fasciitis. Those fusion partners had been previously described in aneurysmal bone cysts, according to investigators.

Despite the promising results for the novel assay, conventional methods were sufficient in this study to confirm translocations in straightforward cases and ordinary rearrangements, according to the investigators.

“Both reverse transcription PCR and FISH are not only quick and easy to conduct but are also of low cost and high analytical validity and accuracy, which make them attractive methods,” they wrote.

The work by Dr. Bovée and her colleagues was supported by Leiden University Medical Center. The department of pathology and the department of cell and chemical biology at the medical center receive royalty payments from Kreatech/Leica, which provided a COL1A1/PDGFB fusion probe used in the research.

SOURCE: Lam SW et al. J Mol Diagn. 2018 Aug 20;20(5):653-63.

The investigational drug selinexor appears to be improving progression-free survival in patients with advanced dedifferentiated liposarcoma, based on phase 2 results from the randomized, placebo-controlled SEAL study.

But the statistical significance of the improvements varied depending on whether progression-free survival (PFS) was assessed by the World Health Organization criteria, which looks at two-dimensional measurements of these irregular three-dimensional objects, or RECIST v1.1 criteria, which only looks at a unidimensional measure, reported Mrinal M. Gounder, MD, of Memorial Sloan Kettering Cancer Center, New York, at the annual meeting of the American Society of Clinical Oncology. When tumor response was based on WHO criteria, there was no difference in median PFS for the 24 patients on active therapy (1.4 months) and the 27 patients on placebo (1.8 months). By RECIST v1.1 criteria, however, median PFS was 5.6 months with selinexor.

Dedifferentiated liposarcoma is incurable, and palliative therapies are associated with an overall survival of 11-20 months in these patients. Selinexor is an oral selective inhibitor of exportin-1 which exports proteins from the nucleus into the cytoplasm. The drug appears to prevent p53 from leaving the nucleus, thereby protecting it from overexpressed MDM2, which is a negative regulator of p53, but the drug might have other potential mechanisms of action.

The double-blind study included 56 evaluable patients who had progressive dedifferentiated liposarcoma and had received at least one prior systemic therapy. Patients’ median age was 61 years and they had received a median of two prior therapies. Patients were randomized to get either 60 mg of selinexor (26 patients) or placebo (30 patients) twice weekly until their disease progressed or they were no longer able to tolerate therapy. Patients whose disease progressed on placebo (24 patients) were allowed to cross over to open-label selinexor therapy.

Treatments were unblinded for 51 of the patients, 24 on selinexor and 27 on placebo. Disease progression as confirmed by Independent Central Radiological Review using WHO criteria was the main reason for ending blinded treatment.

Grade 1/2 adverse events for selinexor versus placebo, respectively, were nausea (85% vs. 31%), anorexia (62% vs. 14%), and fatigue (58% vs. 45%). The comparable rates of grade 3/4 adverse events were hyponatremia (15% vs. 0%), anemia (15% vs. 7%), and thrombocytopenia (12% vs. 0%). Selinexor dose was reduced because of adverse events in 12 patients.

In a discussion of the study’s implications, Mark Andrew Dickson, MD, also of Memorial Sloan Kettering Cancer Center, called the adverse events profile “mostly manageable but predictable grade 1/2 adverse events ... and median progression-free survival of 5 and a half months is quite encouraging.

“Changing response assessment method midtrial in a study with progression-free survival as the primary endpoint is obviously problematic, but it also highlights how difficult it is to measure three-dimensional tumors like complex retroperitoneal liposarcomas, which move and change and grow and shrink over time,” he said. “And I would conclude that RECIST is probably the worst method of tumor assessment for sarcoma, except for all the other methods of tumor assessment.”

To illustrate the difficulty of measuring tumor response, Dr. Dickson presented examples of different tumor shapes and scenarios where one method would indicate tumor progression and the other would indicate stable disease.

“There can be differences between the two methods in how progression responds and is determined. And you can do this experiment with a number of different shapes and find scenarios where one method would call it progression at a different time than the other. So this is really critically important when we look at the results of the clinical trial, because it was designed to look at WHO PFS. And you can see that, based on that, there was no significant difference between the selinexor and placebo arm,” he said.

Additionally, he reviewed cases from the study where “either way you measure this, you can see that [the] tumor is getting smaller over time,” as well as cases where the tumor grew in patients on placebo first, but decreased in size after switching to the active therapy.

“The improvement in progression-free survival is promising and ... selinexor probably does have activity in dediff lipo compared to historical data,” said Dr. Dickson, adding that he looks forward to selinexor progressing to a randomized, phase 3 trial and “seeing those data perhaps next year.”

Dr. Gounder disclosed financial relationships with multiple drug companies including Karyopharm Therapeutics, the maker of selinexor. Dr. Dickson disclosed a consult or adviser role with Celgene and research funding from Eli Lilly.

SOURCE: Gounder M et al. ASCO 2018, Abstract 11512.

The investigational drug selinexor appears to be improving progression-free survival in patients with advanced dedifferentiated liposarcoma, based on phase 2 results from the randomized, placebo-controlled SEAL study.

But the statistical significance of the improvements varied depending on whether progression-free survival (PFS) was assessed by the World Health Organization criteria, which looks at two-dimensional measurements of these irregular three-dimensional objects, or RECIST v1.1 criteria, which only looks at a unidimensional measure, reported Mrinal M. Gounder, MD, of Memorial Sloan Kettering Cancer Center, New York, at the annual meeting of the American Society of Clinical Oncology. When tumor response was based on WHO criteria, there was no difference in median PFS for the 24 patients on active therapy (1.4 months) and the 27 patients on placebo (1.8 months). By RECIST v1.1 criteria, however, median PFS was 5.6 months with selinexor.

Dedifferentiated liposarcoma is incurable, and palliative therapies are associated with an overall survival of 11-20 months in these patients. Selinexor is an oral selective inhibitor of exportin-1 which exports proteins from the nucleus into the cytoplasm. The drug appears to prevent p53 from leaving the nucleus, thereby protecting it from overexpressed MDM2, which is a negative regulator of p53, but the drug might have other potential mechanisms of action.

The double-blind study included 56 evaluable patients who had progressive dedifferentiated liposarcoma and had received at least one prior systemic therapy. Patients’ median age was 61 years and they had received a median of two prior therapies. Patients were randomized to get either 60 mg of selinexor (26 patients) or placebo (30 patients) twice weekly until their disease progressed or they were no longer able to tolerate therapy. Patients whose disease progressed on placebo (24 patients) were allowed to cross over to open-label selinexor therapy.

Treatments were unblinded for 51 of the patients, 24 on selinexor and 27 on placebo. Disease progression as confirmed by Independent Central Radiological Review using WHO criteria was the main reason for ending blinded treatment.

Grade 1/2 adverse events for selinexor versus placebo, respectively, were nausea (85% vs. 31%), anorexia (62% vs. 14%), and fatigue (58% vs. 45%). The comparable rates of grade 3/4 adverse events were hyponatremia (15% vs. 0%), anemia (15% vs. 7%), and thrombocytopenia (12% vs. 0%). Selinexor dose was reduced because of adverse events in 12 patients.

In a discussion of the study’s implications, Mark Andrew Dickson, MD, also of Memorial Sloan Kettering Cancer Center, called the adverse events profile “mostly manageable but predictable grade 1/2 adverse events ... and median progression-free survival of 5 and a half months is quite encouraging.

“Changing response assessment method midtrial in a study with progression-free survival as the primary endpoint is obviously problematic, but it also highlights how difficult it is to measure three-dimensional tumors like complex retroperitoneal liposarcomas, which move and change and grow and shrink over time,” he said. “And I would conclude that RECIST is probably the worst method of tumor assessment for sarcoma, except for all the other methods of tumor assessment.”

To illustrate the difficulty of measuring tumor response, Dr. Dickson presented examples of different tumor shapes and scenarios where one method would indicate tumor progression and the other would indicate stable disease.

“There can be differences between the two methods in how progression responds and is determined. And you can do this experiment with a number of different shapes and find scenarios where one method would call it progression at a different time than the other. So this is really critically important when we look at the results of the clinical trial, because it was designed to look at WHO PFS. And you can see that, based on that, there was no significant difference between the selinexor and placebo arm,” he said.

Additionally, he reviewed cases from the study where “either way you measure this, you can see that [the] tumor is getting smaller over time,” as well as cases where the tumor grew in patients on placebo first, but decreased in size after switching to the active therapy.

“The improvement in progression-free survival is promising and ... selinexor probably does have activity in dediff lipo compared to historical data,” said Dr. Dickson, adding that he looks forward to selinexor progressing to a randomized, phase 3 trial and “seeing those data perhaps next year.”

Dr. Gounder disclosed financial relationships with multiple drug companies including Karyopharm Therapeutics, the maker of selinexor. Dr. Dickson disclosed a consult or adviser role with Celgene and research funding from Eli Lilly.

SOURCE: Gounder M et al. ASCO 2018, Abstract 11512.

The investigational drug selinexor appears to be improving progression-free survival in patients with advanced dedifferentiated liposarcoma, based on phase 2 results from the randomized, placebo-controlled SEAL study.

But the statistical significance of the improvements varied depending on whether progression-free survival (PFS) was assessed by the World Health Organization criteria, which looks at two-dimensional measurements of these irregular three-dimensional objects, or RECIST v1.1 criteria, which only looks at a unidimensional measure, reported Mrinal M. Gounder, MD, of Memorial Sloan Kettering Cancer Center, New York, at the annual meeting of the American Society of Clinical Oncology. When tumor response was based on WHO criteria, there was no difference in median PFS for the 24 patients on active therapy (1.4 months) and the 27 patients on placebo (1.8 months). By RECIST v1.1 criteria, however, median PFS was 5.6 months with selinexor.

Dedifferentiated liposarcoma is incurable, and palliative therapies are associated with an overall survival of 11-20 months in these patients. Selinexor is an oral selective inhibitor of exportin-1 which exports proteins from the nucleus into the cytoplasm. The drug appears to prevent p53 from leaving the nucleus, thereby protecting it from overexpressed MDM2, which is a negative regulator of p53, but the drug might have other potential mechanisms of action.

The double-blind study included 56 evaluable patients who had progressive dedifferentiated liposarcoma and had received at least one prior systemic therapy. Patients’ median age was 61 years and they had received a median of two prior therapies. Patients were randomized to get either 60 mg of selinexor (26 patients) or placebo (30 patients) twice weekly until their disease progressed or they were no longer able to tolerate therapy. Patients whose disease progressed on placebo (24 patients) were allowed to cross over to open-label selinexor therapy.

Treatments were unblinded for 51 of the patients, 24 on selinexor and 27 on placebo. Disease progression as confirmed by Independent Central Radiological Review using WHO criteria was the main reason for ending blinded treatment.

Grade 1/2 adverse events for selinexor versus placebo, respectively, were nausea (85% vs. 31%), anorexia (62% vs. 14%), and fatigue (58% vs. 45%). The comparable rates of grade 3/4 adverse events were hyponatremia (15% vs. 0%), anemia (15% vs. 7%), and thrombocytopenia (12% vs. 0%). Selinexor dose was reduced because of adverse events in 12 patients.

In a discussion of the study’s implications, Mark Andrew Dickson, MD, also of Memorial Sloan Kettering Cancer Center, called the adverse events profile “mostly manageable but predictable grade 1/2 adverse events ... and median progression-free survival of 5 and a half months is quite encouraging.

“Changing response assessment method midtrial in a study with progression-free survival as the primary endpoint is obviously problematic, but it also highlights how difficult it is to measure three-dimensional tumors like complex retroperitoneal liposarcomas, which move and change and grow and shrink over time,” he said. “And I would conclude that RECIST is probably the worst method of tumor assessment for sarcoma, except for all the other methods of tumor assessment.”

To illustrate the difficulty of measuring tumor response, Dr. Dickson presented examples of different tumor shapes and scenarios where one method would indicate tumor progression and the other would indicate stable disease.

“There can be differences between the two methods in how progression responds and is determined. And you can do this experiment with a number of different shapes and find scenarios where one method would call it progression at a different time than the other. So this is really critically important when we look at the results of the clinical trial, because it was designed to look at WHO PFS. And you can see that, based on that, there was no significant difference between the selinexor and placebo arm,” he said.

Additionally, he reviewed cases from the study where “either way you measure this, you can see that [the] tumor is getting smaller over time,” as well as cases where the tumor grew in patients on placebo first, but decreased in size after switching to the active therapy.

“The improvement in progression-free survival is promising and ... selinexor probably does have activity in dediff lipo compared to historical data,” said Dr. Dickson, adding that he looks forward to selinexor progressing to a randomized, phase 3 trial and “seeing those data perhaps next year.”

Dr. Gounder disclosed financial relationships with multiple drug companies including Karyopharm Therapeutics, the maker of selinexor. Dr. Dickson disclosed a consult or adviser role with Celgene and research funding from Eli Lilly.

SOURCE: Gounder M et al. ASCO 2018, Abstract 11512.

Chromoplexy, a sudden burst of complex, loop-like gene rearrangements that gives rise to a fusion gene, appears to be associated with aggressive Ewing sarcomas, based on a study of 124 tumors reported in Science.

Ewing sarcomas with complex karyotypes are associated with a poorer prognosis compared with those with simpler karyotypes. The new findings show that these complex karyotypes are the product of chromoplexy, and that chromoplexy-generated fusions arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.

Analysis of the sequence context surrounding chromoplexy breaks may provide clues and potentially point to a therapeutic vulnerability that could be used to treat Ewing sarcomas. Further, given the preference of chromoplexy events for transcriptionally active regions, Ewing sarcomas arising from chromoplexy may be responsive to immune checkpoint inhibition.

In a study of the whole genomes of 124 Ewing sarcomas, chromoplexy rather than simple reciprocal translocations defined the gene fusions seen in 52 tumors (42%). Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors.

“Our analyses reveal rearrangement bursts (chromoplectic loops) as a source of gene fusion in human bone and soft tissue tumors. Ewing sarcomas with complex karyotypes are associated with a poorer prognosis than those with simpler karyotypes, and here we show chromoplexy as the mechanism in 42% of tumors. It is possible that the chromoplectic tumor’s additional gene disruptions and fusions contribute to the difference in patient survival,” wrote Nathaniel D. Anderson of the Hospital for Sick Children, Toronto, and the University of Toronto, and his colleagues.

Standard reciprocal translocations involve DNA breaks in two fusion partners. Chromoplexy involves three or more breakpoints in the genome. A loop pattern emerges as these three or more broken chromosome ends are forced to find a new partner. The result is the formation of functional EWSR1-FLI1 or EWSR1-ERG fusions that, upon expression, provide a selective growth or survival advantage

The researchers found that the loop rearrangements always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions.

They found similar loops forming canonical fusions in three other sarcoma types.

“Our whole-genome sequence data support a model in which there is an early clone of (Ewing sarcoma), containing EWSR1-ETS and chromoplexy, arising at least 1 year before diagnosis, which gives rise to both the primary and metastatic or relapse tumors. Whether the bursts ... are chance events or driven by specific mutational processes, akin to the RAG machinery operative in leukemia, remains to be established. As an increasing and diverse number of tumor genome sequences become available, we may be able to define further rearrangement processes that underlie fusion genes and thus unravel the causes of fusion-driven human cancers,” the researchers wrote.

The clinical features and demographics of the study patients were typical of Ewing sarcoma patients. Average patient age at diagnosis was 14.8 years (2.8 to 36.6 years); the male to female ratio was 1.38:1; and 14 patients had relapsed, with 13 having died from their disease.

About half of fusions between the EWS RNA binding protein 1 (EWSR1) gene on chromosome 22 and an E26 transformation-specific (ETS) family transcription factor gene, either FLI1 at 11q24 or ERG at 21q11 arose via chromoplexy.

mdales@mdedge.com

SOURCE: Anderson et al. Science 2018 Aug 31. doi: 10.1126/science.aam8419.

Chromoplexy, a sudden burst of complex, loop-like gene rearrangements that gives rise to a fusion gene, appears to be associated with aggressive Ewing sarcomas, based on a study of 124 tumors reported in Science.

Ewing sarcomas with complex karyotypes are associated with a poorer prognosis compared with those with simpler karyotypes. The new findings show that these complex karyotypes are the product of chromoplexy, and that chromoplexy-generated fusions arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.

Analysis of the sequence context surrounding chromoplexy breaks may provide clues and potentially point to a therapeutic vulnerability that could be used to treat Ewing sarcomas. Further, given the preference of chromoplexy events for transcriptionally active regions, Ewing sarcomas arising from chromoplexy may be responsive to immune checkpoint inhibition.

In a study of the whole genomes of 124 Ewing sarcomas, chromoplexy rather than simple reciprocal translocations defined the gene fusions seen in 52 tumors (42%). Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors.

“Our analyses reveal rearrangement bursts (chromoplectic loops) as a source of gene fusion in human bone and soft tissue tumors. Ewing sarcomas with complex karyotypes are associated with a poorer prognosis than those with simpler karyotypes, and here we show chromoplexy as the mechanism in 42% of tumors. It is possible that the chromoplectic tumor’s additional gene disruptions and fusions contribute to the difference in patient survival,” wrote Nathaniel D. Anderson of the Hospital for Sick Children, Toronto, and the University of Toronto, and his colleagues.

Standard reciprocal translocations involve DNA breaks in two fusion partners. Chromoplexy involves three or more breakpoints in the genome. A loop pattern emerges as these three or more broken chromosome ends are forced to find a new partner. The result is the formation of functional EWSR1-FLI1 or EWSR1-ERG fusions that, upon expression, provide a selective growth or survival advantage

The researchers found that the loop rearrangements always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions.

They found similar loops forming canonical fusions in three other sarcoma types.

“Our whole-genome sequence data support a model in which there is an early clone of (Ewing sarcoma), containing EWSR1-ETS and chromoplexy, arising at least 1 year before diagnosis, which gives rise to both the primary and metastatic or relapse tumors. Whether the bursts ... are chance events or driven by specific mutational processes, akin to the RAG machinery operative in leukemia, remains to be established. As an increasing and diverse number of tumor genome sequences become available, we may be able to define further rearrangement processes that underlie fusion genes and thus unravel the causes of fusion-driven human cancers,” the researchers wrote.

The clinical features and demographics of the study patients were typical of Ewing sarcoma patients. Average patient age at diagnosis was 14.8 years (2.8 to 36.6 years); the male to female ratio was 1.38:1; and 14 patients had relapsed, with 13 having died from their disease.

About half of fusions between the EWS RNA binding protein 1 (EWSR1) gene on chromosome 22 and an E26 transformation-specific (ETS) family transcription factor gene, either FLI1 at 11q24 or ERG at 21q11 arose via chromoplexy.

mdales@mdedge.com

SOURCE: Anderson et al. Science 2018 Aug 31. doi: 10.1126/science.aam8419.

Chromoplexy, a sudden burst of complex, loop-like gene rearrangements that gives rise to a fusion gene, appears to be associated with aggressive Ewing sarcomas, based on a study of 124 tumors reported in Science.

Ewing sarcomas with complex karyotypes are associated with a poorer prognosis compared with those with simpler karyotypes. The new findings show that these complex karyotypes are the product of chromoplexy, and that chromoplexy-generated fusions arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.

Analysis of the sequence context surrounding chromoplexy breaks may provide clues and potentially point to a therapeutic vulnerability that could be used to treat Ewing sarcomas. Further, given the preference of chromoplexy events for transcriptionally active regions, Ewing sarcomas arising from chromoplexy may be responsive to immune checkpoint inhibition.

In a study of the whole genomes of 124 Ewing sarcomas, chromoplexy rather than simple reciprocal translocations defined the gene fusions seen in 52 tumors (42%). Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors.

“Our analyses reveal rearrangement bursts (chromoplectic loops) as a source of gene fusion in human bone and soft tissue tumors. Ewing sarcomas with complex karyotypes are associated with a poorer prognosis than those with simpler karyotypes, and here we show chromoplexy as the mechanism in 42% of tumors. It is possible that the chromoplectic tumor’s additional gene disruptions and fusions contribute to the difference in patient survival,” wrote Nathaniel D. Anderson of the Hospital for Sick Children, Toronto, and the University of Toronto, and his colleagues.

Standard reciprocal translocations involve DNA breaks in two fusion partners. Chromoplexy involves three or more breakpoints in the genome. A loop pattern emerges as these three or more broken chromosome ends are forced to find a new partner. The result is the formation of functional EWSR1-FLI1 or EWSR1-ERG fusions that, upon expression, provide a selective growth or survival advantage

The researchers found that the loop rearrangements always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions.

They found similar loops forming canonical fusions in three other sarcoma types.

“Our whole-genome sequence data support a model in which there is an early clone of (Ewing sarcoma), containing EWSR1-ETS and chromoplexy, arising at least 1 year before diagnosis, which gives rise to both the primary and metastatic or relapse tumors. Whether the bursts ... are chance events or driven by specific mutational processes, akin to the RAG machinery operative in leukemia, remains to be established. As an increasing and diverse number of tumor genome sequences become available, we may be able to define further rearrangement processes that underlie fusion genes and thus unravel the causes of fusion-driven human cancers,” the researchers wrote.

The clinical features and demographics of the study patients were typical of Ewing sarcoma patients. Average patient age at diagnosis was 14.8 years (2.8 to 36.6 years); the male to female ratio was 1.38:1; and 14 patients had relapsed, with 13 having died from their disease.

About half of fusions between the EWS RNA binding protein 1 (EWSR1) gene on chromosome 22 and an E26 transformation-specific (ETS) family transcription factor gene, either FLI1 at 11q24 or ERG at 21q11 arose via chromoplexy.

mdales@mdedge.com

SOURCE: Anderson et al. Science 2018 Aug 31. doi: 10.1126/science.aam8419.

A member of the Zygophyllaceae family, Tribulus terrestris, also known as Gokshura, Gokharu, or puncture vine, is an annual herb; its aerial parts, roots, and fruits have been used in traditional medicine for anti-inflammatory, diuretic, tonic, antimicrobial, and aphrodisiac purposes for thousands of years in China, India, Pakistan, and Sudan.^1-3 In modern times, the health benefits of T. terrestris have been attributed to the constituent saponins, flavonoids, alkaloids, lignins, amides, and glycosides that have been isolated and found as bioactive compounds in the plant.^2-4

duckycards/iStock/Getty Images Plus

Skin lightening activity

In a study published in 2002, Deng et al. evaluated the effects of a decoction of T. terrestris on tyrosinase activity and melanogenesis on cultured human melanocytes. They found that the amount of melanin increased when the decoction was administered in higher concentrations (optimally 1.5 mg/mL) but the effects were reversed at lower concentrations (0.5 mg/mL). Similarly, tyrosinase activity was facilitated by high concentrations of the decoction (optimally 100 mg/mL) and hindered at low concentrations (10 mg/mL). The investigators concluded that T. terrestris showed intriguing potential for use as a skin lightening agent that warranted further study.⁷

A mouse study performed by Yang et al. in 2006 revealed that T. terrestris extract administered orally to C57BL/6J mice resulted in a significantly higher expression of melanocyte-stimulating hormone in the hair follicles of treated mice (75%), compared with that in the control group (18.75%). The researchers concluded that T. terrestris galvanizes tyrosinase activity and fosters melanocyte increase, melanin production, and the epidermal movement of dormant melanocytes.⁸
 

Anticancer activity

Kumar et al. showed in 2006 that the aqueous extracts of T. terrestris roots and fruits displayed chemopreventive activity in male Swiss albino mice. Specifically, oral administration of T. terrestris before, during, and after papillomagenesis induced by 7, 12-Dimethylbenz(a)anthracene (DMBA) resulted in significant decreases in tumor incidence, tumor burden, and cumulative number of papillomas, as well as a significant increase in average latent period as compared with the control group treated with DMBA and croton oil.⁹

The next year, Neychev et al. published a study on the effects of T. terrestris–derived saponins on normal human skin fibroblasts with a focus on anticancer activities. The researchers noted that the botanical engendered a dose-dependent reduction in [3H]-thymidine incorporation into the DNA of treated fibroblasts, which was not the case for untreated controls. This and several other metrics suggested that T. terrestris poses much less toxicity to normal human skin fibroblasts than multiple previously explored cancer lines by virtue of the up-regulation and down-regulation of polyamine homeostasis, hampering proliferation, and apoptosis induction.¹⁰

Conclusion

As is the case with numerous botanical agents used for health purposes, where there’s smoke, there’s fire. That is, T. terrestris has warranted investigation for its applicability in the modern health armamentarium. I hope that conservation efforts for this plant will prevail, as much more research is necessary to determine whether it can become useful in the dermatologic realm.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), as well as a New York Times Best Sellers book for consumers,“The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems.

References

1. Qureshi A et al. J Diet Suppl. 2014 Mar;11(1):64-79.

2. Zhu W et al. Chem Cent J. 2017 Jul 11;11(1):60.

3. Chhatre S et al. Pharmacogn Rev. 2014 Jan;8(15):45-51

4. Shahid M et al. J Biol Regul Homeost Agents. 2016 Jul-Sep;30(3):785-8.

5. Singh AG et al. J Ethnobiol Ethnomed. 2012 May 16;8:19.

6. Neychev V et al. J Ethnopharmacol. 2016 Feb 17;179:345-55.

7. Deng Y et al. Di Yi Jun Yi Da Xue Xue Bao. 2002 Nov;22(11):1017-9.

8. Yang L et al. Nan Fang Yi Ke Da Xue Xue Bao. 2006 Dec;26(12):1777-9.

9. Kumar M et al. Asian Pac J Cancer Prev. 2006 Apr-Jun;7(2):289-94.

10. Neychev VK et al. Exp Biol Med (Maywood). 2007 Jan;232(1):126-33.

11. Sisto M et al. J Photochem Photobiol B. 2012 Dec 5;117:193-201.

A member of the Zygophyllaceae family, Tribulus terrestris, also known as Gokshura, Gokharu, or puncture vine, is an annual herb; its aerial parts, roots, and fruits have been used in traditional medicine for anti-inflammatory, diuretic, tonic, antimicrobial, and aphrodisiac purposes for thousands of years in China, India, Pakistan, and Sudan.^1-3 In modern times, the health benefits of T. terrestris have been attributed to the constituent saponins, flavonoids, alkaloids, lignins, amides, and glycosides that have been isolated and found as bioactive compounds in the plant.^2-4

duckycards/iStock/Getty Images Plus

Skin lightening activity

In a study published in 2002, Deng et al. evaluated the effects of a decoction of T. terrestris on tyrosinase activity and melanogenesis on cultured human melanocytes. They found that the amount of melanin increased when the decoction was administered in higher concentrations (optimally 1.5 mg/mL) but the effects were reversed at lower concentrations (0.5 mg/mL). Similarly, tyrosinase activity was facilitated by high concentrations of the decoction (optimally 100 mg/mL) and hindered at low concentrations (10 mg/mL). The investigators concluded that T. terrestris showed intriguing potential for use as a skin lightening agent that warranted further study.⁷

A mouse study performed by Yang et al. in 2006 revealed that T. terrestris extract administered orally to C57BL/6J mice resulted in a significantly higher expression of melanocyte-stimulating hormone in the hair follicles of treated mice (75%), compared with that in the control group (18.75%). The researchers concluded that T. terrestris galvanizes tyrosinase activity and fosters melanocyte increase, melanin production, and the epidermal movement of dormant melanocytes.⁸
 

Anticancer activity

Kumar et al. showed in 2006 that the aqueous extracts of T. terrestris roots and fruits displayed chemopreventive activity in male Swiss albino mice. Specifically, oral administration of T. terrestris before, during, and after papillomagenesis induced by 7, 12-Dimethylbenz(a)anthracene (DMBA) resulted in significant decreases in tumor incidence, tumor burden, and cumulative number of papillomas, as well as a significant increase in average latent period as compared with the control group treated with DMBA and croton oil.⁹

The next year, Neychev et al. published a study on the effects of T. terrestris–derived saponins on normal human skin fibroblasts with a focus on anticancer activities. The researchers noted that the botanical engendered a dose-dependent reduction in [3H]-thymidine incorporation into the DNA of treated fibroblasts, which was not the case for untreated controls. This and several other metrics suggested that T. terrestris poses much less toxicity to normal human skin fibroblasts than multiple previously explored cancer lines by virtue of the up-regulation and down-regulation of polyamine homeostasis, hampering proliferation, and apoptosis induction.¹⁰

Conclusion

As is the case with numerous botanical agents used for health purposes, where there’s smoke, there’s fire. That is, T. terrestris has warranted investigation for its applicability in the modern health armamentarium. I hope that conservation efforts for this plant will prevail, as much more research is necessary to determine whether it can become useful in the dermatologic realm.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), as well as a New York Times Best Sellers book for consumers,“The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems.

References

1. Qureshi A et al. J Diet Suppl. 2014 Mar;11(1):64-79.

2. Zhu W et al. Chem Cent J. 2017 Jul 11;11(1):60.

3. Chhatre S et al. Pharmacogn Rev. 2014 Jan;8(15):45-51

4. Shahid M et al. J Biol Regul Homeost Agents. 2016 Jul-Sep;30(3):785-8.

5. Singh AG et al. J Ethnobiol Ethnomed. 2012 May 16;8:19.

6. Neychev V et al. J Ethnopharmacol. 2016 Feb 17;179:345-55.

7. Deng Y et al. Di Yi Jun Yi Da Xue Xue Bao. 2002 Nov;22(11):1017-9.

8. Yang L et al. Nan Fang Yi Ke Da Xue Xue Bao. 2006 Dec;26(12):1777-9.

9. Kumar M et al. Asian Pac J Cancer Prev. 2006 Apr-Jun;7(2):289-94.

10. Neychev VK et al. Exp Biol Med (Maywood). 2007 Jan;232(1):126-33.

11. Sisto M et al. J Photochem Photobiol B. 2012 Dec 5;117:193-201.

A member of the Zygophyllaceae family, Tribulus terrestris, also known as Gokshura, Gokharu, or puncture vine, is an annual herb; its aerial parts, roots, and fruits have been used in traditional medicine for anti-inflammatory, diuretic, tonic, antimicrobial, and aphrodisiac purposes for thousands of years in China, India, Pakistan, and Sudan.^1-3 In modern times, the health benefits of T. terrestris have been attributed to the constituent saponins, flavonoids, alkaloids, lignins, amides, and glycosides that have been isolated and found as bioactive compounds in the plant.^2-4

duckycards/iStock/Getty Images Plus

Skin lightening activity

In a study published in 2002, Deng et al. evaluated the effects of a decoction of T. terrestris on tyrosinase activity and melanogenesis on cultured human melanocytes. They found that the amount of melanin increased when the decoction was administered in higher concentrations (optimally 1.5 mg/mL) but the effects were reversed at lower concentrations (0.5 mg/mL). Similarly, tyrosinase activity was facilitated by high concentrations of the decoction (optimally 100 mg/mL) and hindered at low concentrations (10 mg/mL). The investigators concluded that T. terrestris showed intriguing potential for use as a skin lightening agent that warranted further study.⁷

A mouse study performed by Yang et al. in 2006 revealed that T. terrestris extract administered orally to C57BL/6J mice resulted in a significantly higher expression of melanocyte-stimulating hormone in the hair follicles of treated mice (75%), compared with that in the control group (18.75%). The researchers concluded that T. terrestris galvanizes tyrosinase activity and fosters melanocyte increase, melanin production, and the epidermal movement of dormant melanocytes.⁸
 

Anticancer activity

Kumar et al. showed in 2006 that the aqueous extracts of T. terrestris roots and fruits displayed chemopreventive activity in male Swiss albino mice. Specifically, oral administration of T. terrestris before, during, and after papillomagenesis induced by 7, 12-Dimethylbenz(a)anthracene (DMBA) resulted in significant decreases in tumor incidence, tumor burden, and cumulative number of papillomas, as well as a significant increase in average latent period as compared with the control group treated with DMBA and croton oil.⁹

The next year, Neychev et al. published a study on the effects of T. terrestris–derived saponins on normal human skin fibroblasts with a focus on anticancer activities. The researchers noted that the botanical engendered a dose-dependent reduction in [3H]-thymidine incorporation into the DNA of treated fibroblasts, which was not the case for untreated controls. This and several other metrics suggested that T. terrestris poses much less toxicity to normal human skin fibroblasts than multiple previously explored cancer lines by virtue of the up-regulation and down-regulation of polyamine homeostasis, hampering proliferation, and apoptosis induction.¹⁰

Conclusion

As is the case with numerous botanical agents used for health purposes, where there’s smoke, there’s fire. That is, T. terrestris has warranted investigation for its applicability in the modern health armamentarium. I hope that conservation efforts for this plant will prevail, as much more research is necessary to determine whether it can become useful in the dermatologic realm.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), as well as a New York Times Best Sellers book for consumers,“The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems.

References

1. Qureshi A et al. J Diet Suppl. 2014 Mar;11(1):64-79.

2. Zhu W et al. Chem Cent J. 2017 Jul 11;11(1):60.

3. Chhatre S et al. Pharmacogn Rev. 2014 Jan;8(15):45-51

4. Shahid M et al. J Biol Regul Homeost Agents. 2016 Jul-Sep;30(3):785-8.

5. Singh AG et al. J Ethnobiol Ethnomed. 2012 May 16;8:19.

6. Neychev V et al. J Ethnopharmacol. 2016 Feb 17;179:345-55.

7. Deng Y et al. Di Yi Jun Yi Da Xue Xue Bao. 2002 Nov;22(11):1017-9.

8. Yang L et al. Nan Fang Yi Ke Da Xue Xue Bao. 2006 Dec;26(12):1777-9.

9. Kumar M et al. Asian Pac J Cancer Prev. 2006 Apr-Jun;7(2):289-94.

10. Neychev VK et al. Exp Biol Med (Maywood). 2007 Jan;232(1):126-33.

11. Sisto M et al. J Photochem Photobiol B. 2012 Dec 5;117:193-201.

Hospital readmissions for acute myocardial infarction (AMI), heart failure, and pneumonia have become central to quality-measurement efforts by the Centers for Medicare & Medicaid Services (CMS), which seek to improve hospital care transitions through public reporting and payment programs.¹ Most current measures are limited to readmissions that require inpatient hospitalization and do not capture return visits to the emergency department (ED) that do not result in readmission but rather ED discharge. These visits may reflect important needs for acute, unscheduled care during the vulnerable posthospitalization period.^2-5 While previous research has suggested that nearly 10% of patients may return to the ED following hospital discharge without readmission, the characteristics of these visits among Medicare beneficiaries and the implications for national care-coordination quality-measurement initiatives have not been explored.^6,7

As the locus of acute outpatient care and the primary portal of hospital admissions and readmissions, ED visits following hospital discharge may convey meaningful information about posthospitalization care transitions.^8,9 In addition, recent reviews and perspectives have highlighted the role of ED care-coordination services as interventions to reduce inpatient hospitalizations and improve care transitions,^10,11 yet no empirical studies have evaluated the relationship between these unique care-coordination opportunities in the ED and care-coordination outcomes, such as hospital readmissions. As policymakers seek to develop accountability measures that capture the totality of acute, unscheduled visits following hospital discharge, describing the relationship between ED visits and readmissions will be essential to providers for benchmarking and to policymakers and payers seeking to reduce the total cost of care.^12,13

Accordingly, we sought to characterize the frequency, diagnoses, and hospital-level variation in treat-and-discharge ED visitation following hospital discharge for 3 conditions for which hospital readmission is publicly reported by the CMS: AMI, heart failure, and pneumonia. We also sought to evaluate the relationship between hospital-level ED visitation following hospital discharge and publicly reported, risk-standardized readmission rates (RSRRs).

Study Design

This study was a cross-sectional analysis of Medicare beneficiaries discharged alive following hospitalization for AMI, heart failure, and pneumonia between July 2011 and June 2012.

Selection of Participants

We used Medicare Standard Analytic Files to identify inpatient hospitalizations for each disease cohort based on principal discharge diagnoses. Each condition-specific cohort was constructed to be consistent with the CMS’s readmission measures using International Classification of Diseases, 9th Revision-Clinical Modification codes to identify AMI, heart failure, and pneumonia discharges.¹ We included only patients who were enrolled in fee-for-service (FFS) Medicare parts A and B for 12 months prior to their index hospitalization to maximize the capture of diagnoses for risk adjustment. Each cohort included only patients who were discharged alive while maintaining FFS coverage for at least 30 days following hospital discharge to minimize bias in outcome ascertainment. We excluded patients who were discharged against medical advice. All contiguous admissions that were identified in a transfer chain were considered to be a single admission. Hospitals with fewer than 25 condition-specific index hospital admissions were excluded from this analysis for consistency with publicly reported measures.¹

Measurements

We measured postdischarge, treat-and release ED visits that occurred at any hospital within 30 days of hospital discharge from the index hospitalization. ED visits were identified as a hospital outpatient claim for ED services using hospital outpatient revenue center codes 0450, 0451, 0452, 0456, and 0981. This definition is consistent with those of previous studies.^3,14 We defined postdischarge ED visits as treat-and-discharge visits or visits that did not result in inpatient readmission or observation stays. Similar to readmission measures, only 1 postdischarge ED visit was counted toward the hospital-level outcome in patients with multiple ED visits within the 30 days following hospital discharge. We defined readmission as the first unplanned, inpatient hospitalization occurring at any hospital within the 30-day period following discharge. Any subsequent inpatient admission following the 30-day period was considered a distinct index admission if it met the inclusion criteria. Consistent with CMS methods, unplanned, inpatient readmissions are from any source and are not limited to patients who were first evaluated in the ED.

Outcomes

We describe hospital-level, postdischarge ED visitation as the risk-standardized postdischarge ED visit rate. The general construct of this measure is consistent with those of prior studies that define postdischarge ED visitation as the proportion of index admissions followed by a treat-and-discharge ED visit without hospital readmission^2,3; however, this outcome also incorporates a risk-standardization model with covariates that are identical to the risk-standardization approach that is used for readmission measurement.

We describe hospital-level readmission by calculating RSRRs consistent with CMS readmission measures, which are endorsed by the National Quality Forum and used for public reporting.^15-17 Detailed technical documentation, including the SAS code used to replicate hospital-level measures of readmission, are available publicly through the CMS QualityNet portal.¹⁸

We calculated risk-standardized postdischarge ED visit rates and RSRRs as the ratio of the predicted number of postdischarge ED visits or readmissions for a hospital given its observed case mix to the expected number of postdischarge ED visits or readmissions based on the nation’s performance with that hospital’s case mix, respectively. This approach estimates a distinct risk-standardized postdischarge ED visit rate and RSRR for each hospital using hierarchical generalized linear models (HGLMs) and using a logit link with a first-level adjustment for age, sex, 29 clinical covariates for AMI, 35 clinical covariates for heart failure, and 38 clinical covariates for pneumonia. Each clinical covariate is identified based on inpatient and outpatient claims during the 12 months prior to the index hospitalization. The second level of the HGLM includes a random hospital-level intercept. This approach to measuring hospital readmissions accounts for the correlated nature of observed readmission rates within a hospital and reflects the assumption that after adjustment for patient characteristics and sampling variability, the remaining variation in postdischarge ED visit rates or readmission rates reflects hospital quality.

Analysis

In order to characterize treat-and-discharge postdischarge ED visits, we first described the clinical conditions that were evaluated during the first postdischarge ED visit. Based on the principal discharge diagnosis, ED visits were grouped into clinically meaningful categories using the Agency for Healthcare Research and Quality Clinical Classifications Software (CCS).¹⁹ We also report hospital-level variation in risk-standardized postdischarge ED visit rates for AMI, heart failure, and pneumonia.

Next, we examined the relationship between hospital characteristics and risk-standardized postdischarge ED visit rates. We linked hospital characteristics from the American Hospital Association (AHA) Annual Survey to the study dataset, including the following: safety-net status, teaching status, and urban or rural status. Consistent with prior work, hospital safety-net status was defined as a hospital Medicaid caseload greater than 1 standard deviation above the mean Medicaid caseload in the hospital’s state. Approximately 94% of the hospitals included in the 3 condition cohorts in the dataset had complete data in the 2011 AHA Annual Survey to be included in this analysis.

We evaluated the relationship between postdischarge ED visit rates and hospital readmission rates in 2 ways. First, we calculated Spearman rank correlation coefficients between hospital-level, risk-standardized postdischarge ED visit rates and RSRRs. Second, we calculated hospital-level variation in RSRRs based on the strata of risk-standardized postdischarge ED visit rates. Given the normal distribution of postdischarge ED visit rates, we grouped hospitals by quartile of postdischarge ED visit rates and 1 group for hospitals with no postdischarge ED visits.

Based on preliminary analyses indicating a relationship between hospital size, measured by condition-specific index hospitalization volume, and postdischarge treat-and-discharge ED visit rates, all descriptive statistics and correlations reported are weighted by the volume of condition-specific index hospitalizations. The study was approved by the Yale University Human Research Protection Program. All analyses were conducted using SAS 9.1 (SAS Institute Inc, Cary, NC). The analytic plan and results reported in this work are in compliance with the Strengthening the Reporting of Observational Studies in Epidemiology checklist.²⁰

During the 1-year study period, we included a total of 157,035 patients who were hospitalized at 1656 hospitals for AMI, 391,209 at 3044 hospitals for heart failure, and 342,376 at 3484 hospitals for pneumonia. Details of study cohort creation are available in supplementary Table 1. After hospitalization for AMI, 14,714 patients experienced a postdischarge ED visit (8.4%) and 27,214 an inpatient readmissions (17.3%) within 30 days of discharge; 31,621 (7.6%) and 88,106 (22.5%) patients after hospitalization for heart failure and 26,681 (7.4%) and 59,352 (17.3%) patients after hospitalization for pneumonia experienced a postdischarge ED visit and an inpatient readmission within 30 days of discharge, respectively.

Postdischarge ED visits were for a wide variety of conditions, with the top 10 CCS categories comprising 44% of postdischarge ED visits following AMI hospitalizations, 44% of following heart failure hospitalizations, and 41% following pneumonia hospitalizations (supplementary Table 2). The first postdischarge ED visit was rarely for the same condition as the index hospitalization in the AMI cohort (224 visits; 1.5%) as well as the pneumonia cohort (1401 visits; 5.3%). Among patients who were originally admitted for heart failure, 10.6% of the first postdischarge ED visits were also for congestive heart failure. However, the first postdischarge ED visit was commonly for associated conditions, such as coronary artery disease in the case of AMI or chronic obstructive pulmonary disease in the case of pneumonia, albeit these related conditions did not comprise the majority of postdischarge ED visitation.

We found wide hospital-level variation in postdischarge ED visit rates for each condition: AMI (median: 8.3%; 5th and 95th percentile: 2.8%-14.3%), heart failure (median: 7.3%; 5th and 95th percentile: 3.0%-13.3%), and pneumonia (median: 7.1%; 5th and 95th percentile: 2.4%-13.2%; supplementary Table 3). The variation persisted after accounting for hospital case mix, as evidenced in the supplementary Figure, which describes hospital variation in risk-standardized postdischarge ED visit rates. This variation was statistically significant (P < .001), as demonstrated by the isolated relationship between the random effect and the outcome (AMI: random effect estimate 0.0849 [95% confidence interval (CI), 0.0832 to 0.0866]; heart failure: random effect estimate 0.0796 [95% CI, 0.0784 to 0.0809]; pneumonia: random effect estimate 0.0753 [95% CI, 0.0741 to 0.0764]).

Across all 3 conditions, hospitals located in rural areas had significantly higher risk-standardized postdischarge ED visit rates than hospitals located in urban areas (10.1% vs 8.6% for AMI, 8.4% vs 7.5% for heart failure, and 8.0% vs 7.4% for pneumonia). In comparison to teaching hospitals, nonteaching hospitals had significantly higher risk-standardized postdischarge ED visit rates following hospital discharge for pneumonia (7.6% vs 7.1%). Safety-net hospitals also had higher risk-standardized postdischarge ED visitation rates following discharge for heart failure (8.4% vs 7.7%) and pneumonia (7.7% vs 7.3%). Risk-standardized postdischarge ED visit rates were higher in publicly owned hospitals than in nonprofit or privately owned hospitals for heart failure (8.0% vs 7.5% in nonprofit hospitals or 7.5% in private hospitals) and pneumonia (7.7% vs 7.4% in nonprofit hospitals and 7.3% in private hospitals; Table).

Across a national cohort of Medicare beneficiaries, we found frequent treat-and-discharge ED utilization following hospital discharge for AMI, heart failure, and pneumonia, suggesting that publicly reported readmission measures are capturing only a portion of postdischarge acute-care use. Our findings confirm prior work describing a 30-day postdischarge ED visit rate of 8% to 9% among Medicare beneficiaries for all hospitalizations in several states.^3,6While many of the first postdischarge ED visits were for conditions related to the index hospitalization, the majority represent acute, unscheduled visits for different diagnoses. These findings are consistent with prior work studying inpatient readmissions and observation readmissions that find similar heterogeneity in the clinical reasons for hospital return.^21,22

We also described substantial hospital-level variation in risk-standardized ED postdischarge rates. Prior work by Vashi et al.³ demonstrated substantial variation in observed postdischarge ED visit rates and inpatient readmissions following hospital discharge between clinical conditions in a population-level study. Our work extends upon this by demonstrating hospital-level variation for 3 conditions of high volume and substantial policy importance after accounting for differences in hospital case mix. Interestingly, our work also found similar rates of postdischarge ED treat-and-discharge visitation as recent work by Sabbatini et al.²³ analyzing an all-payer, adult population with any clinical condition. Taken together, these studies show the substantial volume of postdischarge acute-care utilization in the ED not captured by existing readmission measures.

We found several hospital characteristics of importance in describing variation in postdischarge ED visitation rates. Notably, hospitals located in rural areas and safety-net hospitals demonstrated higher postdischarge ED visitation rates. This may reflect a higher use of the ED as an acute, unscheduled care access point in rural communities without access to alternative acute diagnostic and treatment services.²⁴ Similarly, safety-net hospitals may be more likely to provide unscheduled care for patients with poor access to primary care in the ED setting. Yet, consistent with prior work, our results also indicate that these differences do not result in different readmission rates.²⁵ Regarding hospital teaching status, unlike prior work suggesting that teaching hospitals care for more safety-net Medicare beneficiaries,²⁶ our work found opposite patterns of postdischarge ED visitation between hospital teaching and safety-net status following pneumonia hospitalization. This may reflect differences in the organization of acute care as patients with limited access to unscheduled primary and specialty care in safety-net communities utilize the ED, whereas patients in teaching-hospital communities may be able to access hospital-based clinics for care.

Contrary to the expectations of many clinicians and policymakers, we found an inverse relationship between postdischarge ED visit rates and readmission rates. While the cross-sectional design of our study cannot provide a causal explanation, these findings merit policy attention and future exploration of several hypotheses. One possible explanation for this finding is that hospitals with high postdischarge ED visit rates provide care in communities in which acute, unscheduled care is consolidated to the ED setting and thereby permits the ED to serve a gatekeeper function for scarce inpatient resources. This hypothesis may also be supported by recent interventions demonstrating that the use of ED care coordination and geriatric ED services at higher-volume EDs can reduce hospitalizations. Also, hospitals with greater ED capacity may have easier ED access and may be able to see patients earlier in their disease courses post discharge or more frequently in the ED for follow-up, therefore increasing ED visits but avoiding rehospitalization. Another possible explanation is that hospitals with lower postdischarge ED visit rates may also have a lower propensity to admit patients. Because our definition of postdischarge ED visitation did not include ED visits that result in hospitalization, hospitals with a lower propensity to admit from the ED may therefore appear to have higher ED visit rates. This explanation may be further supported by our finding that many postdischarge ED visits are for conditions that are associated with discretionary hospitalization in the ED.²⁷ A third explanation for this finding may be that poor access to outpatient care outside the hospital setting results in higher postdischarge ED visit rates without increasing the acuity of these revisits or increasing readmission rates²⁸; however, given the validated, risk-standardized approach to readmission measurement, this is unlikely. This is also unlikely given recent work by Sabbatini et al.²³ demonstrating substantial acuity among patients who return to the ED following hospital discharge. Future work should seek to evaluate the relationship between the availability of ED care-coordination services and the specific ED, hospital, and community care-coordination activities undertaken in the ED following hospital discharge to reduce readmission rates.

This work should be interpreted within the confines of its design. First, it is possible that some of the variation detected in postdischarge ED visit rates is mediated by hospital-level variation in postdischarge observation visits that are not captured in this outcome. However, in previous work, we have demonstrated that almost one-third of hospitals have no postdischarge observation stays and that most postdischarge observation stays are for more than 24 hours, which is unlikely to reflect the intensity of care of postdischarge ED visits.²⁷ Second, our analyses were limited to Medicare FFS beneficiaries, which may limit the generalizability of this work to other patient populations. However, this dataset did include a national cohort of Medicare beneficiaries that is identical to those included in publicly reported CMS readmission measures; therefore, these results have substantial policy relevance. Third, this work was limited to 3 conditions of high illness severity of policy focus, and future work applying similar analyses to less severe conditions may find different degrees of hospital-level variation in postdischarge outcomes that are amenable to quality improvement. Finally, we assessed the rate of treat-and-discharge ED visits only after hospital discharge; this understates the frequency of ED visits since repeat ED visits and ED visits resulting in rehospitalization are not included. However, our definition was designed to mirror the definition used to assess hospital readmissions for policy purposes and is a conservative approach.

In summary, ED visits following hospital discharge are common, as Medicare beneficiaries have 1 treat-and-discharge ED visit for every 2 readmissions within 30 days of hospital discharge. Postdischarge ED visits occur for a wide variety of conditions, with wide risk-standardized, hospital-level variation. Hospitals with the highest risk-standardized postdischarge ED visitation rates demonstrated lower RSRRs, suggesting that policymakers and researchers should further examine the role of the hospital-based ED in providing access to acute care and supporting care transitions for the vulnerable Medicare population.

Disclosure

 Dr. Venkatesh received contract support from the CMS, an agency of the U.S. Department of Health & Human Services, and grant support from the Emergency Medicine Foundation’s Health Policy Research Scholar Award during the conduct of the study; and Dr. Wang, Mr. Wang, Ms. Altaf, Dr. Bernheim, and Dr. Horwitz received contract support from the CMS, an agency of the U.S. Department of Health & Human Services, during the conduct of the study.

Hospital readmissions for acute myocardial infarction (AMI), heart failure, and pneumonia have become central to quality-measurement efforts by the Centers for Medicare & Medicaid Services (CMS), which seek to improve hospital care transitions through public reporting and payment programs.¹ Most current measures are limited to readmissions that require inpatient hospitalization and do not capture return visits to the emergency department (ED) that do not result in readmission but rather ED discharge. These visits may reflect important needs for acute, unscheduled care during the vulnerable posthospitalization period.^2-5 While previous research has suggested that nearly 10% of patients may return to the ED following hospital discharge without readmission, the characteristics of these visits among Medicare beneficiaries and the implications for national care-coordination quality-measurement initiatives have not been explored.^6,7

As the locus of acute outpatient care and the primary portal of hospital admissions and readmissions, ED visits following hospital discharge may convey meaningful information about posthospitalization care transitions.^8,9 In addition, recent reviews and perspectives have highlighted the role of ED care-coordination services as interventions to reduce inpatient hospitalizations and improve care transitions,^10,11 yet no empirical studies have evaluated the relationship between these unique care-coordination opportunities in the ED and care-coordination outcomes, such as hospital readmissions. As policymakers seek to develop accountability measures that capture the totality of acute, unscheduled visits following hospital discharge, describing the relationship between ED visits and readmissions will be essential to providers for benchmarking and to policymakers and payers seeking to reduce the total cost of care.^12,13

Accordingly, we sought to characterize the frequency, diagnoses, and hospital-level variation in treat-and-discharge ED visitation following hospital discharge for 3 conditions for which hospital readmission is publicly reported by the CMS: AMI, heart failure, and pneumonia. We also sought to evaluate the relationship between hospital-level ED visitation following hospital discharge and publicly reported, risk-standardized readmission rates (RSRRs).

Study Design

This study was a cross-sectional analysis of Medicare beneficiaries discharged alive following hospitalization for AMI, heart failure, and pneumonia between July 2011 and June 2012.

Selection of Participants

We used Medicare Standard Analytic Files to identify inpatient hospitalizations for each disease cohort based on principal discharge diagnoses. Each condition-specific cohort was constructed to be consistent with the CMS’s readmission measures using International Classification of Diseases, 9th Revision-Clinical Modification codes to identify AMI, heart failure, and pneumonia discharges.¹ We included only patients who were enrolled in fee-for-service (FFS) Medicare parts A and B for 12 months prior to their index hospitalization to maximize the capture of diagnoses for risk adjustment. Each cohort included only patients who were discharged alive while maintaining FFS coverage for at least 30 days following hospital discharge to minimize bias in outcome ascertainment. We excluded patients who were discharged against medical advice. All contiguous admissions that were identified in a transfer chain were considered to be a single admission. Hospitals with fewer than 25 condition-specific index hospital admissions were excluded from this analysis for consistency with publicly reported measures.¹

Measurements

We measured postdischarge, treat-and release ED visits that occurred at any hospital within 30 days of hospital discharge from the index hospitalization. ED visits were identified as a hospital outpatient claim for ED services using hospital outpatient revenue center codes 0450, 0451, 0452, 0456, and 0981. This definition is consistent with those of previous studies.^3,14 We defined postdischarge ED visits as treat-and-discharge visits or visits that did not result in inpatient readmission or observation stays. Similar to readmission measures, only 1 postdischarge ED visit was counted toward the hospital-level outcome in patients with multiple ED visits within the 30 days following hospital discharge. We defined readmission as the first unplanned, inpatient hospitalization occurring at any hospital within the 30-day period following discharge. Any subsequent inpatient admission following the 30-day period was considered a distinct index admission if it met the inclusion criteria. Consistent with CMS methods, unplanned, inpatient readmissions are from any source and are not limited to patients who were first evaluated in the ED.

Outcomes

We describe hospital-level, postdischarge ED visitation as the risk-standardized postdischarge ED visit rate. The general construct of this measure is consistent with those of prior studies that define postdischarge ED visitation as the proportion of index admissions followed by a treat-and-discharge ED visit without hospital readmission^2,3; however, this outcome also incorporates a risk-standardization model with covariates that are identical to the risk-standardization approach that is used for readmission measurement.

We describe hospital-level readmission by calculating RSRRs consistent with CMS readmission measures, which are endorsed by the National Quality Forum and used for public reporting.^15-17 Detailed technical documentation, including the SAS code used to replicate hospital-level measures of readmission, are available publicly through the CMS QualityNet portal.¹⁸

We calculated risk-standardized postdischarge ED visit rates and RSRRs as the ratio of the predicted number of postdischarge ED visits or readmissions for a hospital given its observed case mix to the expected number of postdischarge ED visits or readmissions based on the nation’s performance with that hospital’s case mix, respectively. This approach estimates a distinct risk-standardized postdischarge ED visit rate and RSRR for each hospital using hierarchical generalized linear models (HGLMs) and using a logit link with a first-level adjustment for age, sex, 29 clinical covariates for AMI, 35 clinical covariates for heart failure, and 38 clinical covariates for pneumonia. Each clinical covariate is identified based on inpatient and outpatient claims during the 12 months prior to the index hospitalization. The second level of the HGLM includes a random hospital-level intercept. This approach to measuring hospital readmissions accounts for the correlated nature of observed readmission rates within a hospital and reflects the assumption that after adjustment for patient characteristics and sampling variability, the remaining variation in postdischarge ED visit rates or readmission rates reflects hospital quality.

Analysis

In order to characterize treat-and-discharge postdischarge ED visits, we first described the clinical conditions that were evaluated during the first postdischarge ED visit. Based on the principal discharge diagnosis, ED visits were grouped into clinically meaningful categories using the Agency for Healthcare Research and Quality Clinical Classifications Software (CCS).¹⁹ We also report hospital-level variation in risk-standardized postdischarge ED visit rates for AMI, heart failure, and pneumonia.

Next, we examined the relationship between hospital characteristics and risk-standardized postdischarge ED visit rates. We linked hospital characteristics from the American Hospital Association (AHA) Annual Survey to the study dataset, including the following: safety-net status, teaching status, and urban or rural status. Consistent with prior work, hospital safety-net status was defined as a hospital Medicaid caseload greater than 1 standard deviation above the mean Medicaid caseload in the hospital’s state. Approximately 94% of the hospitals included in the 3 condition cohorts in the dataset had complete data in the 2011 AHA Annual Survey to be included in this analysis.

We evaluated the relationship between postdischarge ED visit rates and hospital readmission rates in 2 ways. First, we calculated Spearman rank correlation coefficients between hospital-level, risk-standardized postdischarge ED visit rates and RSRRs. Second, we calculated hospital-level variation in RSRRs based on the strata of risk-standardized postdischarge ED visit rates. Given the normal distribution of postdischarge ED visit rates, we grouped hospitals by quartile of postdischarge ED visit rates and 1 group for hospitals with no postdischarge ED visits.

Based on preliminary analyses indicating a relationship between hospital size, measured by condition-specific index hospitalization volume, and postdischarge treat-and-discharge ED visit rates, all descriptive statistics and correlations reported are weighted by the volume of condition-specific index hospitalizations. The study was approved by the Yale University Human Research Protection Program. All analyses were conducted using SAS 9.1 (SAS Institute Inc, Cary, NC). The analytic plan and results reported in this work are in compliance with the Strengthening the Reporting of Observational Studies in Epidemiology checklist.²⁰

During the 1-year study period, we included a total of 157,035 patients who were hospitalized at 1656 hospitals for AMI, 391,209 at 3044 hospitals for heart failure, and 342,376 at 3484 hospitals for pneumonia. Details of study cohort creation are available in supplementary Table 1. After hospitalization for AMI, 14,714 patients experienced a postdischarge ED visit (8.4%) and 27,214 an inpatient readmissions (17.3%) within 30 days of discharge; 31,621 (7.6%) and 88,106 (22.5%) patients after hospitalization for heart failure and 26,681 (7.4%) and 59,352 (17.3%) patients after hospitalization for pneumonia experienced a postdischarge ED visit and an inpatient readmission within 30 days of discharge, respectively.

Postdischarge ED visits were for a wide variety of conditions, with the top 10 CCS categories comprising 44% of postdischarge ED visits following AMI hospitalizations, 44% of following heart failure hospitalizations, and 41% following pneumonia hospitalizations (supplementary Table 2). The first postdischarge ED visit was rarely for the same condition as the index hospitalization in the AMI cohort (224 visits; 1.5%) as well as the pneumonia cohort (1401 visits; 5.3%). Among patients who were originally admitted for heart failure, 10.6% of the first postdischarge ED visits were also for congestive heart failure. However, the first postdischarge ED visit was commonly for associated conditions, such as coronary artery disease in the case of AMI or chronic obstructive pulmonary disease in the case of pneumonia, albeit these related conditions did not comprise the majority of postdischarge ED visitation.

We found wide hospital-level variation in postdischarge ED visit rates for each condition: AMI (median: 8.3%; 5th and 95th percentile: 2.8%-14.3%), heart failure (median: 7.3%; 5th and 95th percentile: 3.0%-13.3%), and pneumonia (median: 7.1%; 5th and 95th percentile: 2.4%-13.2%; supplementary Table 3). The variation persisted after accounting for hospital case mix, as evidenced in the supplementary Figure, which describes hospital variation in risk-standardized postdischarge ED visit rates. This variation was statistically significant (P < .001), as demonstrated by the isolated relationship between the random effect and the outcome (AMI: random effect estimate 0.0849 [95% confidence interval (CI), 0.0832 to 0.0866]; heart failure: random effect estimate 0.0796 [95% CI, 0.0784 to 0.0809]; pneumonia: random effect estimate 0.0753 [95% CI, 0.0741 to 0.0764]).

Across all 3 conditions, hospitals located in rural areas had significantly higher risk-standardized postdischarge ED visit rates than hospitals located in urban areas (10.1% vs 8.6% for AMI, 8.4% vs 7.5% for heart failure, and 8.0% vs 7.4% for pneumonia). In comparison to teaching hospitals, nonteaching hospitals had significantly higher risk-standardized postdischarge ED visit rates following hospital discharge for pneumonia (7.6% vs 7.1%). Safety-net hospitals also had higher risk-standardized postdischarge ED visitation rates following discharge for heart failure (8.4% vs 7.7%) and pneumonia (7.7% vs 7.3%). Risk-standardized postdischarge ED visit rates were higher in publicly owned hospitals than in nonprofit or privately owned hospitals for heart failure (8.0% vs 7.5% in nonprofit hospitals or 7.5% in private hospitals) and pneumonia (7.7% vs 7.4% in nonprofit hospitals and 7.3% in private hospitals; Table).

Across a national cohort of Medicare beneficiaries, we found frequent treat-and-discharge ED utilization following hospital discharge for AMI, heart failure, and pneumonia, suggesting that publicly reported readmission measures are capturing only a portion of postdischarge acute-care use. Our findings confirm prior work describing a 30-day postdischarge ED visit rate of 8% to 9% among Medicare beneficiaries for all hospitalizations in several states.^3,6While many of the first postdischarge ED visits were for conditions related to the index hospitalization, the majority represent acute, unscheduled visits for different diagnoses. These findings are consistent with prior work studying inpatient readmissions and observation readmissions that find similar heterogeneity in the clinical reasons for hospital return.^21,22

We also described substantial hospital-level variation in risk-standardized ED postdischarge rates. Prior work by Vashi et al.³ demonstrated substantial variation in observed postdischarge ED visit rates and inpatient readmissions following hospital discharge between clinical conditions in a population-level study. Our work extends upon this by demonstrating hospital-level variation for 3 conditions of high volume and substantial policy importance after accounting for differences in hospital case mix. Interestingly, our work also found similar rates of postdischarge ED treat-and-discharge visitation as recent work by Sabbatini et al.²³ analyzing an all-payer, adult population with any clinical condition. Taken together, these studies show the substantial volume of postdischarge acute-care utilization in the ED not captured by existing readmission measures.

We found several hospital characteristics of importance in describing variation in postdischarge ED visitation rates. Notably, hospitals located in rural areas and safety-net hospitals demonstrated higher postdischarge ED visitation rates. This may reflect a higher use of the ED as an acute, unscheduled care access point in rural communities without access to alternative acute diagnostic and treatment services.²⁴ Similarly, safety-net hospitals may be more likely to provide unscheduled care for patients with poor access to primary care in the ED setting. Yet, consistent with prior work, our results also indicate that these differences do not result in different readmission rates.²⁵ Regarding hospital teaching status, unlike prior work suggesting that teaching hospitals care for more safety-net Medicare beneficiaries,²⁶ our work found opposite patterns of postdischarge ED visitation between hospital teaching and safety-net status following pneumonia hospitalization. This may reflect differences in the organization of acute care as patients with limited access to unscheduled primary and specialty care in safety-net communities utilize the ED, whereas patients in teaching-hospital communities may be able to access hospital-based clinics for care.

Contrary to the expectations of many clinicians and policymakers, we found an inverse relationship between postdischarge ED visit rates and readmission rates. While the cross-sectional design of our study cannot provide a causal explanation, these findings merit policy attention and future exploration of several hypotheses. One possible explanation for this finding is that hospitals with high postdischarge ED visit rates provide care in communities in which acute, unscheduled care is consolidated to the ED setting and thereby permits the ED to serve a gatekeeper function for scarce inpatient resources. This hypothesis may also be supported by recent interventions demonstrating that the use of ED care coordination and geriatric ED services at higher-volume EDs can reduce hospitalizations. Also, hospitals with greater ED capacity may have easier ED access and may be able to see patients earlier in their disease courses post discharge or more frequently in the ED for follow-up, therefore increasing ED visits but avoiding rehospitalization. Another possible explanation is that hospitals with lower postdischarge ED visit rates may also have a lower propensity to admit patients. Because our definition of postdischarge ED visitation did not include ED visits that result in hospitalization, hospitals with a lower propensity to admit from the ED may therefore appear to have higher ED visit rates. This explanation may be further supported by our finding that many postdischarge ED visits are for conditions that are associated with discretionary hospitalization in the ED.²⁷ A third explanation for this finding may be that poor access to outpatient care outside the hospital setting results in higher postdischarge ED visit rates without increasing the acuity of these revisits or increasing readmission rates²⁸; however, given the validated, risk-standardized approach to readmission measurement, this is unlikely. This is also unlikely given recent work by Sabbatini et al.²³ demonstrating substantial acuity among patients who return to the ED following hospital discharge. Future work should seek to evaluate the relationship between the availability of ED care-coordination services and the specific ED, hospital, and community care-coordination activities undertaken in the ED following hospital discharge to reduce readmission rates.

This work should be interpreted within the confines of its design. First, it is possible that some of the variation detected in postdischarge ED visit rates is mediated by hospital-level variation in postdischarge observation visits that are not captured in this outcome. However, in previous work, we have demonstrated that almost one-third of hospitals have no postdischarge observation stays and that most postdischarge observation stays are for more than 24 hours, which is unlikely to reflect the intensity of care of postdischarge ED visits.²⁷ Second, our analyses were limited to Medicare FFS beneficiaries, which may limit the generalizability of this work to other patient populations. However, this dataset did include a national cohort of Medicare beneficiaries that is identical to those included in publicly reported CMS readmission measures; therefore, these results have substantial policy relevance. Third, this work was limited to 3 conditions of high illness severity of policy focus, and future work applying similar analyses to less severe conditions may find different degrees of hospital-level variation in postdischarge outcomes that are amenable to quality improvement. Finally, we assessed the rate of treat-and-discharge ED visits only after hospital discharge; this understates the frequency of ED visits since repeat ED visits and ED visits resulting in rehospitalization are not included. However, our definition was designed to mirror the definition used to assess hospital readmissions for policy purposes and is a conservative approach.

In summary, ED visits following hospital discharge are common, as Medicare beneficiaries have 1 treat-and-discharge ED visit for every 2 readmissions within 30 days of hospital discharge. Postdischarge ED visits occur for a wide variety of conditions, with wide risk-standardized, hospital-level variation. Hospitals with the highest risk-standardized postdischarge ED visitation rates demonstrated lower RSRRs, suggesting that policymakers and researchers should further examine the role of the hospital-based ED in providing access to acute care and supporting care transitions for the vulnerable Medicare population.

Disclosure

 Dr. Venkatesh received contract support from the CMS, an agency of the U.S. Department of Health & Human Services, and grant support from the Emergency Medicine Foundation’s Health Policy Research Scholar Award during the conduct of the study; and Dr. Wang, Mr. Wang, Ms. Altaf, Dr. Bernheim, and Dr. Horwitz received contract support from the CMS, an agency of the U.S. Department of Health & Human Services, during the conduct of the study.

Hospital readmissions for acute myocardial infarction (AMI), heart failure, and pneumonia have become central to quality-measurement efforts by the Centers for Medicare & Medicaid Services (CMS), which seek to improve hospital care transitions through public reporting and payment programs.¹ Most current measures are limited to readmissions that require inpatient hospitalization and do not capture return visits to the emergency department (ED) that do not result in readmission but rather ED discharge. These visits may reflect important needs for acute, unscheduled care during the vulnerable posthospitalization period.^2-5 While previous research has suggested that nearly 10% of patients may return to the ED following hospital discharge without readmission, the characteristics of these visits among Medicare beneficiaries and the implications for national care-coordination quality-measurement initiatives have not been explored.^6,7

As the locus of acute outpatient care and the primary portal of hospital admissions and readmissions, ED visits following hospital discharge may convey meaningful information about posthospitalization care transitions.^8,9 In addition, recent reviews and perspectives have highlighted the role of ED care-coordination services as interventions to reduce inpatient hospitalizations and improve care transitions,^10,11 yet no empirical studies have evaluated the relationship between these unique care-coordination opportunities in the ED and care-coordination outcomes, such as hospital readmissions. As policymakers seek to develop accountability measures that capture the totality of acute, unscheduled visits following hospital discharge, describing the relationship between ED visits and readmissions will be essential to providers for benchmarking and to policymakers and payers seeking to reduce the total cost of care.^12,13

Accordingly, we sought to characterize the frequency, diagnoses, and hospital-level variation in treat-and-discharge ED visitation following hospital discharge for 3 conditions for which hospital readmission is publicly reported by the CMS: AMI, heart failure, and pneumonia. We also sought to evaluate the relationship between hospital-level ED visitation following hospital discharge and publicly reported, risk-standardized readmission rates (RSRRs).

Study Design

This study was a cross-sectional analysis of Medicare beneficiaries discharged alive following hospitalization for AMI, heart failure, and pneumonia between July 2011 and June 2012.

Selection of Participants

We used Medicare Standard Analytic Files to identify inpatient hospitalizations for each disease cohort based on principal discharge diagnoses. Each condition-specific cohort was constructed to be consistent with the CMS’s readmission measures using International Classification of Diseases, 9th Revision-Clinical Modification codes to identify AMI, heart failure, and pneumonia discharges.¹ We included only patients who were enrolled in fee-for-service (FFS) Medicare parts A and B for 12 months prior to their index hospitalization to maximize the capture of diagnoses for risk adjustment. Each cohort included only patients who were discharged alive while maintaining FFS coverage for at least 30 days following hospital discharge to minimize bias in outcome ascertainment. We excluded patients who were discharged against medical advice. All contiguous admissions that were identified in a transfer chain were considered to be a single admission. Hospitals with fewer than 25 condition-specific index hospital admissions were excluded from this analysis for consistency with publicly reported measures.¹

Measurements

We measured postdischarge, treat-and release ED visits that occurred at any hospital within 30 days of hospital discharge from the index hospitalization. ED visits were identified as a hospital outpatient claim for ED services using hospital outpatient revenue center codes 0450, 0451, 0452, 0456, and 0981. This definition is consistent with those of previous studies.^3,14 We defined postdischarge ED visits as treat-and-discharge visits or visits that did not result in inpatient readmission or observation stays. Similar to readmission measures, only 1 postdischarge ED visit was counted toward the hospital-level outcome in patients with multiple ED visits within the 30 days following hospital discharge. We defined readmission as the first unplanned, inpatient hospitalization occurring at any hospital within the 30-day period following discharge. Any subsequent inpatient admission following the 30-day period was considered a distinct index admission if it met the inclusion criteria. Consistent with CMS methods, unplanned, inpatient readmissions are from any source and are not limited to patients who were first evaluated in the ED.

Outcomes

We describe hospital-level, postdischarge ED visitation as the risk-standardized postdischarge ED visit rate. The general construct of this measure is consistent with those of prior studies that define postdischarge ED visitation as the proportion of index admissions followed by a treat-and-discharge ED visit without hospital readmission^2,3; however, this outcome also incorporates a risk-standardization model with covariates that are identical to the risk-standardization approach that is used for readmission measurement.

We describe hospital-level readmission by calculating RSRRs consistent with CMS readmission measures, which are endorsed by the National Quality Forum and used for public reporting.^15-17 Detailed technical documentation, including the SAS code used to replicate hospital-level measures of readmission, are available publicly through the CMS QualityNet portal.¹⁸

We calculated risk-standardized postdischarge ED visit rates and RSRRs as the ratio of the predicted number of postdischarge ED visits or readmissions for a hospital given its observed case mix to the expected number of postdischarge ED visits or readmissions based on the nation’s performance with that hospital’s case mix, respectively. This approach estimates a distinct risk-standardized postdischarge ED visit rate and RSRR for each hospital using hierarchical generalized linear models (HGLMs) and using a logit link with a first-level adjustment for age, sex, 29 clinical covariates for AMI, 35 clinical covariates for heart failure, and 38 clinical covariates for pneumonia. Each clinical covariate is identified based on inpatient and outpatient claims during the 12 months prior to the index hospitalization. The second level of the HGLM includes a random hospital-level intercept. This approach to measuring hospital readmissions accounts for the correlated nature of observed readmission rates within a hospital and reflects the assumption that after adjustment for patient characteristics and sampling variability, the remaining variation in postdischarge ED visit rates or readmission rates reflects hospital quality.

Analysis

In order to characterize treat-and-discharge postdischarge ED visits, we first described the clinical conditions that were evaluated during the first postdischarge ED visit. Based on the principal discharge diagnosis, ED visits were grouped into clinically meaningful categories using the Agency for Healthcare Research and Quality Clinical Classifications Software (CCS).¹⁹ We also report hospital-level variation in risk-standardized postdischarge ED visit rates for AMI, heart failure, and pneumonia.

Next, we examined the relationship between hospital characteristics and risk-standardized postdischarge ED visit rates. We linked hospital characteristics from the American Hospital Association (AHA) Annual Survey to the study dataset, including the following: safety-net status, teaching status, and urban or rural status. Consistent with prior work, hospital safety-net status was defined as a hospital Medicaid caseload greater than 1 standard deviation above the mean Medicaid caseload in the hospital’s state. Approximately 94% of the hospitals included in the 3 condition cohorts in the dataset had complete data in the 2011 AHA Annual Survey to be included in this analysis.

We evaluated the relationship between postdischarge ED visit rates and hospital readmission rates in 2 ways. First, we calculated Spearman rank correlation coefficients between hospital-level, risk-standardized postdischarge ED visit rates and RSRRs. Second, we calculated hospital-level variation in RSRRs based on the strata of risk-standardized postdischarge ED visit rates. Given the normal distribution of postdischarge ED visit rates, we grouped hospitals by quartile of postdischarge ED visit rates and 1 group for hospitals with no postdischarge ED visits.

Based on preliminary analyses indicating a relationship between hospital size, measured by condition-specific index hospitalization volume, and postdischarge treat-and-discharge ED visit rates, all descriptive statistics and correlations reported are weighted by the volume of condition-specific index hospitalizations. The study was approved by the Yale University Human Research Protection Program. All analyses were conducted using SAS 9.1 (SAS Institute Inc, Cary, NC). The analytic plan and results reported in this work are in compliance with the Strengthening the Reporting of Observational Studies in Epidemiology checklist.²⁰

During the 1-year study period, we included a total of 157,035 patients who were hospitalized at 1656 hospitals for AMI, 391,209 at 3044 hospitals for heart failure, and 342,376 at 3484 hospitals for pneumonia. Details of study cohort creation are available in supplementary Table 1. After hospitalization for AMI, 14,714 patients experienced a postdischarge ED visit (8.4%) and 27,214 an inpatient readmissions (17.3%) within 30 days of discharge; 31,621 (7.6%) and 88,106 (22.5%) patients after hospitalization for heart failure and 26,681 (7.4%) and 59,352 (17.3%) patients after hospitalization for pneumonia experienced a postdischarge ED visit and an inpatient readmission within 30 days of discharge, respectively.

Postdischarge ED visits were for a wide variety of conditions, with the top 10 CCS categories comprising 44% of postdischarge ED visits following AMI hospitalizations, 44% of following heart failure hospitalizations, and 41% following pneumonia hospitalizations (supplementary Table 2). The first postdischarge ED visit was rarely for the same condition as the index hospitalization in the AMI cohort (224 visits; 1.5%) as well as the pneumonia cohort (1401 visits; 5.3%). Among patients who were originally admitted for heart failure, 10.6% of the first postdischarge ED visits were also for congestive heart failure. However, the first postdischarge ED visit was commonly for associated conditions, such as coronary artery disease in the case of AMI or chronic obstructive pulmonary disease in the case of pneumonia, albeit these related conditions did not comprise the majority of postdischarge ED visitation.

We found wide hospital-level variation in postdischarge ED visit rates for each condition: AMI (median: 8.3%; 5th and 95th percentile: 2.8%-14.3%), heart failure (median: 7.3%; 5th and 95th percentile: 3.0%-13.3%), and pneumonia (median: 7.1%; 5th and 95th percentile: 2.4%-13.2%; supplementary Table 3). The variation persisted after accounting for hospital case mix, as evidenced in the supplementary Figure, which describes hospital variation in risk-standardized postdischarge ED visit rates. This variation was statistically significant (P < .001), as demonstrated by the isolated relationship between the random effect and the outcome (AMI: random effect estimate 0.0849 [95% confidence interval (CI), 0.0832 to 0.0866]; heart failure: random effect estimate 0.0796 [95% CI, 0.0784 to 0.0809]; pneumonia: random effect estimate 0.0753 [95% CI, 0.0741 to 0.0764]).

Across all 3 conditions, hospitals located in rural areas had significantly higher risk-standardized postdischarge ED visit rates than hospitals located in urban areas (10.1% vs 8.6% for AMI, 8.4% vs 7.5% for heart failure, and 8.0% vs 7.4% for pneumonia). In comparison to teaching hospitals, nonteaching hospitals had significantly higher risk-standardized postdischarge ED visit rates following hospital discharge for pneumonia (7.6% vs 7.1%). Safety-net hospitals also had higher risk-standardized postdischarge ED visitation rates following discharge for heart failure (8.4% vs 7.7%) and pneumonia (7.7% vs 7.3%). Risk-standardized postdischarge ED visit rates were higher in publicly owned hospitals than in nonprofit or privately owned hospitals for heart failure (8.0% vs 7.5% in nonprofit hospitals or 7.5% in private hospitals) and pneumonia (7.7% vs 7.4% in nonprofit hospitals and 7.3% in private hospitals; Table).

Across a national cohort of Medicare beneficiaries, we found frequent treat-and-discharge ED utilization following hospital discharge for AMI, heart failure, and pneumonia, suggesting that publicly reported readmission measures are capturing only a portion of postdischarge acute-care use. Our findings confirm prior work describing a 30-day postdischarge ED visit rate of 8% to 9% among Medicare beneficiaries for all hospitalizations in several states.^3,6While many of the first postdischarge ED visits were for conditions related to the index hospitalization, the majority represent acute, unscheduled visits for different diagnoses. These findings are consistent with prior work studying inpatient readmissions and observation readmissions that find similar heterogeneity in the clinical reasons for hospital return.^21,22

We also described substantial hospital-level variation in risk-standardized ED postdischarge rates. Prior work by Vashi et al.³ demonstrated substantial variation in observed postdischarge ED visit rates and inpatient readmissions following hospital discharge between clinical conditions in a population-level study. Our work extends upon this by demonstrating hospital-level variation for 3 conditions of high volume and substantial policy importance after accounting for differences in hospital case mix. Interestingly, our work also found similar rates of postdischarge ED treat-and-discharge visitation as recent work by Sabbatini et al.²³ analyzing an all-payer, adult population with any clinical condition. Taken together, these studies show the substantial volume of postdischarge acute-care utilization in the ED not captured by existing readmission measures.

We found several hospital characteristics of importance in describing variation in postdischarge ED visitation rates. Notably, hospitals located in rural areas and safety-net hospitals demonstrated higher postdischarge ED visitation rates. This may reflect a higher use of the ED as an acute, unscheduled care access point in rural communities without access to alternative acute diagnostic and treatment services.²⁴ Similarly, safety-net hospitals may be more likely to provide unscheduled care for patients with poor access to primary care in the ED setting. Yet, consistent with prior work, our results also indicate that these differences do not result in different readmission rates.²⁵ Regarding hospital teaching status, unlike prior work suggesting that teaching hospitals care for more safety-net Medicare beneficiaries,²⁶ our work found opposite patterns of postdischarge ED visitation between hospital teaching and safety-net status following pneumonia hospitalization. This may reflect differences in the organization of acute care as patients with limited access to unscheduled primary and specialty care in safety-net communities utilize the ED, whereas patients in teaching-hospital communities may be able to access hospital-based clinics for care.

Contrary to the expectations of many clinicians and policymakers, we found an inverse relationship between postdischarge ED visit rates and readmission rates. While the cross-sectional design of our study cannot provide a causal explanation, these findings merit policy attention and future exploration of several hypotheses. One possible explanation for this finding is that hospitals with high postdischarge ED visit rates provide care in communities in which acute, unscheduled care is consolidated to the ED setting and thereby permits the ED to serve a gatekeeper function for scarce inpatient resources. This hypothesis may also be supported by recent interventions demonstrating that the use of ED care coordination and geriatric ED services at higher-volume EDs can reduce hospitalizations. Also, hospitals with greater ED capacity may have easier ED access and may be able to see patients earlier in their disease courses post discharge or more frequently in the ED for follow-up, therefore increasing ED visits but avoiding rehospitalization. Another possible explanation is that hospitals with lower postdischarge ED visit rates may also have a lower propensity to admit patients. Because our definition of postdischarge ED visitation did not include ED visits that result in hospitalization, hospitals with a lower propensity to admit from the ED may therefore appear to have higher ED visit rates. This explanation may be further supported by our finding that many postdischarge ED visits are for conditions that are associated with discretionary hospitalization in the ED.²⁷ A third explanation for this finding may be that poor access to outpatient care outside the hospital setting results in higher postdischarge ED visit rates without increasing the acuity of these revisits or increasing readmission rates²⁸; however, given the validated, risk-standardized approach to readmission measurement, this is unlikely. This is also unlikely given recent work by Sabbatini et al.²³ demonstrating substantial acuity among patients who return to the ED following hospital discharge. Future work should seek to evaluate the relationship between the availability of ED care-coordination services and the specific ED, hospital, and community care-coordination activities undertaken in the ED following hospital discharge to reduce readmission rates.

This work should be interpreted within the confines of its design. First, it is possible that some of the variation detected in postdischarge ED visit rates is mediated by hospital-level variation in postdischarge observation visits that are not captured in this outcome. However, in previous work, we have demonstrated that almost one-third of hospitals have no postdischarge observation stays and that most postdischarge observation stays are for more than 24 hours, which is unlikely to reflect the intensity of care of postdischarge ED visits.²⁷ Second, our analyses were limited to Medicare FFS beneficiaries, which may limit the generalizability of this work to other patient populations. However, this dataset did include a national cohort of Medicare beneficiaries that is identical to those included in publicly reported CMS readmission measures; therefore, these results have substantial policy relevance. Third, this work was limited to 3 conditions of high illness severity of policy focus, and future work applying similar analyses to less severe conditions may find different degrees of hospital-level variation in postdischarge outcomes that are amenable to quality improvement. Finally, we assessed the rate of treat-and-discharge ED visits only after hospital discharge; this understates the frequency of ED visits since repeat ED visits and ED visits resulting in rehospitalization are not included. However, our definition was designed to mirror the definition used to assess hospital readmissions for policy purposes and is a conservative approach.

In summary, ED visits following hospital discharge are common, as Medicare beneficiaries have 1 treat-and-discharge ED visit for every 2 readmissions within 30 days of hospital discharge. Postdischarge ED visits occur for a wide variety of conditions, with wide risk-standardized, hospital-level variation. Hospitals with the highest risk-standardized postdischarge ED visitation rates demonstrated lower RSRRs, suggesting that policymakers and researchers should further examine the role of the hospital-based ED in providing access to acute care and supporting care transitions for the vulnerable Medicare population.

Disclosure

 Dr. Venkatesh received contract support from the CMS, an agency of the U.S. Department of Health & Human Services, and grant support from the Emergency Medicine Foundation’s Health Policy Research Scholar Award during the conduct of the study; and Dr. Wang, Mr. Wang, Ms. Altaf, Dr. Bernheim, and Dr. Horwitz received contract support from the CMS, an agency of the U.S. Department of Health & Human Services, during the conduct of the study.