I’m guilty. I feel a sense of entitlement, as many of us do. I have always had access to the best health care available. Even as a child, whenever I had a runny nose, my parents not only knew what to do but could afford whatever it took to make me feel better. And vaccine-preventable illnesses? They didn’t stand a chance at my house. I remember the day when I was a little girl and my father, a general practitioner, figured out my plan to wait him out as he stood patiently outside the bathroom door, vaccine in hand. He eventually got tired of waiting, barged in, oblivious to the fact that I was sitting on the potty (twiddling my fingers), and shot me right in arm. The nerve!

Many of us have no concept of what it is like to be ill. I mean really ill with no one to help, and no way to pay for that help even if we could find it. In the March 6, 2014, issue of the New England Journal of Medicine, authors of "Global Supply of Health Professionals" note that there’s a worldwide crisis of severe shortages, as well as maldistribution of health care professionals intensified by three global transitions: redistribution of the disability burden, demographic changes, and epidemiologic shifts. An estimated 25% of physicians in America come from other countries. Naturally, in some cases the countries of origin have their own health care challenges, so the trend to immigrate to America has significant potential to exacerbate an already critical shortage.

© Matthew Benoit/Fotolia.com

Of the estimated 9.2 million doctors worldwide, 8% reside in the United States. Of the 18.1 million nurses, 17% are in here. To put it in perspective, only 4% of the world’s population lives in the United States, yet we command a lion’s share of the global health care workforce, leaving the citizens of many other countries vulnerable to excessive suffering, premature death, and preventable diseases.

With all that America has to offer, I don’t see the pendulum shifting back in the other direction any time soon, but many of us are in a position to provide much needed health care to our brothers and sisters in even the most remote areas of the world.

As squeamish as I am about charting unknown territory, even I went on a medical missions trip to Nicaragua a few years ago and I will never forget it. We had to climb up the side of a mountain to get to a clearing that would hold the makeshift medical clinic. Of course, the locals came out in large numbers to receive much-needed medical care.

On the way back to the hotel I noticed some little boys tossing an object back and forth in the street. It seemed like pleasant fun until we got closer and I saw the object they were tossing was a dead rat. Even what we consider an inexpensive child’s toy is a luxury for many. If you consider salary and benefits, we hospitalists make more, on average, in a single shift than many Nicaraguans make in an entire year.

Every physician should spend some time caring for the poorest of the poor, whether it be in a needy foreign country, Appalachia or rural America, or in the inner city, often just 30 minutes from our homes.

Surely it will help or change the patient’s life. But, too, it just might change your perspective, forever, and renew your passion for what we do – help others.

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a patient-engagement app for iOS.

I’m guilty. I feel a sense of entitlement, as many of us do. I have always had access to the best health care available. Even as a child, whenever I had a runny nose, my parents not only knew what to do but could afford whatever it took to make me feel better. And vaccine-preventable illnesses? They didn’t stand a chance at my house. I remember the day when I was a little girl and my father, a general practitioner, figured out my plan to wait him out as he stood patiently outside the bathroom door, vaccine in hand. He eventually got tired of waiting, barged in, oblivious to the fact that I was sitting on the potty (twiddling my fingers), and shot me right in arm. The nerve!

Many of us have no concept of what it is like to be ill. I mean really ill with no one to help, and no way to pay for that help even if we could find it. In the March 6, 2014, issue of the New England Journal of Medicine, authors of "Global Supply of Health Professionals" note that there’s a worldwide crisis of severe shortages, as well as maldistribution of health care professionals intensified by three global transitions: redistribution of the disability burden, demographic changes, and epidemiologic shifts. An estimated 25% of physicians in America come from other countries. Naturally, in some cases the countries of origin have their own health care challenges, so the trend to immigrate to America has significant potential to exacerbate an already critical shortage.

© Matthew Benoit/Fotolia.com

Of the estimated 9.2 million doctors worldwide, 8% reside in the United States. Of the 18.1 million nurses, 17% are in here. To put it in perspective, only 4% of the world’s population lives in the United States, yet we command a lion’s share of the global health care workforce, leaving the citizens of many other countries vulnerable to excessive suffering, premature death, and preventable diseases.

With all that America has to offer, I don’t see the pendulum shifting back in the other direction any time soon, but many of us are in a position to provide much needed health care to our brothers and sisters in even the most remote areas of the world.

As squeamish as I am about charting unknown territory, even I went on a medical missions trip to Nicaragua a few years ago and I will never forget it. We had to climb up the side of a mountain to get to a clearing that would hold the makeshift medical clinic. Of course, the locals came out in large numbers to receive much-needed medical care.

On the way back to the hotel I noticed some little boys tossing an object back and forth in the street. It seemed like pleasant fun until we got closer and I saw the object they were tossing was a dead rat. Even what we consider an inexpensive child’s toy is a luxury for many. If you consider salary and benefits, we hospitalists make more, on average, in a single shift than many Nicaraguans make in an entire year.

Every physician should spend some time caring for the poorest of the poor, whether it be in a needy foreign country, Appalachia or rural America, or in the inner city, often just 30 minutes from our homes.

Surely it will help or change the patient’s life. But, too, it just might change your perspective, forever, and renew your passion for what we do – help others.

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a patient-engagement app for iOS.

I’m guilty. I feel a sense of entitlement, as many of us do. I have always had access to the best health care available. Even as a child, whenever I had a runny nose, my parents not only knew what to do but could afford whatever it took to make me feel better. And vaccine-preventable illnesses? They didn’t stand a chance at my house. I remember the day when I was a little girl and my father, a general practitioner, figured out my plan to wait him out as he stood patiently outside the bathroom door, vaccine in hand. He eventually got tired of waiting, barged in, oblivious to the fact that I was sitting on the potty (twiddling my fingers), and shot me right in arm. The nerve!

Many of us have no concept of what it is like to be ill. I mean really ill with no one to help, and no way to pay for that help even if we could find it. In the March 6, 2014, issue of the New England Journal of Medicine, authors of "Global Supply of Health Professionals" note that there’s a worldwide crisis of severe shortages, as well as maldistribution of health care professionals intensified by three global transitions: redistribution of the disability burden, demographic changes, and epidemiologic shifts. An estimated 25% of physicians in America come from other countries. Naturally, in some cases the countries of origin have their own health care challenges, so the trend to immigrate to America has significant potential to exacerbate an already critical shortage.

© Matthew Benoit/Fotolia.com

Of the estimated 9.2 million doctors worldwide, 8% reside in the United States. Of the 18.1 million nurses, 17% are in here. To put it in perspective, only 4% of the world’s population lives in the United States, yet we command a lion’s share of the global health care workforce, leaving the citizens of many other countries vulnerable to excessive suffering, premature death, and preventable diseases.

With all that America has to offer, I don’t see the pendulum shifting back in the other direction any time soon, but many of us are in a position to provide much needed health care to our brothers and sisters in even the most remote areas of the world.

As squeamish as I am about charting unknown territory, even I went on a medical missions trip to Nicaragua a few years ago and I will never forget it. We had to climb up the side of a mountain to get to a clearing that would hold the makeshift medical clinic. Of course, the locals came out in large numbers to receive much-needed medical care.

On the way back to the hotel I noticed some little boys tossing an object back and forth in the street. It seemed like pleasant fun until we got closer and I saw the object they were tossing was a dead rat. Even what we consider an inexpensive child’s toy is a luxury for many. If you consider salary and benefits, we hospitalists make more, on average, in a single shift than many Nicaraguans make in an entire year.

Every physician should spend some time caring for the poorest of the poor, whether it be in a needy foreign country, Appalachia or rural America, or in the inner city, often just 30 minutes from our homes.

Surely it will help or change the patient’s life. But, too, it just might change your perspective, forever, and renew your passion for what we do – help others.

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a patient-engagement app for iOS.

MILAN – The combination of doxorubicin and ifosfamide is the best treatment for most patients with a sarcoma that does not have a proven targeted therapy, although a recent report from a large randomized study failed to prove that the combination surpassed doxorubicin alone for improving overall survival, said Dr. Robert S. Benjamin.

"From my point of view, this was clearly a positive study, but it was interpreted as a negative study" by the investigators who ran it, Dr. Benjamin said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

Among patients who received doxorubicin (Adriamycin) plus ifosfamide (Ifex), compared with those randomized to doxorubicin only, "the incidence of progressive disease was cut by more than half, the objective response rate was twice as high, and the time to progression was increased by more than 50%. Overall survival was also better" but did not reach statistical significance. "It was supposed to be 10% better for overall survival [based on the study’s design], but it was only 9% better and they considered that the same as zero," noted Dr. Benjamin, professor and chairman of sarcoma medical oncology at the University of Texas M.D. Anderson Cancer Center, Houston.

"Overall survival is a lousy endpoint," he said. "It measures everything that happens when you treat, but also everything that happens after" treatment is finished. Dr. Benjamin said his center was invited by the organizers of this phase III trial to participate, but he declined because the trial used overall survival as its primary endpoint.

The trial enrolled 455 patients with a locally-advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, aged 18-60 years at 38 centers in nine European countries and Canada. It included patients with more than 10 different sarcoma types including liposarcomas, synovial sarcomas, leiomyosarcomas, undifferentiated pleomorphic sarcomas, and unclassified high-grade sarcomas. The study randomized patients to either doxorubicin alone or intensified doxorubicin plus ifosfamide as first-line treatment. Patients were treated every 3 weeks for up to six cycles and were followed for a median of 56-59 months (Lancet Oncol. 2014 [doi:10.1016/S1470-2045(14)70063-4]).

The study’s primary endpoint, overall survival, averaged 12.8 months in the monotherapy arm and 14.3 months in the dual-agent arm, a hazard ratio of 0.83 that failed to meet statistical significance (P =.076), reported Dr. Ian Judson, professor and head of the sarcoma unit at the Royal Marsden Hospital in London, and his associates. However, median progression-free survival was 4.6 months in the doxorubicin-only arm and 7.4 months for the combined-treatment arm, a statistically significant difference (P = .003). Progressive disease occurred in 32% of the patients on monotherapy and in 13% of those on combined treatment.

The study’s authors concluded that if chemotherapy is used palliatively to relieve acute symptoms, then sequential treatment with single drugs would probably be less toxic without significantly impairing survival. For patients in whom symptoms could be relieved by tumor shrinkage, or if debulking of the tumor before surgery or radiotherapy is the goal, or if delaying disease progression as long as possible is the goal, then combination treatment is justified. They also cautioned against extrapolating the findings to patients older than 60 years, a limitation seconded by Dr. Benjamin. He cautioned against administering the combination to any patient older than 65 years or to patients with substantially impaired renal function.

But he disagreed with using doxorubicin as monotherapy unless tolerance was an issue. "Doxorubicin is a very good drug; it just shouldn’t be used by itself," he said.

Dr. Benjamin offered a few tips for using the doxorubicin and ifosfamide combination in practice: It’s important to use doxorubicin at the recommended dosage of 75 mg/m². If a patient cannot tolerate that dosage in combination with ifosfamide then the best option is to change to doxorubicin monotherapy to be sure the patient receives 75 mg/m². He recommended starting patients first on the doxorubicin and ifosfamide combination because it is the most toxic, with a less toxic pairing like gemcitabine (Gemzar) and docetaxel (Dosefirez) as second-line therapy because it’s harder for patients to switch to a more toxic regimen, he said. Dacarbazine also can pair effectively with doxorubicin. This combination is "almost as good as doxorubicin plus ifosfamide and is less toxic." He also noted the efficacy of trabectedin (Yondelis), which is available in European countries but not in the United States.

"These drugs all work, and the patient will need everything you have. You need to put it all together," Dr. Benjamin advised. "All the chemotherapy we currently have is grossly inadequate, but given what we have, use doxorubicin and ifosfamide for most patients with soft tissue sarcomas."

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

MILAN – The combination of doxorubicin and ifosfamide is the best treatment for most patients with a sarcoma that does not have a proven targeted therapy, although a recent report from a large randomized study failed to prove that the combination surpassed doxorubicin alone for improving overall survival, said Dr. Robert S. Benjamin.

"From my point of view, this was clearly a positive study, but it was interpreted as a negative study" by the investigators who ran it, Dr. Benjamin said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

Among patients who received doxorubicin (Adriamycin) plus ifosfamide (Ifex), compared with those randomized to doxorubicin only, "the incidence of progressive disease was cut by more than half, the objective response rate was twice as high, and the time to progression was increased by more than 50%. Overall survival was also better" but did not reach statistical significance. "It was supposed to be 10% better for overall survival [based on the study’s design], but it was only 9% better and they considered that the same as zero," noted Dr. Benjamin, professor and chairman of sarcoma medical oncology at the University of Texas M.D. Anderson Cancer Center, Houston.

"Overall survival is a lousy endpoint," he said. "It measures everything that happens when you treat, but also everything that happens after" treatment is finished. Dr. Benjamin said his center was invited by the organizers of this phase III trial to participate, but he declined because the trial used overall survival as its primary endpoint.

The trial enrolled 455 patients with a locally-advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, aged 18-60 years at 38 centers in nine European countries and Canada. It included patients with more than 10 different sarcoma types including liposarcomas, synovial sarcomas, leiomyosarcomas, undifferentiated pleomorphic sarcomas, and unclassified high-grade sarcomas. The study randomized patients to either doxorubicin alone or intensified doxorubicin plus ifosfamide as first-line treatment. Patients were treated every 3 weeks for up to six cycles and were followed for a median of 56-59 months (Lancet Oncol. 2014 [doi:10.1016/S1470-2045(14)70063-4]).

The study’s primary endpoint, overall survival, averaged 12.8 months in the monotherapy arm and 14.3 months in the dual-agent arm, a hazard ratio of 0.83 that failed to meet statistical significance (P =.076), reported Dr. Ian Judson, professor and head of the sarcoma unit at the Royal Marsden Hospital in London, and his associates. However, median progression-free survival was 4.6 months in the doxorubicin-only arm and 7.4 months for the combined-treatment arm, a statistically significant difference (P = .003). Progressive disease occurred in 32% of the patients on monotherapy and in 13% of those on combined treatment.

The study’s authors concluded that if chemotherapy is used palliatively to relieve acute symptoms, then sequential treatment with single drugs would probably be less toxic without significantly impairing survival. For patients in whom symptoms could be relieved by tumor shrinkage, or if debulking of the tumor before surgery or radiotherapy is the goal, or if delaying disease progression as long as possible is the goal, then combination treatment is justified. They also cautioned against extrapolating the findings to patients older than 60 years, a limitation seconded by Dr. Benjamin. He cautioned against administering the combination to any patient older than 65 years or to patients with substantially impaired renal function.

But he disagreed with using doxorubicin as monotherapy unless tolerance was an issue. "Doxorubicin is a very good drug; it just shouldn’t be used by itself," he said.

Dr. Benjamin offered a few tips for using the doxorubicin and ifosfamide combination in practice: It’s important to use doxorubicin at the recommended dosage of 75 mg/m². If a patient cannot tolerate that dosage in combination with ifosfamide then the best option is to change to doxorubicin monotherapy to be sure the patient receives 75 mg/m². He recommended starting patients first on the doxorubicin and ifosfamide combination because it is the most toxic, with a less toxic pairing like gemcitabine (Gemzar) and docetaxel (Dosefirez) as second-line therapy because it’s harder for patients to switch to a more toxic regimen, he said. Dacarbazine also can pair effectively with doxorubicin. This combination is "almost as good as doxorubicin plus ifosfamide and is less toxic." He also noted the efficacy of trabectedin (Yondelis), which is available in European countries but not in the United States.

"These drugs all work, and the patient will need everything you have. You need to put it all together," Dr. Benjamin advised. "All the chemotherapy we currently have is grossly inadequate, but given what we have, use doxorubicin and ifosfamide for most patients with soft tissue sarcomas."

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

MILAN – The combination of doxorubicin and ifosfamide is the best treatment for most patients with a sarcoma that does not have a proven targeted therapy, although a recent report from a large randomized study failed to prove that the combination surpassed doxorubicin alone for improving overall survival, said Dr. Robert S. Benjamin.

"From my point of view, this was clearly a positive study, but it was interpreted as a negative study" by the investigators who ran it, Dr. Benjamin said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

Among patients who received doxorubicin (Adriamycin) plus ifosfamide (Ifex), compared with those randomized to doxorubicin only, "the incidence of progressive disease was cut by more than half, the objective response rate was twice as high, and the time to progression was increased by more than 50%. Overall survival was also better" but did not reach statistical significance. "It was supposed to be 10% better for overall survival [based on the study’s design], but it was only 9% better and they considered that the same as zero," noted Dr. Benjamin, professor and chairman of sarcoma medical oncology at the University of Texas M.D. Anderson Cancer Center, Houston.

"Overall survival is a lousy endpoint," he said. "It measures everything that happens when you treat, but also everything that happens after" treatment is finished. Dr. Benjamin said his center was invited by the organizers of this phase III trial to participate, but he declined because the trial used overall survival as its primary endpoint.

The trial enrolled 455 patients with a locally-advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, aged 18-60 years at 38 centers in nine European countries and Canada. It included patients with more than 10 different sarcoma types including liposarcomas, synovial sarcomas, leiomyosarcomas, undifferentiated pleomorphic sarcomas, and unclassified high-grade sarcomas. The study randomized patients to either doxorubicin alone or intensified doxorubicin plus ifosfamide as first-line treatment. Patients were treated every 3 weeks for up to six cycles and were followed for a median of 56-59 months (Lancet Oncol. 2014 [doi:10.1016/S1470-2045(14)70063-4]).

The study’s primary endpoint, overall survival, averaged 12.8 months in the monotherapy arm and 14.3 months in the dual-agent arm, a hazard ratio of 0.83 that failed to meet statistical significance (P =.076), reported Dr. Ian Judson, professor and head of the sarcoma unit at the Royal Marsden Hospital in London, and his associates. However, median progression-free survival was 4.6 months in the doxorubicin-only arm and 7.4 months for the combined-treatment arm, a statistically significant difference (P = .003). Progressive disease occurred in 32% of the patients on monotherapy and in 13% of those on combined treatment.

The study’s authors concluded that if chemotherapy is used palliatively to relieve acute symptoms, then sequential treatment with single drugs would probably be less toxic without significantly impairing survival. For patients in whom symptoms could be relieved by tumor shrinkage, or if debulking of the tumor before surgery or radiotherapy is the goal, or if delaying disease progression as long as possible is the goal, then combination treatment is justified. They also cautioned against extrapolating the findings to patients older than 60 years, a limitation seconded by Dr. Benjamin. He cautioned against administering the combination to any patient older than 65 years or to patients with substantially impaired renal function.

But he disagreed with using doxorubicin as monotherapy unless tolerance was an issue. "Doxorubicin is a very good drug; it just shouldn’t be used by itself," he said.

Dr. Benjamin offered a few tips for using the doxorubicin and ifosfamide combination in practice: It’s important to use doxorubicin at the recommended dosage of 75 mg/m². If a patient cannot tolerate that dosage in combination with ifosfamide then the best option is to change to doxorubicin monotherapy to be sure the patient receives 75 mg/m². He recommended starting patients first on the doxorubicin and ifosfamide combination because it is the most toxic, with a less toxic pairing like gemcitabine (Gemzar) and docetaxel (Dosefirez) as second-line therapy because it’s harder for patients to switch to a more toxic regimen, he said. Dacarbazine also can pair effectively with doxorubicin. This combination is "almost as good as doxorubicin plus ifosfamide and is less toxic." He also noted the efficacy of trabectedin (Yondelis), which is available in European countries but not in the United States.

"These drugs all work, and the patient will need everything you have. You need to put it all together," Dr. Benjamin advised. "All the chemotherapy we currently have is grossly inadequate, but given what we have, use doxorubicin and ifosfamide for most patients with soft tissue sarcomas."

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The US Food and Drug Administration (FDA) has issued a full clinical hold for the telomerase inhibitor imetelstat, citing concerns that long-term exposure to the drug may pose a risk of chronic liver injury.

The hold temporarily suspends all ongoing clinical trials of imetelstat sponsored by the drug’s maker, Geron Corporation.

It’s possible that other studies of imetelstat, such as ongoing investigator-sponsored trials, may be placed on hold as well.

At present, the hold affects the remaining 8 patients enrolled on Geron’s phase 2 study of imetelstat in essential thrombocythemia and polycythemia vera.

It also affects the remaining 2 patients in the company’s phase 2 study of the drug in previously treated multiple myeloma. And Geron believes its planned phase 2 trial of imetelstat in myelofibrosis will likely be delayed as well.

The FDA has not yet issued a written notice of the hold but has given Geron verbal notice.

The agency indicated that the hold is due to persistent low-grade liver function test abnormalities observed in the study of imetelstat in patients with essential thrombocythemia or polycythemia vera and the potential risk of chronic liver injury following long-term exposure to imetelstat.

The FDA expressed concerns about whether these abnormalities are reversible. Geron said it plans to work with the FDA to put an end to the hold.

The US Food and Drug Administration (FDA) has issued a full clinical hold for the telomerase inhibitor imetelstat, citing concerns that long-term exposure to the drug may pose a risk of chronic liver injury.

The hold temporarily suspends all ongoing clinical trials of imetelstat sponsored by the drug’s maker, Geron Corporation.

It’s possible that other studies of imetelstat, such as ongoing investigator-sponsored trials, may be placed on hold as well.

At present, the hold affects the remaining 8 patients enrolled on Geron’s phase 2 study of imetelstat in essential thrombocythemia and polycythemia vera.

It also affects the remaining 2 patients in the company’s phase 2 study of the drug in previously treated multiple myeloma. And Geron believes its planned phase 2 trial of imetelstat in myelofibrosis will likely be delayed as well.

The FDA has not yet issued a written notice of the hold but has given Geron verbal notice.

The agency indicated that the hold is due to persistent low-grade liver function test abnormalities observed in the study of imetelstat in patients with essential thrombocythemia or polycythemia vera and the potential risk of chronic liver injury following long-term exposure to imetelstat.

The FDA expressed concerns about whether these abnormalities are reversible. Geron said it plans to work with the FDA to put an end to the hold.

The US Food and Drug Administration (FDA) has issued a full clinical hold for the telomerase inhibitor imetelstat, citing concerns that long-term exposure to the drug may pose a risk of chronic liver injury.

The hold temporarily suspends all ongoing clinical trials of imetelstat sponsored by the drug’s maker, Geron Corporation.

It’s possible that other studies of imetelstat, such as ongoing investigator-sponsored trials, may be placed on hold as well.

At present, the hold affects the remaining 8 patients enrolled on Geron’s phase 2 study of imetelstat in essential thrombocythemia and polycythemia vera.

It also affects the remaining 2 patients in the company’s phase 2 study of the drug in previously treated multiple myeloma. And Geron believes its planned phase 2 trial of imetelstat in myelofibrosis will likely be delayed as well.

The FDA has not yet issued a written notice of the hold but has given Geron verbal notice.

The agency indicated that the hold is due to persistent low-grade liver function test abnormalities observed in the study of imetelstat in patients with essential thrombocythemia or polycythemia vera and the potential risk of chronic liver injury following long-term exposure to imetelstat.

The FDA expressed concerns about whether these abnormalities are reversible. Geron said it plans to work with the FDA to put an end to the hold.

Leukemia patient

Credit: Bill Branson

The stress and lifestyle changes mothers experience after a child’s leukemia diagnosis do not disappear once the disease is in the maintenance phase, new research suggests.

One study showed that mothers of patients with acute lymphoblastic leukemia (ALL) continued to exhibit signs of stress, anxiety, and depression when their child’s disease was in the maintenance phase.

And another study showed that a family’s daily schedule and sleeping arrangements did not return to the way they were before the child’s diagnosis.

“Even though these mothers were in the maintenance phase of their child’s illness, and the prognosis was good, we heard them say over and over that things could never go back to what they were before,” said study author Madalynn Neu, PhD, RN, of the Colorado University College of Nursing.

Stress, depression, and anxiety

In the Journal of Pediatric Oncology Nursing, Dr Neu and her colleagues reported their analysis of stress, anxiety, and depression among the mothers of patients with ALL. The team evaluated 26 mothers of ALL patients and 26 mothers of healthy children, who were matched according to the child’s age and gender.

To assess anxiety, the researchers collected salivary cortisol from the mothers 4 times a day for 3 consecutive days. The mothers also completed questionnaires—the Hospital Anxiety and Depression Scale and the Perceived Stress Scale.

More mothers in the ALL group had questionnaire scores indicating clinical anxiety (46%) and depressive symptoms (27%). And there was a trend toward increased stress in the mothers of ALL patients.

However, the researchers were surprised to find that the mothers’ anxiety levels—as measured by salivary cortisol—were similar to the mothers of well children.

“This may have been affected by the fact that even the control group wasn’t without anxiety,” said study author Ellen Matthews, PhD, RN, of the Colorado University College of Nursing.

“Financial, marital, social, and career concerns mean that parents of young children experience anxiety even without ALL.”

The sleep-wake experience

In the Journal of Pediatric Nursing, the researchers described their assessment of the sleep-wake experience for mothers of ALL patients. The team conducted interviews with 20 mothers, using open-ended, semi-structured questions, and the answers were transcribed verbatim.

Two main themes emerged during these interviews. The first was dubbed, “It’s a whole new cancer world” and contained 4 subthemes: losing normality, being off-balance/insecure, juggling duties, and making transitions.

“Many [of the mothers] had lost their normal lives—lost jobs, houses, friends,” Dr Matthews said. “Some were juggling their time around their child’s needs, and they had fears about many things—fear of recurrence, fear of making a mistake with medication, fear their kids might get sick with an infection.”

The second theme that emerged in interviews was, “I don’t remember what it’s like to have sleep.” This also contained 4 subthemes: sleeping trouble before and after ALL, the child feeling sick at night, worrying, and coping with exhaustion.

The mothers also noted that once sleep arrangements had changed, they often did not return to their pretreatment “normal.”

“Mothers talked about the difficulty of sleep while giving steroid medication,” Dr Neu said. “And if the ill child got to stay up late watching movies, the siblings wanted to stay up too.”

“The same was true of sleeping in a parent’s room. If an ill child wanted to sleep close to a parent (or if a parent wanted to sleep close to an ill child), siblings tended to move in as well. Sleep can be challenging for parents of well children, and our studies show it’s even more so for parents of children who have experienced ALL.”

The researchers hope these studies increase awareness of maternal concerns after a child’s leukemia diagnosis and that leads to interventions to help mothers manage these lifestyle issues.

Leukemia patient

Credit: Bill Branson

The stress and lifestyle changes mothers experience after a child’s leukemia diagnosis do not disappear once the disease is in the maintenance phase, new research suggests.

One study showed that mothers of patients with acute lymphoblastic leukemia (ALL) continued to exhibit signs of stress, anxiety, and depression when their child’s disease was in the maintenance phase.

And another study showed that a family’s daily schedule and sleeping arrangements did not return to the way they were before the child’s diagnosis.

“Even though these mothers were in the maintenance phase of their child’s illness, and the prognosis was good, we heard them say over and over that things could never go back to what they were before,” said study author Madalynn Neu, PhD, RN, of the Colorado University College of Nursing.

Stress, depression, and anxiety

In the Journal of Pediatric Oncology Nursing, Dr Neu and her colleagues reported their analysis of stress, anxiety, and depression among the mothers of patients with ALL. The team evaluated 26 mothers of ALL patients and 26 mothers of healthy children, who were matched according to the child’s age and gender.

To assess anxiety, the researchers collected salivary cortisol from the mothers 4 times a day for 3 consecutive days. The mothers also completed questionnaires—the Hospital Anxiety and Depression Scale and the Perceived Stress Scale.

More mothers in the ALL group had questionnaire scores indicating clinical anxiety (46%) and depressive symptoms (27%). And there was a trend toward increased stress in the mothers of ALL patients.

However, the researchers were surprised to find that the mothers’ anxiety levels—as measured by salivary cortisol—were similar to the mothers of well children.

“This may have been affected by the fact that even the control group wasn’t without anxiety,” said study author Ellen Matthews, PhD, RN, of the Colorado University College of Nursing.

“Financial, marital, social, and career concerns mean that parents of young children experience anxiety even without ALL.”

The sleep-wake experience

In the Journal of Pediatric Nursing, the researchers described their assessment of the sleep-wake experience for mothers of ALL patients. The team conducted interviews with 20 mothers, using open-ended, semi-structured questions, and the answers were transcribed verbatim.

Two main themes emerged during these interviews. The first was dubbed, “It’s a whole new cancer world” and contained 4 subthemes: losing normality, being off-balance/insecure, juggling duties, and making transitions.

“Many [of the mothers] had lost their normal lives—lost jobs, houses, friends,” Dr Matthews said. “Some were juggling their time around their child’s needs, and they had fears about many things—fear of recurrence, fear of making a mistake with medication, fear their kids might get sick with an infection.”

The second theme that emerged in interviews was, “I don’t remember what it’s like to have sleep.” This also contained 4 subthemes: sleeping trouble before and after ALL, the child feeling sick at night, worrying, and coping with exhaustion.

The mothers also noted that once sleep arrangements had changed, they often did not return to their pretreatment “normal.”

“Mothers talked about the difficulty of sleep while giving steroid medication,” Dr Neu said. “And if the ill child got to stay up late watching movies, the siblings wanted to stay up too.”

“The same was true of sleeping in a parent’s room. If an ill child wanted to sleep close to a parent (or if a parent wanted to sleep close to an ill child), siblings tended to move in as well. Sleep can be challenging for parents of well children, and our studies show it’s even more so for parents of children who have experienced ALL.”

The researchers hope these studies increase awareness of maternal concerns after a child’s leukemia diagnosis and that leads to interventions to help mothers manage these lifestyle issues.

Leukemia patient

Credit: Bill Branson

The stress and lifestyle changes mothers experience after a child’s leukemia diagnosis do not disappear once the disease is in the maintenance phase, new research suggests.

One study showed that mothers of patients with acute lymphoblastic leukemia (ALL) continued to exhibit signs of stress, anxiety, and depression when their child’s disease was in the maintenance phase.

And another study showed that a family’s daily schedule and sleeping arrangements did not return to the way they were before the child’s diagnosis.

“Even though these mothers were in the maintenance phase of their child’s illness, and the prognosis was good, we heard them say over and over that things could never go back to what they were before,” said study author Madalynn Neu, PhD, RN, of the Colorado University College of Nursing.

Stress, depression, and anxiety

In the Journal of Pediatric Oncology Nursing, Dr Neu and her colleagues reported their analysis of stress, anxiety, and depression among the mothers of patients with ALL. The team evaluated 26 mothers of ALL patients and 26 mothers of healthy children, who were matched according to the child’s age and gender.

To assess anxiety, the researchers collected salivary cortisol from the mothers 4 times a day for 3 consecutive days. The mothers also completed questionnaires—the Hospital Anxiety and Depression Scale and the Perceived Stress Scale.

More mothers in the ALL group had questionnaire scores indicating clinical anxiety (46%) and depressive symptoms (27%). And there was a trend toward increased stress in the mothers of ALL patients.

However, the researchers were surprised to find that the mothers’ anxiety levels—as measured by salivary cortisol—were similar to the mothers of well children.

“This may have been affected by the fact that even the control group wasn’t without anxiety,” said study author Ellen Matthews, PhD, RN, of the Colorado University College of Nursing.

“Financial, marital, social, and career concerns mean that parents of young children experience anxiety even without ALL.”

The sleep-wake experience

In the Journal of Pediatric Nursing, the researchers described their assessment of the sleep-wake experience for mothers of ALL patients. The team conducted interviews with 20 mothers, using open-ended, semi-structured questions, and the answers were transcribed verbatim.

Two main themes emerged during these interviews. The first was dubbed, “It’s a whole new cancer world” and contained 4 subthemes: losing normality, being off-balance/insecure, juggling duties, and making transitions.

“Many [of the mothers] had lost their normal lives—lost jobs, houses, friends,” Dr Matthews said. “Some were juggling their time around their child’s needs, and they had fears about many things—fear of recurrence, fear of making a mistake with medication, fear their kids might get sick with an infection.”

The second theme that emerged in interviews was, “I don’t remember what it’s like to have sleep.” This also contained 4 subthemes: sleeping trouble before and after ALL, the child feeling sick at night, worrying, and coping with exhaustion.

The mothers also noted that once sleep arrangements had changed, they often did not return to their pretreatment “normal.”

“Mothers talked about the difficulty of sleep while giving steroid medication,” Dr Neu said. “And if the ill child got to stay up late watching movies, the siblings wanted to stay up too.”

“The same was true of sleeping in a parent’s room. If an ill child wanted to sleep close to a parent (or if a parent wanted to sleep close to an ill child), siblings tended to move in as well. Sleep can be challenging for parents of well children, and our studies show it’s even more so for parents of children who have experienced ALL.”

The researchers hope these studies increase awareness of maternal concerns after a child’s leukemia diagnosis and that leads to interventions to help mothers manage these lifestyle issues.

Researcher in the lab

Credit: Rhoda Baer

Mutations in the gene PTPN1 may drive the development of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL), according to a study published in Nature Genetics.

Whole-genome and whole-transcriptome sequencing revealed recurrent PTPN1 mutations in samples and cell lines of HL and PMBCL.

And experiments suggested the mutations contribute to lymphomagenesis by activating JAK-STAT signaling pathways.

“Our work identifies, for the first time, the entirety of genetic mutations in primary mediastinal B-cell lymphoma and first-of-its kind-mutations in the PTPN1 gene,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver.

To discover these mutations, Dr Steidl and his colleagues sequenced samples from 77 PMBCL patients and 3 PMBCL-derived cell lines. The team found mutations in 2 negative regulators of the JAK-STAT signaling pathway—SOCS1 and PTPN1.

As SOCS1 is already well-characterized, the researchers decided to focus on PTPN1. They identified PTPN1 mutations in 22% (17/77) of PMBCL cases and 33% (1/3) of the PMBCL-derived cell lines.

Because classical HL is closely related to PMBCL, the investigators also screened 30 samples from HL patients and 9 HL-derived cell lines. PTPN1 mutations were present in 20% (6/30) of the samples and 67% (6/9) of the cell lines.

In all, the team identified 18 (60%) missense mutations, 4 (13.3%) frameshift mutations, 3 (10%) single-amino acid deletions, 4 (13.3%) nonsense mutations, and 1 (3.3%) promoter mutation.

The researchers also discovered that PTPN1 mutations were significantly associated with diminished PTP1B expression in patient samples. However, they said future studies will need to confirm whether PTP1B immunohistochemistry can be used as a surrogate for PTPN1 mutations.

Another key finding was that PTPN1 mutations led to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members.

When the investigators silenced PTPN1 in the HL cell line KM-H2, they observed hyperphosphorylation and overexpression of downstream oncogenic targets—STAT3, STAT5, STAT6, JAK1, JAK2, and AKT.

The researchers said these results suggest PTPN1 mutations drive lymphomagenesis. The mutations likely synergize with other driver mutations known to be involved in the pathogenesis of HL and PMBCL—such as SOCS1 and STAT6—and that contribute to aberrant JAK-STAT signaling.

Researcher in the lab

Credit: Rhoda Baer

Mutations in the gene PTPN1 may drive the development of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL), according to a study published in Nature Genetics.

Whole-genome and whole-transcriptome sequencing revealed recurrent PTPN1 mutations in samples and cell lines of HL and PMBCL.

And experiments suggested the mutations contribute to lymphomagenesis by activating JAK-STAT signaling pathways.

“Our work identifies, for the first time, the entirety of genetic mutations in primary mediastinal B-cell lymphoma and first-of-its kind-mutations in the PTPN1 gene,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver.

To discover these mutations, Dr Steidl and his colleagues sequenced samples from 77 PMBCL patients and 3 PMBCL-derived cell lines. The team found mutations in 2 negative regulators of the JAK-STAT signaling pathway—SOCS1 and PTPN1.

As SOCS1 is already well-characterized, the researchers decided to focus on PTPN1. They identified PTPN1 mutations in 22% (17/77) of PMBCL cases and 33% (1/3) of the PMBCL-derived cell lines.

Because classical HL is closely related to PMBCL, the investigators also screened 30 samples from HL patients and 9 HL-derived cell lines. PTPN1 mutations were present in 20% (6/30) of the samples and 67% (6/9) of the cell lines.

In all, the team identified 18 (60%) missense mutations, 4 (13.3%) frameshift mutations, 3 (10%) single-amino acid deletions, 4 (13.3%) nonsense mutations, and 1 (3.3%) promoter mutation.

The researchers also discovered that PTPN1 mutations were significantly associated with diminished PTP1B expression in patient samples. However, they said future studies will need to confirm whether PTP1B immunohistochemistry can be used as a surrogate for PTPN1 mutations.

Another key finding was that PTPN1 mutations led to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members.

When the investigators silenced PTPN1 in the HL cell line KM-H2, they observed hyperphosphorylation and overexpression of downstream oncogenic targets—STAT3, STAT5, STAT6, JAK1, JAK2, and AKT.

The researchers said these results suggest PTPN1 mutations drive lymphomagenesis. The mutations likely synergize with other driver mutations known to be involved in the pathogenesis of HL and PMBCL—such as SOCS1 and STAT6—and that contribute to aberrant JAK-STAT signaling.

Researcher in the lab

Credit: Rhoda Baer

Mutations in the gene PTPN1 may drive the development of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL), according to a study published in Nature Genetics.

Whole-genome and whole-transcriptome sequencing revealed recurrent PTPN1 mutations in samples and cell lines of HL and PMBCL.

And experiments suggested the mutations contribute to lymphomagenesis by activating JAK-STAT signaling pathways.

“Our work identifies, for the first time, the entirety of genetic mutations in primary mediastinal B-cell lymphoma and first-of-its kind-mutations in the PTPN1 gene,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver.

To discover these mutations, Dr Steidl and his colleagues sequenced samples from 77 PMBCL patients and 3 PMBCL-derived cell lines. The team found mutations in 2 negative regulators of the JAK-STAT signaling pathway—SOCS1 and PTPN1.

As SOCS1 is already well-characterized, the researchers decided to focus on PTPN1. They identified PTPN1 mutations in 22% (17/77) of PMBCL cases and 33% (1/3) of the PMBCL-derived cell lines.

Because classical HL is closely related to PMBCL, the investigators also screened 30 samples from HL patients and 9 HL-derived cell lines. PTPN1 mutations were present in 20% (6/30) of the samples and 67% (6/9) of the cell lines.

In all, the team identified 18 (60%) missense mutations, 4 (13.3%) frameshift mutations, 3 (10%) single-amino acid deletions, 4 (13.3%) nonsense mutations, and 1 (3.3%) promoter mutation.

The researchers also discovered that PTPN1 mutations were significantly associated with diminished PTP1B expression in patient samples. However, they said future studies will need to confirm whether PTP1B immunohistochemistry can be used as a surrogate for PTPN1 mutations.

Another key finding was that PTPN1 mutations led to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members.

When the investigators silenced PTPN1 in the HL cell line KM-H2, they observed hyperphosphorylation and overexpression of downstream oncogenic targets—STAT3, STAT5, STAT6, JAK1, JAK2, and AKT.

The researchers said these results suggest PTPN1 mutations drive lymphomagenesis. The mutations likely synergize with other driver mutations known to be involved in the pathogenesis of HL and PMBCL—such as SOCS1 and STAT6—and that contribute to aberrant JAK-STAT signaling.

Credit: National Institute

of General Medical Sciences

There are significant challenges to overcome before whole-genome sequencing can be routinely used in the clinic, researchers have reported in JAMA.

In sequencing the entire genome of 12 healthy individuals, the team found they sometimes had difficulty identifying

variants in disease-associated genes, disagreed about which variants were particularly important for disease, and were uncertain about clinically reportable findings.

The research also revealed that detailed genome analysis required up to 100 hours of manual assessment per person, and the total cost of this process (including follow-up tests) could exceed $15,000 per person.

This is more expensive and labor-intensive than previous estimates, the researchers noted.

“We need to be very honest about what we can and cannot do at this point in time,” said study author Euan Ashley, MB ChB, DPhil, of Stanford University in California.

“Our hope is that the identification of specific hurdles will allow researchers in this field to focus their efforts on overcoming them to make this technique clinically useful.”

To identify these hurdles, Dr Ashley and his colleagues evaluated whole-genome sequencing in 12 healthy individuals. The team took note of the degree of sequencing accuracy necessary to make clinical decisions, the time it took to manually analyze each person’s results, and the costs involved.

The researchers discovered that sequencing could not provide reliable results regarding all inherited disease genes or consistently detect variants with the highest potential clinical effects.

Depending on the sequencing platform used, 10% to 19% of inherited disease genes were not covered to accepted standards for single-nucleotide variant discovery.

And although genotype concordance was high for previously described single-nucleotide variants—99% to 100%—it was low for small insertions and deletions—53% to 59%.

“It’s ironic, and slightly sobering, that we struggle the most in identifying insertions and deletions—those changes in the genome that are most impactful,” Dr Ashley said.

Nevertheless, he and his colleagues were able to identify an average of about 100 variants per person that were considered important enough for follow-up. Each variant required about an hour of investigation to assess the relevant scientific literature and determine whether the change was likely to modify disease risk in the individual.

After this process, the researchers were left with approximately 2 to 6 results they felt could be clinically important.

The variants expected to have potential health consequences were shared with 3 primary care physicians and 2 medical geneticists, who independently studied the results and recommended possible follow-up tests for each person.

The researchers estimated that the median cost for sequencing and variant interpretation was $14,815 (range, $14,050 to $15,715), plus the costs of computing infrastructure and data storage. And the projected costs for follow-up tests ranged from $351 to $776.

Despite the challenges they identified, the team said they are confident that whole-genome sequencing is worth pursuing.

“Our intention in doing this analysis was to draw a line describing where we are with this technology at this point in time and identify how best to move forward,” Dr Ashley said. “Things are becoming more clear, and the challenges to bringing this technique to the clinic are becoming crystallized.”

Credit: National Institute

of General Medical Sciences

There are significant challenges to overcome before whole-genome sequencing can be routinely used in the clinic, researchers have reported in JAMA.

In sequencing the entire genome of 12 healthy individuals, the team found they sometimes had difficulty identifying

variants in disease-associated genes, disagreed about which variants were particularly important for disease, and were uncertain about clinically reportable findings.

The research also revealed that detailed genome analysis required up to 100 hours of manual assessment per person, and the total cost of this process (including follow-up tests) could exceed $15,000 per person.

This is more expensive and labor-intensive than previous estimates, the researchers noted.

“We need to be very honest about what we can and cannot do at this point in time,” said study author Euan Ashley, MB ChB, DPhil, of Stanford University in California.

“Our hope is that the identification of specific hurdles will allow researchers in this field to focus their efforts on overcoming them to make this technique clinically useful.”

To identify these hurdles, Dr Ashley and his colleagues evaluated whole-genome sequencing in 12 healthy individuals. The team took note of the degree of sequencing accuracy necessary to make clinical decisions, the time it took to manually analyze each person’s results, and the costs involved.

The researchers discovered that sequencing could not provide reliable results regarding all inherited disease genes or consistently detect variants with the highest potential clinical effects.

Depending on the sequencing platform used, 10% to 19% of inherited disease genes were not covered to accepted standards for single-nucleotide variant discovery.

And although genotype concordance was high for previously described single-nucleotide variants—99% to 100%—it was low for small insertions and deletions—53% to 59%.

“It’s ironic, and slightly sobering, that we struggle the most in identifying insertions and deletions—those changes in the genome that are most impactful,” Dr Ashley said.

Nevertheless, he and his colleagues were able to identify an average of about 100 variants per person that were considered important enough for follow-up. Each variant required about an hour of investigation to assess the relevant scientific literature and determine whether the change was likely to modify disease risk in the individual.

After this process, the researchers were left with approximately 2 to 6 results they felt could be clinically important.

The variants expected to have potential health consequences were shared with 3 primary care physicians and 2 medical geneticists, who independently studied the results and recommended possible follow-up tests for each person.

The researchers estimated that the median cost for sequencing and variant interpretation was $14,815 (range, $14,050 to $15,715), plus the costs of computing infrastructure and data storage. And the projected costs for follow-up tests ranged from $351 to $776.

Despite the challenges they identified, the team said they are confident that whole-genome sequencing is worth pursuing.

“Our intention in doing this analysis was to draw a line describing where we are with this technology at this point in time and identify how best to move forward,” Dr Ashley said. “Things are becoming more clear, and the challenges to bringing this technique to the clinic are becoming crystallized.”

Credit: National Institute

of General Medical Sciences

There are significant challenges to overcome before whole-genome sequencing can be routinely used in the clinic, researchers have reported in JAMA.

In sequencing the entire genome of 12 healthy individuals, the team found they sometimes had difficulty identifying

variants in disease-associated genes, disagreed about which variants were particularly important for disease, and were uncertain about clinically reportable findings.

The research also revealed that detailed genome analysis required up to 100 hours of manual assessment per person, and the total cost of this process (including follow-up tests) could exceed $15,000 per person.

This is more expensive and labor-intensive than previous estimates, the researchers noted.

“We need to be very honest about what we can and cannot do at this point in time,” said study author Euan Ashley, MB ChB, DPhil, of Stanford University in California.

“Our hope is that the identification of specific hurdles will allow researchers in this field to focus their efforts on overcoming them to make this technique clinically useful.”

To identify these hurdles, Dr Ashley and his colleagues evaluated whole-genome sequencing in 12 healthy individuals. The team took note of the degree of sequencing accuracy necessary to make clinical decisions, the time it took to manually analyze each person’s results, and the costs involved.

The researchers discovered that sequencing could not provide reliable results regarding all inherited disease genes or consistently detect variants with the highest potential clinical effects.

Depending on the sequencing platform used, 10% to 19% of inherited disease genes were not covered to accepted standards for single-nucleotide variant discovery.

And although genotype concordance was high for previously described single-nucleotide variants—99% to 100%—it was low for small insertions and deletions—53% to 59%.

“It’s ironic, and slightly sobering, that we struggle the most in identifying insertions and deletions—those changes in the genome that are most impactful,” Dr Ashley said.

Nevertheless, he and his colleagues were able to identify an average of about 100 variants per person that were considered important enough for follow-up. Each variant required about an hour of investigation to assess the relevant scientific literature and determine whether the change was likely to modify disease risk in the individual.

After this process, the researchers were left with approximately 2 to 6 results they felt could be clinically important.

The variants expected to have potential health consequences were shared with 3 primary care physicians and 2 medical geneticists, who independently studied the results and recommended possible follow-up tests for each person.

The researchers estimated that the median cost for sequencing and variant interpretation was $14,815 (range, $14,050 to $15,715), plus the costs of computing infrastructure and data storage. And the projected costs for follow-up tests ranged from $351 to $776.

Despite the challenges they identified, the team said they are confident that whole-genome sequencing is worth pursuing.

“Our intention in doing this analysis was to draw a line describing where we are with this technology at this point in time and identify how best to move forward,” Dr Ashley said. “Things are becoming more clear, and the challenges to bringing this technique to the clinic are becoming crystallized.”

An adnexal mass is a common gynecological presentation that can affect women of all ages. Typically, the mass is identified during an annual pelvic exam or incidentally when patients undergo pelvic imaging for evaluation of gastrointestinal or gynecological complaints.

The main goal of evaluating an adnexal mass in the nonacute setting is to rule out malignancy. A careful evaluation is needed to accurately distinguish benign from malignant masses, but often a definitive diagnosis only can be achieved with surgery. Hence, in the United States, women have a 5%-10% chance of undergoing surgery to evaluate a mass, but only 13%-21% of these patients are diagnosed with an ovarian cancer (Obstet. Gynecol. 2007;110:201-14).

We will review a stepwise approach for the evaluation of a newly diagnosed mass. As part of our review, we will discuss imaging findings that should prompt surgical evaluation or continued observation, as well as the correct use of the currently available serum biomarkers.

The majority of adnexal masses are benign and present most commonly in premenopausal women. However, in the outpatient setting, the evaluation approach should be aimed at ruling out malignancy regardless of age or reproductive status. The patient’s age should be considered clinically, as the suspicion for ovarian cancer should be heightened in postmenopausal women.

The evaluation should start with a detailed history because it may help in determining the etiology of the mass. Pelvic pain and pressure are very common but nonspecific symptoms in women with adnexal masses. However, if the pain is of sudden onset, urgent evaluation is warranted to rule out adnexal torsion or a ruptured hemorrhagic cyst. A history of dysmenorrhea and/or dyspareunia may suggest endometriosis and coexisting endometrioma, whereas a patient with fever and a vaginal discharge should be evaluated for a tubo-ovarian abscess.

Patients also should be asked about symptoms associated with ovarian cancer including early satiety, constipation, and bloating, as well as their duration. In addition, abnormal uterine bleeding or virilization may suggest the presence of estrogen- or testosterone-secreting tumors. Lastly, a detailed family history is important, as the presence of ovarian, breast, or colon cancer in the family would increase suspicion for hereditary ovarian cancer syndromes.

A thorough physical exam should include a speculum exam as well as bimanual and rectovaginal exams. The focus of the pelvic exam should be determining the size, mobility, and consistency of the mass, as well as other findings that may help discriminate benign versus malignant neoplasms. Malignant masses are usually solid, irregular in shape, and tend to be fixed. Nodularity in the posterior cul-de-sac also is associated with malignancy. The abdominal exam should focus on the presence or absence of ascites (fluid wave), an omental mass, or inguinal adenopathy. However, none of the findings on exam are specific for an ovarian or fallopian tube malignancy, and imaging should be obtained for further evaluation.

Ultrasound is the imaging study of choice for the evaluation of an adnexal mass because it is less expensive than and diagnostically equivalent to other imaging modalities. A pelvic ultrasound can help delineate the anatomic origin of the mass, but it also can detect characteristics of the mass that may help with the diagnosis, and the decision of whether or not to proceed to surgery. Endometriomas, mature teratomas (dermoid cysts), simple ovarian cysts, and hemorrhagic cysts have sonographic features that are highly predictive of the histology. Depending on whether or not the patient is symptomatic, the patient’s age, and comorbidities, these masses might be followed expectantly.

Ultrasound features that are suggestive of malignancy include solid components, septations greater than 2-3 mm, and vascular flow. The presence of ascites or peritoneal nodules detected at the time of ultrasound also is highly suspicious of malignancy in patients with a pelvic mass. If a pelvic ultrasound is equivocal, pelvic magnetic resonance imaging (MRI) is the second study of choice. Computed tomography (CT scan) should be used to evaluate for metastatic disease in patients with suspected ovarian carcinoma (ascites, adenopathy, peritoneal thickening or nodularity, omental thickening).

Serum biomarkers also may aid in the evaluation. The most well-studied and commonly used biomarker in the evaluation of an adnexal mass is CA-125. In general, the utility of CA-125 is limited mainly because of its low specificity, especially in premenopausal women. However, it can be used as adjunct when an ovarian malignancy is suspected based on the patient’s history, risk factors, and imaging findings. The American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncologists (SGO) advise referral to a gynecologic oncologist for postmenopausal women with an elevated CA-125. Meanwhile, for premenopausal women, the recommendation is for referral of those with a "very elevated" CA-125. However, a specific value has not been established (Obstet. Gynecol. 2011;117:742-6).

CA-125 by itself should not be used to decide whether or not to take a patient to surgery. Nevertheless, once the decision to operate has been made, CA-125 can be used in conjunction with HE4 to calculate a Risk of Malignancy Algorithm (ROMA) score. The score is based on menopausal status, and if the calculated risk is elevated, patient referral to a gynecologic oncologist for her surgery should be strongly considered.

Similarly, the OVA1 test is currently approved by the Food and Drug Administration to assess the likelihood of malignancy in patients who are having surgery for an adnexal mass. The test is also based on menopausal status, and if elevated, a referral to a gynecologic oncologist is recommended. In young women with adnexal masses, germ cell tumor markers may be more helpful (lactate dehydrogenase [LDH], human chorionic gonadotropin [hCG], alpha-fetoprotein [AFP]), while in patients with signs or symptoms of estrogen or androgen excess, sex cord-stromal tumor markers (inhibin B, anti-Müllerian hormone [AMH], testosterone, dehydroepiandrosterone [DHEA], estradiol) would be appropriate to obtain. While no tumor marker is "diagnostic," the results may assist in the decision to perform surgery and consider referral to a gynecologic oncologist.

In summary, the workup for an adnexal mass should include a detailed medical and family history, a thorough physical exam, and imaging with pelvic ultrasound. For premenopausal women, there is a higher incidence of adnexal masses, and, in fact, most of them are benign. In these women, one must weigh the risk/benefit of close monitoring with pelvic ultrasound versus surgical intervention. A serum CA-125 can be helpful, but only if it is significantly elevated.

If uncertainty remains after a complete evaluation has been performed, it is appropriate to refer to a gynecologic oncologist. In postmenopausal women, serum biomarkers should be used in conjunction with the history, physical, and ultrasound because of the higher risk of malignancy. In addition, surgical intervention should be offered to these patients regardless of serum marker values in the setting of a complex mass. If there is high suspicion for malignancy by history and imaging or elevated ROMA or OVA1, referral to a gynecologic oncologist is prudent.

Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina. Neither Dr. Clarke-Pearson nor Dr. Roque has any relevant financial disclosures. E-mail them at obnews@frontlinemedcom.com.

An adnexal mass is a common gynecological presentation that can affect women of all ages. Typically, the mass is identified during an annual pelvic exam or incidentally when patients undergo pelvic imaging for evaluation of gastrointestinal or gynecological complaints.

The main goal of evaluating an adnexal mass in the nonacute setting is to rule out malignancy. A careful evaluation is needed to accurately distinguish benign from malignant masses, but often a definitive diagnosis only can be achieved with surgery. Hence, in the United States, women have a 5%-10% chance of undergoing surgery to evaluate a mass, but only 13%-21% of these patients are diagnosed with an ovarian cancer (Obstet. Gynecol. 2007;110:201-14).

We will review a stepwise approach for the evaluation of a newly diagnosed mass. As part of our review, we will discuss imaging findings that should prompt surgical evaluation or continued observation, as well as the correct use of the currently available serum biomarkers.

The majority of adnexal masses are benign and present most commonly in premenopausal women. However, in the outpatient setting, the evaluation approach should be aimed at ruling out malignancy regardless of age or reproductive status. The patient’s age should be considered clinically, as the suspicion for ovarian cancer should be heightened in postmenopausal women.

The evaluation should start with a detailed history because it may help in determining the etiology of the mass. Pelvic pain and pressure are very common but nonspecific symptoms in women with adnexal masses. However, if the pain is of sudden onset, urgent evaluation is warranted to rule out adnexal torsion or a ruptured hemorrhagic cyst. A history of dysmenorrhea and/or dyspareunia may suggest endometriosis and coexisting endometrioma, whereas a patient with fever and a vaginal discharge should be evaluated for a tubo-ovarian abscess.

Patients also should be asked about symptoms associated with ovarian cancer including early satiety, constipation, and bloating, as well as their duration. In addition, abnormal uterine bleeding or virilization may suggest the presence of estrogen- or testosterone-secreting tumors. Lastly, a detailed family history is important, as the presence of ovarian, breast, or colon cancer in the family would increase suspicion for hereditary ovarian cancer syndromes.

A thorough physical exam should include a speculum exam as well as bimanual and rectovaginal exams. The focus of the pelvic exam should be determining the size, mobility, and consistency of the mass, as well as other findings that may help discriminate benign versus malignant neoplasms. Malignant masses are usually solid, irregular in shape, and tend to be fixed. Nodularity in the posterior cul-de-sac also is associated with malignancy. The abdominal exam should focus on the presence or absence of ascites (fluid wave), an omental mass, or inguinal adenopathy. However, none of the findings on exam are specific for an ovarian or fallopian tube malignancy, and imaging should be obtained for further evaluation.

Ultrasound is the imaging study of choice for the evaluation of an adnexal mass because it is less expensive than and diagnostically equivalent to other imaging modalities. A pelvic ultrasound can help delineate the anatomic origin of the mass, but it also can detect characteristics of the mass that may help with the diagnosis, and the decision of whether or not to proceed to surgery. Endometriomas, mature teratomas (dermoid cysts), simple ovarian cysts, and hemorrhagic cysts have sonographic features that are highly predictive of the histology. Depending on whether or not the patient is symptomatic, the patient’s age, and comorbidities, these masses might be followed expectantly.

Ultrasound features that are suggestive of malignancy include solid components, septations greater than 2-3 mm, and vascular flow. The presence of ascites or peritoneal nodules detected at the time of ultrasound also is highly suspicious of malignancy in patients with a pelvic mass. If a pelvic ultrasound is equivocal, pelvic magnetic resonance imaging (MRI) is the second study of choice. Computed tomography (CT scan) should be used to evaluate for metastatic disease in patients with suspected ovarian carcinoma (ascites, adenopathy, peritoneal thickening or nodularity, omental thickening).

Serum biomarkers also may aid in the evaluation. The most well-studied and commonly used biomarker in the evaluation of an adnexal mass is CA-125. In general, the utility of CA-125 is limited mainly because of its low specificity, especially in premenopausal women. However, it can be used as adjunct when an ovarian malignancy is suspected based on the patient’s history, risk factors, and imaging findings. The American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncologists (SGO) advise referral to a gynecologic oncologist for postmenopausal women with an elevated CA-125. Meanwhile, for premenopausal women, the recommendation is for referral of those with a "very elevated" CA-125. However, a specific value has not been established (Obstet. Gynecol. 2011;117:742-6).

CA-125 by itself should not be used to decide whether or not to take a patient to surgery. Nevertheless, once the decision to operate has been made, CA-125 can be used in conjunction with HE4 to calculate a Risk of Malignancy Algorithm (ROMA) score. The score is based on menopausal status, and if the calculated risk is elevated, patient referral to a gynecologic oncologist for her surgery should be strongly considered.

Similarly, the OVA1 test is currently approved by the Food and Drug Administration to assess the likelihood of malignancy in patients who are having surgery for an adnexal mass. The test is also based on menopausal status, and if elevated, a referral to a gynecologic oncologist is recommended. In young women with adnexal masses, germ cell tumor markers may be more helpful (lactate dehydrogenase [LDH], human chorionic gonadotropin [hCG], alpha-fetoprotein [AFP]), while in patients with signs or symptoms of estrogen or androgen excess, sex cord-stromal tumor markers (inhibin B, anti-Müllerian hormone [AMH], testosterone, dehydroepiandrosterone [DHEA], estradiol) would be appropriate to obtain. While no tumor marker is "diagnostic," the results may assist in the decision to perform surgery and consider referral to a gynecologic oncologist.

In summary, the workup for an adnexal mass should include a detailed medical and family history, a thorough physical exam, and imaging with pelvic ultrasound. For premenopausal women, there is a higher incidence of adnexal masses, and, in fact, most of them are benign. In these women, one must weigh the risk/benefit of close monitoring with pelvic ultrasound versus surgical intervention. A serum CA-125 can be helpful, but only if it is significantly elevated.

If uncertainty remains after a complete evaluation has been performed, it is appropriate to refer to a gynecologic oncologist. In postmenopausal women, serum biomarkers should be used in conjunction with the history, physical, and ultrasound because of the higher risk of malignancy. In addition, surgical intervention should be offered to these patients regardless of serum marker values in the setting of a complex mass. If there is high suspicion for malignancy by history and imaging or elevated ROMA or OVA1, referral to a gynecologic oncologist is prudent.

Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina. Neither Dr. Clarke-Pearson nor Dr. Roque has any relevant financial disclosures. E-mail them at obnews@frontlinemedcom.com.

An adnexal mass is a common gynecological presentation that can affect women of all ages. Typically, the mass is identified during an annual pelvic exam or incidentally when patients undergo pelvic imaging for evaluation of gastrointestinal or gynecological complaints.

The main goal of evaluating an adnexal mass in the nonacute setting is to rule out malignancy. A careful evaluation is needed to accurately distinguish benign from malignant masses, but often a definitive diagnosis only can be achieved with surgery. Hence, in the United States, women have a 5%-10% chance of undergoing surgery to evaluate a mass, but only 13%-21% of these patients are diagnosed with an ovarian cancer (Obstet. Gynecol. 2007;110:201-14).

We will review a stepwise approach for the evaluation of a newly diagnosed mass. As part of our review, we will discuss imaging findings that should prompt surgical evaluation or continued observation, as well as the correct use of the currently available serum biomarkers.

The majority of adnexal masses are benign and present most commonly in premenopausal women. However, in the outpatient setting, the evaluation approach should be aimed at ruling out malignancy regardless of age or reproductive status. The patient’s age should be considered clinically, as the suspicion for ovarian cancer should be heightened in postmenopausal women.

The evaluation should start with a detailed history because it may help in determining the etiology of the mass. Pelvic pain and pressure are very common but nonspecific symptoms in women with adnexal masses. However, if the pain is of sudden onset, urgent evaluation is warranted to rule out adnexal torsion or a ruptured hemorrhagic cyst. A history of dysmenorrhea and/or dyspareunia may suggest endometriosis and coexisting endometrioma, whereas a patient with fever and a vaginal discharge should be evaluated for a tubo-ovarian abscess.

Patients also should be asked about symptoms associated with ovarian cancer including early satiety, constipation, and bloating, as well as their duration. In addition, abnormal uterine bleeding or virilization may suggest the presence of estrogen- or testosterone-secreting tumors. Lastly, a detailed family history is important, as the presence of ovarian, breast, or colon cancer in the family would increase suspicion for hereditary ovarian cancer syndromes.

A thorough physical exam should include a speculum exam as well as bimanual and rectovaginal exams. The focus of the pelvic exam should be determining the size, mobility, and consistency of the mass, as well as other findings that may help discriminate benign versus malignant neoplasms. Malignant masses are usually solid, irregular in shape, and tend to be fixed. Nodularity in the posterior cul-de-sac also is associated with malignancy. The abdominal exam should focus on the presence or absence of ascites (fluid wave), an omental mass, or inguinal adenopathy. However, none of the findings on exam are specific for an ovarian or fallopian tube malignancy, and imaging should be obtained for further evaluation.

Ultrasound is the imaging study of choice for the evaluation of an adnexal mass because it is less expensive than and diagnostically equivalent to other imaging modalities. A pelvic ultrasound can help delineate the anatomic origin of the mass, but it also can detect characteristics of the mass that may help with the diagnosis, and the decision of whether or not to proceed to surgery. Endometriomas, mature teratomas (dermoid cysts), simple ovarian cysts, and hemorrhagic cysts have sonographic features that are highly predictive of the histology. Depending on whether or not the patient is symptomatic, the patient’s age, and comorbidities, these masses might be followed expectantly.

Ultrasound features that are suggestive of malignancy include solid components, septations greater than 2-3 mm, and vascular flow. The presence of ascites or peritoneal nodules detected at the time of ultrasound also is highly suspicious of malignancy in patients with a pelvic mass. If a pelvic ultrasound is equivocal, pelvic magnetic resonance imaging (MRI) is the second study of choice. Computed tomography (CT scan) should be used to evaluate for metastatic disease in patients with suspected ovarian carcinoma (ascites, adenopathy, peritoneal thickening or nodularity, omental thickening).

Serum biomarkers also may aid in the evaluation. The most well-studied and commonly used biomarker in the evaluation of an adnexal mass is CA-125. In general, the utility of CA-125 is limited mainly because of its low specificity, especially in premenopausal women. However, it can be used as adjunct when an ovarian malignancy is suspected based on the patient’s history, risk factors, and imaging findings. The American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncologists (SGO) advise referral to a gynecologic oncologist for postmenopausal women with an elevated CA-125. Meanwhile, for premenopausal women, the recommendation is for referral of those with a "very elevated" CA-125. However, a specific value has not been established (Obstet. Gynecol. 2011;117:742-6).

CA-125 by itself should not be used to decide whether or not to take a patient to surgery. Nevertheless, once the decision to operate has been made, CA-125 can be used in conjunction with HE4 to calculate a Risk of Malignancy Algorithm (ROMA) score. The score is based on menopausal status, and if the calculated risk is elevated, patient referral to a gynecologic oncologist for her surgery should be strongly considered.

Similarly, the OVA1 test is currently approved by the Food and Drug Administration to assess the likelihood of malignancy in patients who are having surgery for an adnexal mass. The test is also based on menopausal status, and if elevated, a referral to a gynecologic oncologist is recommended. In young women with adnexal masses, germ cell tumor markers may be more helpful (lactate dehydrogenase [LDH], human chorionic gonadotropin [hCG], alpha-fetoprotein [AFP]), while in patients with signs or symptoms of estrogen or androgen excess, sex cord-stromal tumor markers (inhibin B, anti-Müllerian hormone [AMH], testosterone, dehydroepiandrosterone [DHEA], estradiol) would be appropriate to obtain. While no tumor marker is "diagnostic," the results may assist in the decision to perform surgery and consider referral to a gynecologic oncologist.

In summary, the workup for an adnexal mass should include a detailed medical and family history, a thorough physical exam, and imaging with pelvic ultrasound. For premenopausal women, there is a higher incidence of adnexal masses, and, in fact, most of them are benign. In these women, one must weigh the risk/benefit of close monitoring with pelvic ultrasound versus surgical intervention. A serum CA-125 can be helpful, but only if it is significantly elevated.

If uncertainty remains after a complete evaluation has been performed, it is appropriate to refer to a gynecologic oncologist. In postmenopausal women, serum biomarkers should be used in conjunction with the history, physical, and ultrasound because of the higher risk of malignancy. In addition, surgical intervention should be offered to these patients regardless of serum marker values in the setting of a complex mass. If there is high suspicion for malignancy by history and imaging or elevated ROMA or OVA1, referral to a gynecologic oncologist is prudent.

Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina. Neither Dr. Clarke-Pearson nor Dr. Roque has any relevant financial disclosures. E-mail them at obnews@frontlinemedcom.com.

An Institute of Medicine committee could not reach consensus on a single definition of Gulf War illness and recommended in a new report that clinicians and researchers at least narrow it down to two definitions.

That’s the preferred term – Gulf War illness – for a slew of health problems that occur at a higher rate in the approximately 697,000 U.S. veterans who served in the 1990-1991 Gulf War than in other veterans, the committee said. Gulf War illness is widely used and is more accurate than other terms used over the years for the same problems, including Gulf War syndrome, chronic multisystem illness, unexplained illness, medically unexplained symptoms, and medically unexplained physical symptoms, the report stated.

The Institute of Medicine (IOM) drafted a committee of 16 experts at the request of the Department of Veterans Affairs to try to develop a case definition for what's now called Gulf War illness in order to help standardize diagnosis, inclusion in research studies, and treatments. The committee's 120-page report, "Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined," is available on the IOM website.

Unable to find validation for one definition because of methodologic limitations in the studies, the committee recommended using either a broader definition from the Centers for Disease Control and Prevention (CDC) or a more restrictive one from studies of Kansas veterans, depending on the situation. Between the two of them, the definitions capture the most common symptoms of Gulf War illness and provide a framework for more focused research and treatment, the report said.

The committee found 2,033 articles in the literature focused on Gulf War illness symptoms and closely reviewed 718 of them. It found no objective diagnostic criteria but saw cumulative evidence that Gulf War illness is real. Fatigue, pain, and neurocognitive, gastrointestinal, respiratory, and/or dermatologic symptoms were reported with higher frequency in Gulf War veterans than in veterans of the same era who had not been deployed or were deployed elsewhere.

To identify the illness in a Gulf War veteran, the CDC definition requires one or more symptoms in at least two of the following categories: fatigue, pain, or mood and cognition. The Kansas definition requires symptoms in at least three of the following domains: fatigue or sleep, pain, neurologic or cognitive or mood symptoms, gastrointestinal symptoms, respiratory symptoms, and skin symptoms.

The CDC definition identified the illness in 29%-60% of Gulf War veterans, depending on the population studied. The Kansas definition identified the illness in 34% of Kansas veterans of the Gulf War.

The reason the committee couldn’t compile a single case definition is that the studies in the literature do not report on key features of the illness including onset, duration, severity, frequency of symptoms, and exclusionary criteria. The Department of Veterans Affairs should boost efforts to collect these kinds of data, conduct earlier in-depth assessments after deployment when unexpected complaints occur, and track troops’ exposures to vaccinations, drugs, and environmental factors, the report recommends.

The name Gulf War illness won out over Gulf War syndrome because "syndrome" indicates a new group of signs and symptoms, while the types and patterns of symptoms in this illness commonly are seen with other illnesses. The committee rejected "chronic multisymptom illness" because the phrase is not specific to Gulf War veterans.

The committee included experts in clinical medicine, toxicology, psychiatry, neurology, gastroenterology, epidemiology, sociology, psychometrics, biostatistics, occupational medicine, and basic science.

The report does not include potential disclosures of conflicts of interest.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

An Institute of Medicine committee could not reach consensus on a single definition of Gulf War illness and recommended in a new report that clinicians and researchers at least narrow it down to two definitions.

That’s the preferred term – Gulf War illness – for a slew of health problems that occur at a higher rate in the approximately 697,000 U.S. veterans who served in the 1990-1991 Gulf War than in other veterans, the committee said. Gulf War illness is widely used and is more accurate than other terms used over the years for the same problems, including Gulf War syndrome, chronic multisystem illness, unexplained illness, medically unexplained symptoms, and medically unexplained physical symptoms, the report stated.

The Institute of Medicine (IOM) drafted a committee of 16 experts at the request of the Department of Veterans Affairs to try to develop a case definition for what's now called Gulf War illness in order to help standardize diagnosis, inclusion in research studies, and treatments. The committee's 120-page report, "Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined," is available on the IOM website.

Unable to find validation for one definition because of methodologic limitations in the studies, the committee recommended using either a broader definition from the Centers for Disease Control and Prevention (CDC) or a more restrictive one from studies of Kansas veterans, depending on the situation. Between the two of them, the definitions capture the most common symptoms of Gulf War illness and provide a framework for more focused research and treatment, the report said.

The committee found 2,033 articles in the literature focused on Gulf War illness symptoms and closely reviewed 718 of them. It found no objective diagnostic criteria but saw cumulative evidence that Gulf War illness is real. Fatigue, pain, and neurocognitive, gastrointestinal, respiratory, and/or dermatologic symptoms were reported with higher frequency in Gulf War veterans than in veterans of the same era who had not been deployed or were deployed elsewhere.

To identify the illness in a Gulf War veteran, the CDC definition requires one or more symptoms in at least two of the following categories: fatigue, pain, or mood and cognition. The Kansas definition requires symptoms in at least three of the following domains: fatigue or sleep, pain, neurologic or cognitive or mood symptoms, gastrointestinal symptoms, respiratory symptoms, and skin symptoms.

The CDC definition identified the illness in 29%-60% of Gulf War veterans, depending on the population studied. The Kansas definition identified the illness in 34% of Kansas veterans of the Gulf War.

The reason the committee couldn’t compile a single case definition is that the studies in the literature do not report on key features of the illness including onset, duration, severity, frequency of symptoms, and exclusionary criteria. The Department of Veterans Affairs should boost efforts to collect these kinds of data, conduct earlier in-depth assessments after deployment when unexpected complaints occur, and track troops’ exposures to vaccinations, drugs, and environmental factors, the report recommends.

The name Gulf War illness won out over Gulf War syndrome because "syndrome" indicates a new group of signs and symptoms, while the types and patterns of symptoms in this illness commonly are seen with other illnesses. The committee rejected "chronic multisymptom illness" because the phrase is not specific to Gulf War veterans.

The committee included experts in clinical medicine, toxicology, psychiatry, neurology, gastroenterology, epidemiology, sociology, psychometrics, biostatistics, occupational medicine, and basic science.

The report does not include potential disclosures of conflicts of interest.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

An Institute of Medicine committee could not reach consensus on a single definition of Gulf War illness and recommended in a new report that clinicians and researchers at least narrow it down to two definitions.

That’s the preferred term – Gulf War illness – for a slew of health problems that occur at a higher rate in the approximately 697,000 U.S. veterans who served in the 1990-1991 Gulf War than in other veterans, the committee said. Gulf War illness is widely used and is more accurate than other terms used over the years for the same problems, including Gulf War syndrome, chronic multisystem illness, unexplained illness, medically unexplained symptoms, and medically unexplained physical symptoms, the report stated.

The Institute of Medicine (IOM) drafted a committee of 16 experts at the request of the Department of Veterans Affairs to try to develop a case definition for what's now called Gulf War illness in order to help standardize diagnosis, inclusion in research studies, and treatments. The committee's 120-page report, "Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined," is available on the IOM website.

Unable to find validation for one definition because of methodologic limitations in the studies, the committee recommended using either a broader definition from the Centers for Disease Control and Prevention (CDC) or a more restrictive one from studies of Kansas veterans, depending on the situation. Between the two of them, the definitions capture the most common symptoms of Gulf War illness and provide a framework for more focused research and treatment, the report said.

The committee found 2,033 articles in the literature focused on Gulf War illness symptoms and closely reviewed 718 of them. It found no objective diagnostic criteria but saw cumulative evidence that Gulf War illness is real. Fatigue, pain, and neurocognitive, gastrointestinal, respiratory, and/or dermatologic symptoms were reported with higher frequency in Gulf War veterans than in veterans of the same era who had not been deployed or were deployed elsewhere.

To identify the illness in a Gulf War veteran, the CDC definition requires one or more symptoms in at least two of the following categories: fatigue, pain, or mood and cognition. The Kansas definition requires symptoms in at least three of the following domains: fatigue or sleep, pain, neurologic or cognitive or mood symptoms, gastrointestinal symptoms, respiratory symptoms, and skin symptoms.

The CDC definition identified the illness in 29%-60% of Gulf War veterans, depending on the population studied. The Kansas definition identified the illness in 34% of Kansas veterans of the Gulf War.

The reason the committee couldn’t compile a single case definition is that the studies in the literature do not report on key features of the illness including onset, duration, severity, frequency of symptoms, and exclusionary criteria. The Department of Veterans Affairs should boost efforts to collect these kinds of data, conduct earlier in-depth assessments after deployment when unexpected complaints occur, and track troops’ exposures to vaccinations, drugs, and environmental factors, the report recommends.

The name Gulf War illness won out over Gulf War syndrome because "syndrome" indicates a new group of signs and symptoms, while the types and patterns of symptoms in this illness commonly are seen with other illnesses. The committee rejected "chronic multisymptom illness" because the phrase is not specific to Gulf War veterans.

The committee included experts in clinical medicine, toxicology, psychiatry, neurology, gastroenterology, epidemiology, sociology, psychometrics, biostatistics, occupational medicine, and basic science.

The report does not include potential disclosures of conflicts of interest.

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

Worker prepares capsules

for use in a clinical trial

Credit: Esther Dyson

Too many discontinued clinical trials go unreported to ethics committees and remain unpublished, according to a paper published in JAMA.

Investigators evaluated more than 1000 randomized clinical trials (RCTs) initiated in 3 countries between 2000 and 2003. And they found that roughly a quarter of these trials were ultimately discontinued.

Although all of these RCTs had been approved by research ethics committees, less than 40% of the discontinuations were reported to the committees.

And discontinued trials were significantly more likely than completed trials to remain unpublished.

The most common reason for discontinuation was insufficient subject enrollment.

Benjamin Kasenda, MD, of University Hospital Basel in Switzerland, and his colleagues conducted this research. They examined the characteristics of 1017 RCTs approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. The last follow-up of these trials was April 27, 2013.

Overall, 253 RCTs (24.9%) were discontinued, but only 38% of these discontinuations were reported to ethics committees.

Discontinued trials were more likely than completed trials to remain unpublished—55.1% vs 33.6% (P<0.001).

The most common reasons for discontinuation were poor recruitment (9.9%, 101/1017), administrative reasons (3.8%, 39/1017), and futility (3.6%, 37/1017).

A multivariate analysis revealed that industry sponsorship, compared to investigator sponsorship, and a larger planned sample size in increments of 100 were associated with lower rates of discontinuation due to poor recruitment. The adjusted odds ratios were 0.25 (P<0.001) and 0.96 (P=0.04), respectively.

Dr Kasenda and his colleagues said these results suggest researchers must put forth more effort to ensure that trial discontinuation is reported to ethics committees and that results of discontinued trials are published.

They said failure to publish these results is “a waste of valid data that could contribute to systematic reviews and meta-analyses.” In addition, taking steps to improve subject recruitment could greatly reduce RCT discontinuation.

Worker prepares capsules

for use in a clinical trial

Credit: Esther Dyson

Too many discontinued clinical trials go unreported to ethics committees and remain unpublished, according to a paper published in JAMA.

Investigators evaluated more than 1000 randomized clinical trials (RCTs) initiated in 3 countries between 2000 and 2003. And they found that roughly a quarter of these trials were ultimately discontinued.

Although all of these RCTs had been approved by research ethics committees, less than 40% of the discontinuations were reported to the committees.

And discontinued trials were significantly more likely than completed trials to remain unpublished.

The most common reason for discontinuation was insufficient subject enrollment.

Benjamin Kasenda, MD, of University Hospital Basel in Switzerland, and his colleagues conducted this research. They examined the characteristics of 1017 RCTs approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. The last follow-up of these trials was April 27, 2013.

Overall, 253 RCTs (24.9%) were discontinued, but only 38% of these discontinuations were reported to ethics committees.

Discontinued trials were more likely than completed trials to remain unpublished—55.1% vs 33.6% (P<0.001).

The most common reasons for discontinuation were poor recruitment (9.9%, 101/1017), administrative reasons (3.8%, 39/1017), and futility (3.6%, 37/1017).

A multivariate analysis revealed that industry sponsorship, compared to investigator sponsorship, and a larger planned sample size in increments of 100 were associated with lower rates of discontinuation due to poor recruitment. The adjusted odds ratios were 0.25 (P<0.001) and 0.96 (P=0.04), respectively.

Dr Kasenda and his colleagues said these results suggest researchers must put forth more effort to ensure that trial discontinuation is reported to ethics committees and that results of discontinued trials are published.

They said failure to publish these results is “a waste of valid data that could contribute to systematic reviews and meta-analyses.” In addition, taking steps to improve subject recruitment could greatly reduce RCT discontinuation.

Worker prepares capsules

for use in a clinical trial

Credit: Esther Dyson

Too many discontinued clinical trials go unreported to ethics committees and remain unpublished, according to a paper published in JAMA.

Investigators evaluated more than 1000 randomized clinical trials (RCTs) initiated in 3 countries between 2000 and 2003. And they found that roughly a quarter of these trials were ultimately discontinued.

Although all of these RCTs had been approved by research ethics committees, less than 40% of the discontinuations were reported to the committees.

And discontinued trials were significantly more likely than completed trials to remain unpublished.

The most common reason for discontinuation was insufficient subject enrollment.

Benjamin Kasenda, MD, of University Hospital Basel in Switzerland, and his colleagues conducted this research. They examined the characteristics of 1017 RCTs approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. The last follow-up of these trials was April 27, 2013.

Overall, 253 RCTs (24.9%) were discontinued, but only 38% of these discontinuations were reported to ethics committees.

Discontinued trials were more likely than completed trials to remain unpublished—55.1% vs 33.6% (P<0.001).

The most common reasons for discontinuation were poor recruitment (9.9%, 101/1017), administrative reasons (3.8%, 39/1017), and futility (3.6%, 37/1017).

A multivariate analysis revealed that industry sponsorship, compared to investigator sponsorship, and a larger planned sample size in increments of 100 were associated with lower rates of discontinuation due to poor recruitment. The adjusted odds ratios were 0.25 (P<0.001) and 0.96 (P=0.04), respectively.

Dr Kasenda and his colleagues said these results suggest researchers must put forth more effort to ensure that trial discontinuation is reported to ethics committees and that results of discontinued trials are published.

They said failure to publish these results is “a waste of valid data that could contribute to systematic reviews and meta-analyses.” In addition, taking steps to improve subject recruitment could greatly reduce RCT discontinuation.

GRAPEVINE, TEXAS—Adding specialized T cells to allogeneic bone marrow transplants can prevent graft-vs-host disease (GVHD) while preserving the graft-vs-tumor (GVT) effect, preclinical research suggests.

Donor-derived CD4+ invariant natural killer T cells (iNKT cells) helped protect mice from developing GVHD and lymphoma, thereby improving their survival.

As human CD4+ iNKT cells can be expanded in vitro, these findings may translate to the clinic, said study investigator Dominik Schneidawind, MD, of Stanford University in California.

Dr Schneidawind discussed this research at the 2014 BMT Tandem Meetings as abstract 2*, which was designated one of the meeting’s “Best Abstracts.”

Improved survival

Dr Schneidawind and his colleagues created a model of allogeneic bone marrow transplant in Balb/c (H-2Kd) mice. The mice were first irradiated with 8 Gy and then received T cell-depleted bone marrow, along with 1 x 10⁶ CD4/CD8 T cells (Tcon) from C57Bl/6 (H-2Kb) donor mice and varying doses of CD4+ iNKT cells: 1 x 10⁴ to 1 x 10⁵.

Mice that received 100,000 CD4+ iNKT cells had significantly improved survival (P=0.002)—and better weight and GVHD scores—compared to mice that received bone marrow grafts alone. But a CD4+ iNKT dose as low as 10,000 cells also conferred a significant improvement in survival (P=0.03).

“In contrast, you need roughly 500,000 to 1 million donor-derived regulatory T cells to achieve a comparable survival benefit in this model of bone marrow transplantation,” Dr Schneidawind noted.

GVT effect

Dr Schneidawind and his colleagues also evaluated the impact of CD4+ iNKT cells on the GVT effect. They used luciferase-transfected BCL1 cells to induce lymphoma development, injecting the cells into mice 1 day before transplant.

Mice that received BCL1 cells, with or without CD4+ iNKT cells, showed increasing bioluminescence imaging (BLI) signals and all died from progressive lymphoma. The mice that received BLC1 and Tcon did not show an increase in BLI signals, but they all died from GVHD.

However, the mice that received BCL1, Tcon, and CD4+ iNKT cells didn’t show any sign of lymphoma or GVHD and survived through the whole experiment (P=0.002).

The investigators conducted the same experiment with the luciferase-positive A20 cell line. And they observed similar results. Mice that received A20 cells, Tcon, and CD4+ iNKT cells showed no sign of lymphoma and had significantly improved survival (P=0.002) over animals that received A20 and Tcon.

“Interestingly, animals that received A20 cells and 50,000 CD4+ iNKT cells only, without Tcon, showed a significant decrease in BLI signal and significantly improved survival,” Dr Schneidawind noted.

“So we conclude from these experiments that CD4+ iNKT cells do not abrogate the Tcon-mediated [GVT] effect but might exert some distinct antitumor activity by themselves.”

Mechanism of GVHD prevention

Lastly, Dr Schneidawind and his colleagues wanted to determine exactly how CD4+ iNKT cells prevent GVHD. The group’s experiments showed that the cells inhibit the proliferation of alloreactive T cells and promote the expansion of donor-derived CD4+ FoxP3+ Tregs.

The investigators decided to take a closer look at the Tregs, evaluating their role in GVHD-related death.

To do this, the team evaluated survival in 4 groups of mice: (1) irradiated controls; (2) mice that received only bone marrow; (3) mice that received Tcon, CD4+ iNKT cells, and a graft depleted of CD4+ FoxP3+ Tregs; and (4) mice that received Tcon, CD4+ iNKT cells, and a non-depleted graft.

“Animals that received a Treg-depleted graft and were treated with CD4+ iNKT [plus Tcon] did not show a significant improvement in survival [over controls],” Dr Schneidawind said.

“In contrast, animals that received a Treg-non-depleted graft showed a significant improvement in survival [P=0.006]. So we conclude that the expansion of these Tregs is necessary to protect from GVHD lethality and that they are required in this context.”

In closing, Dr Schneidawind noted that, although human CD4+ iNKT cells are rare, they can be isolated from peripheral blood and expanded in vitro. This suggests his group’s findings might ultimately prove useful for patients.

*Information in the abstract differs from that presented.

GRAPEVINE, TEXAS—Adding specialized T cells to allogeneic bone marrow transplants can prevent graft-vs-host disease (GVHD) while preserving the graft-vs-tumor (GVT) effect, preclinical research suggests.

Donor-derived CD4+ invariant natural killer T cells (iNKT cells) helped protect mice from developing GVHD and lymphoma, thereby improving their survival.

As human CD4+ iNKT cells can be expanded in vitro, these findings may translate to the clinic, said study investigator Dominik Schneidawind, MD, of Stanford University in California.

Dr Schneidawind discussed this research at the 2014 BMT Tandem Meetings as abstract 2*, which was designated one of the meeting’s “Best Abstracts.”

Improved survival

Dr Schneidawind and his colleagues created a model of allogeneic bone marrow transplant in Balb/c (H-2Kd) mice. The mice were first irradiated with 8 Gy and then received T cell-depleted bone marrow, along with 1 x 10⁶ CD4/CD8 T cells (Tcon) from C57Bl/6 (H-2Kb) donor mice and varying doses of CD4+ iNKT cells: 1 x 10⁴ to 1 x 10⁵.

Mice that received 100,000 CD4+ iNKT cells had significantly improved survival (P=0.002)—and better weight and GVHD scores—compared to mice that received bone marrow grafts alone. But a CD4+ iNKT dose as low as 10,000 cells also conferred a significant improvement in survival (P=0.03).

“In contrast, you need roughly 500,000 to 1 million donor-derived regulatory T cells to achieve a comparable survival benefit in this model of bone marrow transplantation,” Dr Schneidawind noted.

GVT effect

Dr Schneidawind and his colleagues also evaluated the impact of CD4+ iNKT cells on the GVT effect. They used luciferase-transfected BCL1 cells to induce lymphoma development, injecting the cells into mice 1 day before transplant.

Mice that received BCL1 cells, with or without CD4+ iNKT cells, showed increasing bioluminescence imaging (BLI) signals and all died from progressive lymphoma. The mice that received BLC1 and Tcon did not show an increase in BLI signals, but they all died from GVHD.

However, the mice that received BCL1, Tcon, and CD4+ iNKT cells didn’t show any sign of lymphoma or GVHD and survived through the whole experiment (P=0.002).

The investigators conducted the same experiment with the luciferase-positive A20 cell line. And they observed similar results. Mice that received A20 cells, Tcon, and CD4+ iNKT cells showed no sign of lymphoma and had significantly improved survival (P=0.002) over animals that received A20 and Tcon.

“Interestingly, animals that received A20 cells and 50,000 CD4+ iNKT cells only, without Tcon, showed a significant decrease in BLI signal and significantly improved survival,” Dr Schneidawind noted.

“So we conclude from these experiments that CD4+ iNKT cells do not abrogate the Tcon-mediated [GVT] effect but might exert some distinct antitumor activity by themselves.”

Mechanism of GVHD prevention

Lastly, Dr Schneidawind and his colleagues wanted to determine exactly how CD4+ iNKT cells prevent GVHD. The group’s experiments showed that the cells inhibit the proliferation of alloreactive T cells and promote the expansion of donor-derived CD4+ FoxP3+ Tregs.

The investigators decided to take a closer look at the Tregs, evaluating their role in GVHD-related death.

To do this, the team evaluated survival in 4 groups of mice: (1) irradiated controls; (2) mice that received only bone marrow; (3) mice that received Tcon, CD4+ iNKT cells, and a graft depleted of CD4+ FoxP3+ Tregs; and (4) mice that received Tcon, CD4+ iNKT cells, and a non-depleted graft.

“Animals that received a Treg-depleted graft and were treated with CD4+ iNKT [plus Tcon] did not show a significant improvement in survival [over controls],” Dr Schneidawind said.

“In contrast, animals that received a Treg-non-depleted graft showed a significant improvement in survival [P=0.006]. So we conclude that the expansion of these Tregs is necessary to protect from GVHD lethality and that they are required in this context.”

In closing, Dr Schneidawind noted that, although human CD4+ iNKT cells are rare, they can be isolated from peripheral blood and expanded in vitro. This suggests his group’s findings might ultimately prove useful for patients.

*Information in the abstract differs from that presented.

GRAPEVINE, TEXAS—Adding specialized T cells to allogeneic bone marrow transplants can prevent graft-vs-host disease (GVHD) while preserving the graft-vs-tumor (GVT) effect, preclinical research suggests.

Donor-derived CD4+ invariant natural killer T cells (iNKT cells) helped protect mice from developing GVHD and lymphoma, thereby improving their survival.

As human CD4+ iNKT cells can be expanded in vitro, these findings may translate to the clinic, said study investigator Dominik Schneidawind, MD, of Stanford University in California.

Dr Schneidawind discussed this research at the 2014 BMT Tandem Meetings as abstract 2*, which was designated one of the meeting’s “Best Abstracts.”

Improved survival

Dr Schneidawind and his colleagues created a model of allogeneic bone marrow transplant in Balb/c (H-2Kd) mice. The mice were first irradiated with 8 Gy and then received T cell-depleted bone marrow, along with 1 x 10⁶ CD4/CD8 T cells (Tcon) from C57Bl/6 (H-2Kb) donor mice and varying doses of CD4+ iNKT cells: 1 x 10⁴ to 1 x 10⁵.

Mice that received 100,000 CD4+ iNKT cells had significantly improved survival (P=0.002)—and better weight and GVHD scores—compared to mice that received bone marrow grafts alone. But a CD4+ iNKT dose as low as 10,000 cells also conferred a significant improvement in survival (P=0.03).

“In contrast, you need roughly 500,000 to 1 million donor-derived regulatory T cells to achieve a comparable survival benefit in this model of bone marrow transplantation,” Dr Schneidawind noted.

GVT effect

Dr Schneidawind and his colleagues also evaluated the impact of CD4+ iNKT cells on the GVT effect. They used luciferase-transfected BCL1 cells to induce lymphoma development, injecting the cells into mice 1 day before transplant.

Mice that received BCL1 cells, with or without CD4+ iNKT cells, showed increasing bioluminescence imaging (BLI) signals and all died from progressive lymphoma. The mice that received BLC1 and Tcon did not show an increase in BLI signals, but they all died from GVHD.

However, the mice that received BCL1, Tcon, and CD4+ iNKT cells didn’t show any sign of lymphoma or GVHD and survived through the whole experiment (P=0.002).

The investigators conducted the same experiment with the luciferase-positive A20 cell line. And they observed similar results. Mice that received A20 cells, Tcon, and CD4+ iNKT cells showed no sign of lymphoma and had significantly improved survival (P=0.002) over animals that received A20 and Tcon.

“Interestingly, animals that received A20 cells and 50,000 CD4+ iNKT cells only, without Tcon, showed a significant decrease in BLI signal and significantly improved survival,” Dr Schneidawind noted.

“So we conclude from these experiments that CD4+ iNKT cells do not abrogate the Tcon-mediated [GVT] effect but might exert some distinct antitumor activity by themselves.”

Mechanism of GVHD prevention

Lastly, Dr Schneidawind and his colleagues wanted to determine exactly how CD4+ iNKT cells prevent GVHD. The group’s experiments showed that the cells inhibit the proliferation of alloreactive T cells and promote the expansion of donor-derived CD4+ FoxP3+ Tregs.

The investigators decided to take a closer look at the Tregs, evaluating their role in GVHD-related death.

To do this, the team evaluated survival in 4 groups of mice: (1) irradiated controls; (2) mice that received only bone marrow; (3) mice that received Tcon, CD4+ iNKT cells, and a graft depleted of CD4+ FoxP3+ Tregs; and (4) mice that received Tcon, CD4+ iNKT cells, and a non-depleted graft.

“Animals that received a Treg-depleted graft and were treated with CD4+ iNKT [plus Tcon] did not show a significant improvement in survival [over controls],” Dr Schneidawind said.

“In contrast, animals that received a Treg-non-depleted graft showed a significant improvement in survival [P=0.006]. So we conclude that the expansion of these Tregs is necessary to protect from GVHD lethality and that they are required in this context.”

In closing, Dr Schneidawind noted that, although human CD4+ iNKT cells are rare, they can be isolated from peripheral blood and expanded in vitro. This suggests his group’s findings might ultimately prove useful for patients.

*Information in the abstract differs from that presented.