HOLLYWOOD, FLA. – The National Comprehensive Cancer Network has issued new guidelines for the diagnosis and management of vulvar cancer.

Vulvar cancers are rare neoplasms, with an estimated U.S. annual incidence of 5,950 cases, and 1,110 deaths. The majority of cases (about 90%) are of squamous cell histology.

Treatment of vulvar cancer has evolved from en bloc resections used throughout most of the 20th century, to more refined techniques, said Dr. Benjamin E. Greer, professor of gynecological oncology at the University of Washington in Seattle.

“In the 1980s, we started to modify treatment to reduce morbidity,” he said at the annual conference of the National Comprehensive Cancer Network.

With older, more radical techniques, groin breakdown, leg edema, and impaired sexual function were common post-surgery consequences. Current practice, however, is to perform regional lymph node management for unilateral cancers, radical local excision rather than en bloc resections, separate groin incisions, lymphatic mapping, radiation, chemotherapy, and, if necessary, exenteration, Dr. Greer noted.

The guidelines note that adequate surgical margins – 1 to 2 cm – at the time of primary surgery appear to be essential for reducing risk of local recurrence, and that if margins are within 8 mm of tumor, the surgeon should consider re-excision or adjuvant radiation.

Lymph node status is the most important determinant of survival, with historical reports showing overall survival following surgery of 70% to 80% among patients with negative nodes, compared with 30% to 40% of those with positive nodes, he said.

Evaluation of bilateral inguinofemoral groin nodes should be performed in patients with lesions in the vulvar midline, and ipsilateral groin node evaluation should be performed for those with lateral lesions lying more than 2 cm from the vulvar midline. Additionally, select patients may require sentinel lymph node biopsy, the guidelines state.

Unilateral carcinomas of the vulva can be treated with limited radical vulvectomy and ipsilateral inguinal femoral node dissection. Lymph node dissection can be performed through a separate incision. For patients with positive nodes, adjuvant radiation may aid in disease control. Patients with inoperable carcinomas are recommended to receive radiation and chemotherapy.

Radiation for vulvar cancer

“For early stage tumors, adjuvant radiotherapy is an effective treatment modality that significantly decreases recurrence, especially in surgically resected groins, and it leads to improvement in relapse-free and overall survival,” said Dr. Wui-Jin Koh, medical director for radiation oncology at the Fred Hutchinson Cancer Research Center in Seattle.

Concurrent chemotherapy and radiation may provide additional therapeutic benefit, especially for patients with advanced, unresectable tumors, and it may help to address systemic risk in patients with multiple positive lymph nodes, Dr. Koh said.

The guidelines state that radiation can be given with external beam radiation delivered via a 3D-conformal or intensity modulated (IMRT) technique, with brachytherapy boost for some tumors where the anatomy permits.

“Careful attention should be taken to ensure adequate tumor coverage by combining clinical examination, imaging findings, and appropriate nodal volumes at risk to define the target volume,” the guideline states.

For adjuvant therapy, doses of 50.4 Gy divided in 1.8 Gy fractions should be delivered once daily 5 days per week, with minimal treatment breaks.

For treatment of unresectable tumors, doses range from 59.4 Gy to 64.8 Gy in 1.8 Gy fractions, with a boost dose to approximately 70 Gy for large lymph nodes in select cases.

Residual disease

The decision to provide additional treatment following surgery is based on whether the patient is clinically negative for residual tumor at the primary site and nodes.

“If one has negative margins and negative nodes? Observation, absolutely,” Dr. Koh said. “If one has positive margins for invasive disease, our recommendation is to re-excise and not go straight to radiation, and if one can do it and get negative margins, again observe the majority of them.”

“Use radiation very judiciously,” he added. “Only if patients have positive margins or have unresectable primary disease do we routinely recommend radiation.”

Locally advanced disease

For patients who cannot be treated with conventional or sphincter-sparing, organ preserving surgery upfront, the recommendation is to provide chemoradiation, with initial radiation to the primary site, groins, and pelvis, and concurrent week cisplatin at a dose of 30-40 mg/m² per week. The recommended radiation doses are 45 Gy to at-risk, microscopic clinical tumor volume, and 57.6 to 60 Gy to gross tumor volume (primary site and nodes).

“If one uses IMRT, you need to be very generous with the volumes,” Dr. Koh said.

The panelists also recommend re-imaging and re-evaluating patients 6 to 8 weeks after the completion of chemoradiation, with possible resection or biopsy of the primary tumor site, and limited groin resection of imaged residual disease.

For patients with clearly node-positive disease, “my general preference is to give upfront chemoradiation therapy to avoid delay of primary therapy, and then resect residual nodes after the chemoradiation is done,” he said.

HOLLYWOOD, FLA. – The National Comprehensive Cancer Network has issued new guidelines for the diagnosis and management of vulvar cancer.

Vulvar cancers are rare neoplasms, with an estimated U.S. annual incidence of 5,950 cases, and 1,110 deaths. The majority of cases (about 90%) are of squamous cell histology.

Treatment of vulvar cancer has evolved from en bloc resections used throughout most of the 20th century, to more refined techniques, said Dr. Benjamin E. Greer, professor of gynecological oncology at the University of Washington in Seattle.

“In the 1980s, we started to modify treatment to reduce morbidity,” he said at the annual conference of the National Comprehensive Cancer Network.

With older, more radical techniques, groin breakdown, leg edema, and impaired sexual function were common post-surgery consequences. Current practice, however, is to perform regional lymph node management for unilateral cancers, radical local excision rather than en bloc resections, separate groin incisions, lymphatic mapping, radiation, chemotherapy, and, if necessary, exenteration, Dr. Greer noted.

The guidelines note that adequate surgical margins – 1 to 2 cm – at the time of primary surgery appear to be essential for reducing risk of local recurrence, and that if margins are within 8 mm of tumor, the surgeon should consider re-excision or adjuvant radiation.

Lymph node status is the most important determinant of survival, with historical reports showing overall survival following surgery of 70% to 80% among patients with negative nodes, compared with 30% to 40% of those with positive nodes, he said.

Evaluation of bilateral inguinofemoral groin nodes should be performed in patients with lesions in the vulvar midline, and ipsilateral groin node evaluation should be performed for those with lateral lesions lying more than 2 cm from the vulvar midline. Additionally, select patients may require sentinel lymph node biopsy, the guidelines state.

Unilateral carcinomas of the vulva can be treated with limited radical vulvectomy and ipsilateral inguinal femoral node dissection. Lymph node dissection can be performed through a separate incision. For patients with positive nodes, adjuvant radiation may aid in disease control. Patients with inoperable carcinomas are recommended to receive radiation and chemotherapy.

Radiation for vulvar cancer

“For early stage tumors, adjuvant radiotherapy is an effective treatment modality that significantly decreases recurrence, especially in surgically resected groins, and it leads to improvement in relapse-free and overall survival,” said Dr. Wui-Jin Koh, medical director for radiation oncology at the Fred Hutchinson Cancer Research Center in Seattle.

Concurrent chemotherapy and radiation may provide additional therapeutic benefit, especially for patients with advanced, unresectable tumors, and it may help to address systemic risk in patients with multiple positive lymph nodes, Dr. Koh said.

The guidelines state that radiation can be given with external beam radiation delivered via a 3D-conformal or intensity modulated (IMRT) technique, with brachytherapy boost for some tumors where the anatomy permits.

“Careful attention should be taken to ensure adequate tumor coverage by combining clinical examination, imaging findings, and appropriate nodal volumes at risk to define the target volume,” the guideline states.

For adjuvant therapy, doses of 50.4 Gy divided in 1.8 Gy fractions should be delivered once daily 5 days per week, with minimal treatment breaks.

For treatment of unresectable tumors, doses range from 59.4 Gy to 64.8 Gy in 1.8 Gy fractions, with a boost dose to approximately 70 Gy for large lymph nodes in select cases.

Residual disease

The decision to provide additional treatment following surgery is based on whether the patient is clinically negative for residual tumor at the primary site and nodes.

“If one has negative margins and negative nodes? Observation, absolutely,” Dr. Koh said. “If one has positive margins for invasive disease, our recommendation is to re-excise and not go straight to radiation, and if one can do it and get negative margins, again observe the majority of them.”

“Use radiation very judiciously,” he added. “Only if patients have positive margins or have unresectable primary disease do we routinely recommend radiation.”

Locally advanced disease

For patients who cannot be treated with conventional or sphincter-sparing, organ preserving surgery upfront, the recommendation is to provide chemoradiation, with initial radiation to the primary site, groins, and pelvis, and concurrent week cisplatin at a dose of 30-40 mg/m² per week. The recommended radiation doses are 45 Gy to at-risk, microscopic clinical tumor volume, and 57.6 to 60 Gy to gross tumor volume (primary site and nodes).

“If one uses IMRT, you need to be very generous with the volumes,” Dr. Koh said.

The panelists also recommend re-imaging and re-evaluating patients 6 to 8 weeks after the completion of chemoradiation, with possible resection or biopsy of the primary tumor site, and limited groin resection of imaged residual disease.

For patients with clearly node-positive disease, “my general preference is to give upfront chemoradiation therapy to avoid delay of primary therapy, and then resect residual nodes after the chemoradiation is done,” he said.

HOLLYWOOD, FLA. – The National Comprehensive Cancer Network has issued new guidelines for the diagnosis and management of vulvar cancer.

Vulvar cancers are rare neoplasms, with an estimated U.S. annual incidence of 5,950 cases, and 1,110 deaths. The majority of cases (about 90%) are of squamous cell histology.

Treatment of vulvar cancer has evolved from en bloc resections used throughout most of the 20th century, to more refined techniques, said Dr. Benjamin E. Greer, professor of gynecological oncology at the University of Washington in Seattle.

“In the 1980s, we started to modify treatment to reduce morbidity,” he said at the annual conference of the National Comprehensive Cancer Network.

With older, more radical techniques, groin breakdown, leg edema, and impaired sexual function were common post-surgery consequences. Current practice, however, is to perform regional lymph node management for unilateral cancers, radical local excision rather than en bloc resections, separate groin incisions, lymphatic mapping, radiation, chemotherapy, and, if necessary, exenteration, Dr. Greer noted.

The guidelines note that adequate surgical margins – 1 to 2 cm – at the time of primary surgery appear to be essential for reducing risk of local recurrence, and that if margins are within 8 mm of tumor, the surgeon should consider re-excision or adjuvant radiation.

Lymph node status is the most important determinant of survival, with historical reports showing overall survival following surgery of 70% to 80% among patients with negative nodes, compared with 30% to 40% of those with positive nodes, he said.

Evaluation of bilateral inguinofemoral groin nodes should be performed in patients with lesions in the vulvar midline, and ipsilateral groin node evaluation should be performed for those with lateral lesions lying more than 2 cm from the vulvar midline. Additionally, select patients may require sentinel lymph node biopsy, the guidelines state.

Unilateral carcinomas of the vulva can be treated with limited radical vulvectomy and ipsilateral inguinal femoral node dissection. Lymph node dissection can be performed through a separate incision. For patients with positive nodes, adjuvant radiation may aid in disease control. Patients with inoperable carcinomas are recommended to receive radiation and chemotherapy.

Radiation for vulvar cancer

“For early stage tumors, adjuvant radiotherapy is an effective treatment modality that significantly decreases recurrence, especially in surgically resected groins, and it leads to improvement in relapse-free and overall survival,” said Dr. Wui-Jin Koh, medical director for radiation oncology at the Fred Hutchinson Cancer Research Center in Seattle.

Concurrent chemotherapy and radiation may provide additional therapeutic benefit, especially for patients with advanced, unresectable tumors, and it may help to address systemic risk in patients with multiple positive lymph nodes, Dr. Koh said.

The guidelines state that radiation can be given with external beam radiation delivered via a 3D-conformal or intensity modulated (IMRT) technique, with brachytherapy boost for some tumors where the anatomy permits.

“Careful attention should be taken to ensure adequate tumor coverage by combining clinical examination, imaging findings, and appropriate nodal volumes at risk to define the target volume,” the guideline states.

For adjuvant therapy, doses of 50.4 Gy divided in 1.8 Gy fractions should be delivered once daily 5 days per week, with minimal treatment breaks.

For treatment of unresectable tumors, doses range from 59.4 Gy to 64.8 Gy in 1.8 Gy fractions, with a boost dose to approximately 70 Gy for large lymph nodes in select cases.

Residual disease

The decision to provide additional treatment following surgery is based on whether the patient is clinically negative for residual tumor at the primary site and nodes.

“If one has negative margins and negative nodes? Observation, absolutely,” Dr. Koh said. “If one has positive margins for invasive disease, our recommendation is to re-excise and not go straight to radiation, and if one can do it and get negative margins, again observe the majority of them.”

“Use radiation very judiciously,” he added. “Only if patients have positive margins or have unresectable primary disease do we routinely recommend radiation.”

Locally advanced disease

For patients who cannot be treated with conventional or sphincter-sparing, organ preserving surgery upfront, the recommendation is to provide chemoradiation, with initial radiation to the primary site, groins, and pelvis, and concurrent week cisplatin at a dose of 30-40 mg/m² per week. The recommended radiation doses are 45 Gy to at-risk, microscopic clinical tumor volume, and 57.6 to 60 Gy to gross tumor volume (primary site and nodes).

“If one uses IMRT, you need to be very generous with the volumes,” Dr. Koh said.

The panelists also recommend re-imaging and re-evaluating patients 6 to 8 weeks after the completion of chemoradiation, with possible resection or biopsy of the primary tumor site, and limited groin resection of imaged residual disease.

For patients with clearly node-positive disease, “my general preference is to give upfront chemoradiation therapy to avoid delay of primary therapy, and then resect residual nodes after the chemoradiation is done,” he said.

Two academic hospitalists talk about why they teach, what they're learning from their students, and what they see as the future of hospital medicine. Since academic HM is the new-hospitalist pipeline, hearing what they're seeing in their student and resident trainee corps is a snapshot of HM's sustainability.

Two academic hospitalists talk about why they teach, what they're learning from their students, and what they see as the future of hospital medicine. Since academic HM is the new-hospitalist pipeline, hearing what they're seeing in their student and resident trainee corps is a snapshot of HM's sustainability.

Two academic hospitalists talk about why they teach, what they're learning from their students, and what they see as the future of hospital medicine. Since academic HM is the new-hospitalist pipeline, hearing what they're seeing in their student and resident trainee corps is a snapshot of HM's sustainability.

AMSTERDAM – Patients with milder knee osteoarthritis symptoms or better quality of life before undergoing total knee replacement surgery gained less benefit from the surgery than did those who had more severe symptoms in two separate analyses of British and U.S. patients.

Additional evidence from total knee replacements (TKRs) performed on U.S. participants of the Osteoarthritis Initiative also suggest that as the use of TKR has increased to include less symptomatic patients, the overall cost-effectiveness of the procedure has declined.

©pixologicstudio/ thinkstockphotos.com

“Knee replacements are one of those interventions that are known to be very effective and very cost-effective,” Rafael Pinedo-Villanueva, Ph.D., of the University of Oxford (England) said during his presentation of National Health Service data from England at the World Congress on Osteoarthritis. Indeed, knee replacements are associated with significant improvements in pain, function, and quality of life, he said, but that is if you look at the mean values.

As the deciles for baseline knee pain and function decrease in severity, there are diminishing mean improvements and an increasing proportion of patients who do worse after the operation, he reported. Up to 17% of patients had unchanged or improved knee pain scores and up to 27% had lower quality of life scores. If minimally important differences were considered, these percentages rose to 40% and 48% of patients being worse off, respectively.

“The significant improvements seem to be overshadowing what happens to those patients who are doing worse,” Dr. Pinedo-Villanueva suggested. “So essentially cost-effectiveness is being driven by the magnitude of the change in those who do improve, and we don’t really see much about what is happening to those who are doing worse.”

Of over 215,000 records of knee replacement collected from all patients undergoing TKR in England during 2008-2012, Dr. Pinedo-Villanueva and his study coauthors found 117,844 had data on pre- and post-operative knee pain assessed using the Oxford Knee Score (OKS) and quality of life measured with the EQ-5D instrument. The majority of replacements were in women (55%) and almost three quarters of patients had one or no comorbidities. Overall, the mean change in OKS was 15 points, improving from 19 to 34 (the higher the score the lesser the knee pain). EQ-5D scores also improved by a mean difference of 0.30 (from 0.41 to 0.70 where 1.0 is perfect health). Although the vast majority of patients had improved OKS and EQ-5D scores after surgery, unchanged or decreased scores were seen in 8% and 22% of patients, respectively.

“As we breakdown these data by deciles of baseline pain and function we see clearly that those starting at the lower decile improved the most, and that’s to be expected; they’ve a lot more to improve than the ones that came into the operation at the higher decile,” Dr. Pinedo-Villanueva said at the Congress, sponsored by the Osteoarthritis Research Society International. But there were patients who fared worse at every decile, he noted.

Dr. Pinedo-Villanueva concluded that outcome prediction models were needed to try to reduce the number of patients who are apparently worse off after knee replacement and improve the efficiency of resource allocation.

The value of TKR in a contemporary U.S. population was the focus of a separate presentation by Dr. Bart Ferket of Mount Sinai Hospital in New York. Dr. Ferket reported the results of a study looking at the impact of TKR on patients’ quality of life, lifetime costs, and quality-adjusted life years (QALYs) while varying the use of TKR by patients’ functional status at baseline.

“In the United States, the rate at which total knee replacement is performed has doubled in the last two decades,” Dr. Ferket observed. This “disproportionate” increase has been attributed to expanding the eligibility criteria to include less symptomatic patients.

Using data collected over an 8-year period on 1,327 participants from the Osteoarthritis Initiative, Dr. Ferket and his associates at Mount Sinai and Erasmus University Medical Center in Rotterdam (The Netherlands) discovered that the increased uptake of TKR might have affected the likely benefit and reduced the overall cost-effectiveness of the procedure.

At baseline, 17% of the participants, who all had knee osteoarthritis, had had a prior knee replacement.

Quality of life measured on the physical component scores (PCS) of the 12-item Short Form (SF-12) were generally improved after TKR but decreased in those who did not have a knee replaced. The effect on the mental component of the SF-12 was less clear, with possibly a decrease seen in some patients. Changes on the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and Knee injury and Osteoarthritis Outcome Score (KOOS) showed a considerable benefit for knee replacement and there was a general decrease in pain medication over time in those who had surgery. The overall effect was more pronounced if patients with greater baseline symptoms were considered.

Cost-effectiveness modeling showed that reserving TKR for more seriously affected patients may make it more economically attractive. The QALYs gained from TKR was about 11 but as the number of QALYs increased, so did the relative lifetime cost, with increasing incremental cost-effectiveness ratios (ICERs) as SF-12 PCS rose. ICERs were around $143,000, $160,000, $217,000, $385,000, and $1,175,000 considering patients with SF-12 PCS of less than 30, 35, 40, 45, and 50, respectively.

“The more lenient the eligibility criteria are, the higher the effectiveness, but also the higher the costs,” Dr. Ferket said. “The most cost-effective scenarios are actually more restrictive that what is currently seen in current practice in the U.S.”

Dr. Pinedo-Villanueva and Dr. Ferket reported having no financial disclosures.

AMSTERDAM – Patients with milder knee osteoarthritis symptoms or better quality of life before undergoing total knee replacement surgery gained less benefit from the surgery than did those who had more severe symptoms in two separate analyses of British and U.S. patients.

Additional evidence from total knee replacements (TKRs) performed on U.S. participants of the Osteoarthritis Initiative also suggest that as the use of TKR has increased to include less symptomatic patients, the overall cost-effectiveness of the procedure has declined.

©pixologicstudio/ thinkstockphotos.com

“Knee replacements are one of those interventions that are known to be very effective and very cost-effective,” Rafael Pinedo-Villanueva, Ph.D., of the University of Oxford (England) said during his presentation of National Health Service data from England at the World Congress on Osteoarthritis. Indeed, knee replacements are associated with significant improvements in pain, function, and quality of life, he said, but that is if you look at the mean values.

As the deciles for baseline knee pain and function decrease in severity, there are diminishing mean improvements and an increasing proportion of patients who do worse after the operation, he reported. Up to 17% of patients had unchanged or improved knee pain scores and up to 27% had lower quality of life scores. If minimally important differences were considered, these percentages rose to 40% and 48% of patients being worse off, respectively.

“The significant improvements seem to be overshadowing what happens to those patients who are doing worse,” Dr. Pinedo-Villanueva suggested. “So essentially cost-effectiveness is being driven by the magnitude of the change in those who do improve, and we don’t really see much about what is happening to those who are doing worse.”

Of over 215,000 records of knee replacement collected from all patients undergoing TKR in England during 2008-2012, Dr. Pinedo-Villanueva and his study coauthors found 117,844 had data on pre- and post-operative knee pain assessed using the Oxford Knee Score (OKS) and quality of life measured with the EQ-5D instrument. The majority of replacements were in women (55%) and almost three quarters of patients had one or no comorbidities. Overall, the mean change in OKS was 15 points, improving from 19 to 34 (the higher the score the lesser the knee pain). EQ-5D scores also improved by a mean difference of 0.30 (from 0.41 to 0.70 where 1.0 is perfect health). Although the vast majority of patients had improved OKS and EQ-5D scores after surgery, unchanged or decreased scores were seen in 8% and 22% of patients, respectively.

“As we breakdown these data by deciles of baseline pain and function we see clearly that those starting at the lower decile improved the most, and that’s to be expected; they’ve a lot more to improve than the ones that came into the operation at the higher decile,” Dr. Pinedo-Villanueva said at the Congress, sponsored by the Osteoarthritis Research Society International. But there were patients who fared worse at every decile, he noted.

Dr. Pinedo-Villanueva concluded that outcome prediction models were needed to try to reduce the number of patients who are apparently worse off after knee replacement and improve the efficiency of resource allocation.

The value of TKR in a contemporary U.S. population was the focus of a separate presentation by Dr. Bart Ferket of Mount Sinai Hospital in New York. Dr. Ferket reported the results of a study looking at the impact of TKR on patients’ quality of life, lifetime costs, and quality-adjusted life years (QALYs) while varying the use of TKR by patients’ functional status at baseline.

“In the United States, the rate at which total knee replacement is performed has doubled in the last two decades,” Dr. Ferket observed. This “disproportionate” increase has been attributed to expanding the eligibility criteria to include less symptomatic patients.

Using data collected over an 8-year period on 1,327 participants from the Osteoarthritis Initiative, Dr. Ferket and his associates at Mount Sinai and Erasmus University Medical Center in Rotterdam (The Netherlands) discovered that the increased uptake of TKR might have affected the likely benefit and reduced the overall cost-effectiveness of the procedure.

At baseline, 17% of the participants, who all had knee osteoarthritis, had had a prior knee replacement.

Quality of life measured on the physical component scores (PCS) of the 12-item Short Form (SF-12) were generally improved after TKR but decreased in those who did not have a knee replaced. The effect on the mental component of the SF-12 was less clear, with possibly a decrease seen in some patients. Changes on the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and Knee injury and Osteoarthritis Outcome Score (KOOS) showed a considerable benefit for knee replacement and there was a general decrease in pain medication over time in those who had surgery. The overall effect was more pronounced if patients with greater baseline symptoms were considered.

Cost-effectiveness modeling showed that reserving TKR for more seriously affected patients may make it more economically attractive. The QALYs gained from TKR was about 11 but as the number of QALYs increased, so did the relative lifetime cost, with increasing incremental cost-effectiveness ratios (ICERs) as SF-12 PCS rose. ICERs were around $143,000, $160,000, $217,000, $385,000, and $1,175,000 considering patients with SF-12 PCS of less than 30, 35, 40, 45, and 50, respectively.

“The more lenient the eligibility criteria are, the higher the effectiveness, but also the higher the costs,” Dr. Ferket said. “The most cost-effective scenarios are actually more restrictive that what is currently seen in current practice in the U.S.”

Dr. Pinedo-Villanueva and Dr. Ferket reported having no financial disclosures.

AMSTERDAM – Patients with milder knee osteoarthritis symptoms or better quality of life before undergoing total knee replacement surgery gained less benefit from the surgery than did those who had more severe symptoms in two separate analyses of British and U.S. patients.

Additional evidence from total knee replacements (TKRs) performed on U.S. participants of the Osteoarthritis Initiative also suggest that as the use of TKR has increased to include less symptomatic patients, the overall cost-effectiveness of the procedure has declined.

©pixologicstudio/ thinkstockphotos.com

“Knee replacements are one of those interventions that are known to be very effective and very cost-effective,” Rafael Pinedo-Villanueva, Ph.D., of the University of Oxford (England) said during his presentation of National Health Service data from England at the World Congress on Osteoarthritis. Indeed, knee replacements are associated with significant improvements in pain, function, and quality of life, he said, but that is if you look at the mean values.

As the deciles for baseline knee pain and function decrease in severity, there are diminishing mean improvements and an increasing proportion of patients who do worse after the operation, he reported. Up to 17% of patients had unchanged or improved knee pain scores and up to 27% had lower quality of life scores. If minimally important differences were considered, these percentages rose to 40% and 48% of patients being worse off, respectively.

“The significant improvements seem to be overshadowing what happens to those patients who are doing worse,” Dr. Pinedo-Villanueva suggested. “So essentially cost-effectiveness is being driven by the magnitude of the change in those who do improve, and we don’t really see much about what is happening to those who are doing worse.”

Of over 215,000 records of knee replacement collected from all patients undergoing TKR in England during 2008-2012, Dr. Pinedo-Villanueva and his study coauthors found 117,844 had data on pre- and post-operative knee pain assessed using the Oxford Knee Score (OKS) and quality of life measured with the EQ-5D instrument. The majority of replacements were in women (55%) and almost three quarters of patients had one or no comorbidities. Overall, the mean change in OKS was 15 points, improving from 19 to 34 (the higher the score the lesser the knee pain). EQ-5D scores also improved by a mean difference of 0.30 (from 0.41 to 0.70 where 1.0 is perfect health). Although the vast majority of patients had improved OKS and EQ-5D scores after surgery, unchanged or decreased scores were seen in 8% and 22% of patients, respectively.

“As we breakdown these data by deciles of baseline pain and function we see clearly that those starting at the lower decile improved the most, and that’s to be expected; they’ve a lot more to improve than the ones that came into the operation at the higher decile,” Dr. Pinedo-Villanueva said at the Congress, sponsored by the Osteoarthritis Research Society International. But there were patients who fared worse at every decile, he noted.

Dr. Pinedo-Villanueva concluded that outcome prediction models were needed to try to reduce the number of patients who are apparently worse off after knee replacement and improve the efficiency of resource allocation.

The value of TKR in a contemporary U.S. population was the focus of a separate presentation by Dr. Bart Ferket of Mount Sinai Hospital in New York. Dr. Ferket reported the results of a study looking at the impact of TKR on patients’ quality of life, lifetime costs, and quality-adjusted life years (QALYs) while varying the use of TKR by patients’ functional status at baseline.

“In the United States, the rate at which total knee replacement is performed has doubled in the last two decades,” Dr. Ferket observed. This “disproportionate” increase has been attributed to expanding the eligibility criteria to include less symptomatic patients.

Using data collected over an 8-year period on 1,327 participants from the Osteoarthritis Initiative, Dr. Ferket and his associates at Mount Sinai and Erasmus University Medical Center in Rotterdam (The Netherlands) discovered that the increased uptake of TKR might have affected the likely benefit and reduced the overall cost-effectiveness of the procedure.

At baseline, 17% of the participants, who all had knee osteoarthritis, had had a prior knee replacement.

Quality of life measured on the physical component scores (PCS) of the 12-item Short Form (SF-12) were generally improved after TKR but decreased in those who did not have a knee replaced. The effect on the mental component of the SF-12 was less clear, with possibly a decrease seen in some patients. Changes on the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and Knee injury and Osteoarthritis Outcome Score (KOOS) showed a considerable benefit for knee replacement and there was a general decrease in pain medication over time in those who had surgery. The overall effect was more pronounced if patients with greater baseline symptoms were considered.

Cost-effectiveness modeling showed that reserving TKR for more seriously affected patients may make it more economically attractive. The QALYs gained from TKR was about 11 but as the number of QALYs increased, so did the relative lifetime cost, with increasing incremental cost-effectiveness ratios (ICERs) as SF-12 PCS rose. ICERs were around $143,000, $160,000, $217,000, $385,000, and $1,175,000 considering patients with SF-12 PCS of less than 30, 35, 40, 45, and 50, respectively.

“The more lenient the eligibility criteria are, the higher the effectiveness, but also the higher the costs,” Dr. Ferket said. “The most cost-effective scenarios are actually more restrictive that what is currently seen in current practice in the U.S.”

Dr. Pinedo-Villanueva and Dr. Ferket reported having no financial disclosures.

Lab mouse

Results of preclinical research indicate that combining 2 kinase inhibitors may be a promising treatment strategy for Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL).

Researchers found that combining a tyrosine kinase inhibitor (TKI) and an inhibitor of focal adhesion kinase (FAK) was “remarkably effective” against Ph+ B-ALL in vitro and in vivo.

The TKI dasatinib and the FAK inhibitor VS-4718 decreased leukemic cell survival and adhesion, inhibited tumor growth, and prolonged survival in mouse models of Ph+ B-ALL.

Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported their results in JCI Insight.

The researchers noted that patients with Ph+ ALL have shown resistance to TKI therapy, and this resistance has been tied to alterations in IKZF1.

As FAK expression is elevated in IKZF1-mutated leukemias, the team speculated that adding a FAK inhibitor to TKI therapy might lead to better results.

First, the researchers set out to confirm that FAK is overexpressed in Ph+ B-ALL. Their experiments revealed upregulation of the FAK pathway in Ph+ B-ALL cells, with further overexpression of FAK in IKZF1-mutated Ph+ B-ALL cells.

When they inhibited FAK with VS-4718, the team observed decreases in the survival, clonogenicity, and adhesion of IKZF1-mutated Ph+ B-ALL cells from both mice and humans.

Next, the researchers found that VS-4718 synergizes with the TKI dasatinib in vitro and in vivo.

In in vitro experiments with both mouse and human Ph+ B-ALL cells, the combination decreased cell survival and adhesion and inhibited downstream targets of FAK.

In mouse models of Ph+ B-ALL, VS-4718 proved ineffective when given alone.

However, the researchers said the combination of VS-4718 and dasatinib “dramatically” decreased leukemic burden and extended the lives of mice.

In fact, 1 long-term survivor achieved a complete remission that endured after treatment was stopped.

The researchers said these results suggest that targeting FAK with VS-4718 can overcome the deleterious effects of FAK overexpression in Ph+ B-ALL, potentiating responsiveness to TKIs.

Lab mouse

Results of preclinical research indicate that combining 2 kinase inhibitors may be a promising treatment strategy for Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL).

Researchers found that combining a tyrosine kinase inhibitor (TKI) and an inhibitor of focal adhesion kinase (FAK) was “remarkably effective” against Ph+ B-ALL in vitro and in vivo.

The TKI dasatinib and the FAK inhibitor VS-4718 decreased leukemic cell survival and adhesion, inhibited tumor growth, and prolonged survival in mouse models of Ph+ B-ALL.

Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported their results in JCI Insight.

The researchers noted that patients with Ph+ ALL have shown resistance to TKI therapy, and this resistance has been tied to alterations in IKZF1.

As FAK expression is elevated in IKZF1-mutated leukemias, the team speculated that adding a FAK inhibitor to TKI therapy might lead to better results.

First, the researchers set out to confirm that FAK is overexpressed in Ph+ B-ALL. Their experiments revealed upregulation of the FAK pathway in Ph+ B-ALL cells, with further overexpression of FAK in IKZF1-mutated Ph+ B-ALL cells.

When they inhibited FAK with VS-4718, the team observed decreases in the survival, clonogenicity, and adhesion of IKZF1-mutated Ph+ B-ALL cells from both mice and humans.

Next, the researchers found that VS-4718 synergizes with the TKI dasatinib in vitro and in vivo.

In in vitro experiments with both mouse and human Ph+ B-ALL cells, the combination decreased cell survival and adhesion and inhibited downstream targets of FAK.

In mouse models of Ph+ B-ALL, VS-4718 proved ineffective when given alone.

However, the researchers said the combination of VS-4718 and dasatinib “dramatically” decreased leukemic burden and extended the lives of mice.

In fact, 1 long-term survivor achieved a complete remission that endured after treatment was stopped.

The researchers said these results suggest that targeting FAK with VS-4718 can overcome the deleterious effects of FAK overexpression in Ph+ B-ALL, potentiating responsiveness to TKIs.

Lab mouse

Results of preclinical research indicate that combining 2 kinase inhibitors may be a promising treatment strategy for Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL).

Researchers found that combining a tyrosine kinase inhibitor (TKI) and an inhibitor of focal adhesion kinase (FAK) was “remarkably effective” against Ph+ B-ALL in vitro and in vivo.

The TKI dasatinib and the FAK inhibitor VS-4718 decreased leukemic cell survival and adhesion, inhibited tumor growth, and prolonged survival in mouse models of Ph+ B-ALL.

Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported their results in JCI Insight.

The researchers noted that patients with Ph+ ALL have shown resistance to TKI therapy, and this resistance has been tied to alterations in IKZF1.

As FAK expression is elevated in IKZF1-mutated leukemias, the team speculated that adding a FAK inhibitor to TKI therapy might lead to better results.

First, the researchers set out to confirm that FAK is overexpressed in Ph+ B-ALL. Their experiments revealed upregulation of the FAK pathway in Ph+ B-ALL cells, with further overexpression of FAK in IKZF1-mutated Ph+ B-ALL cells.

When they inhibited FAK with VS-4718, the team observed decreases in the survival, clonogenicity, and adhesion of IKZF1-mutated Ph+ B-ALL cells from both mice and humans.

Next, the researchers found that VS-4718 synergizes with the TKI dasatinib in vitro and in vivo.

In in vitro experiments with both mouse and human Ph+ B-ALL cells, the combination decreased cell survival and adhesion and inhibited downstream targets of FAK.

In mouse models of Ph+ B-ALL, VS-4718 proved ineffective when given alone.

However, the researchers said the combination of VS-4718 and dasatinib “dramatically” decreased leukemic burden and extended the lives of mice.

In fact, 1 long-term survivor achieved a complete remission that endured after treatment was stopped.

The researchers said these results suggest that targeting FAK with VS-4718 can overcome the deleterious effects of FAK overexpression in Ph+ B-ALL, potentiating responsiveness to TKIs.

Clinical question: What are the factors that increase risk of Clostridium difficile infection (CDI) in postoperative patients?

Background: CDI has become an important infectious etiology for morbidity, lengthy and costly hospital admissions, and mortality. This study focused on the risks for postoperative patients to be infected with C. diff. Awareness of the risk factors for CDI allows for processes to be implemented that can decrease the rate of infection.

Study design: Retrospective, observational study.

Setting: Multiple Veterans Health Administration surgery programs.

Synopsis: The study investigated 468,386 surgical procedures in 134 surgical programs in 12 subspecialties over a four-year period. Overall, the postoperative CDI rate was 0.4% per year. Rates were higher in emergency or complex procedures, older patients, patients with longer preoperative hospital stays, and those who received three or more classes of antibiotics. CDI in postoperative patients was associated with five times higher risk of mortality, a 12 times higher risk of morbidity, and longer hospital stays (17.9 versus 3.6 days) compared with those without CDI. Further studies with a larger population size will confirm the findings of this study.

The study was conducted on middle-aged to elderly male veterans, and it can only be assumed that these results will translate to other populations. Nevertheless, CDI can lead to significant morbidity and mortality, and the study reinforces the importance of infection control and prevention to reduce CDI incidence and disease severity.

Bottom line: Postoperative CDI is significantly associated with the number of postoperative antibiotics, surgical procedure complexity, preoperative length of stay, and patient comorbidities.

Citation: Li X, Wilson M, Nylander W, Smith T, Lynn M, Gunnar W. Analysis of morbidity and mortality outcomes in postoperative Clostridium difficile infection in the Veterans Health Administration. JAMA Surg. 2015;25:1-9.

Clinical question: What are the factors that increase risk of Clostridium difficile infection (CDI) in postoperative patients?

Background: CDI has become an important infectious etiology for morbidity, lengthy and costly hospital admissions, and mortality. This study focused on the risks for postoperative patients to be infected with C. diff. Awareness of the risk factors for CDI allows for processes to be implemented that can decrease the rate of infection.

Study design: Retrospective, observational study.

Setting: Multiple Veterans Health Administration surgery programs.

Synopsis: The study investigated 468,386 surgical procedures in 134 surgical programs in 12 subspecialties over a four-year period. Overall, the postoperative CDI rate was 0.4% per year. Rates were higher in emergency or complex procedures, older patients, patients with longer preoperative hospital stays, and those who received three or more classes of antibiotics. CDI in postoperative patients was associated with five times higher risk of mortality, a 12 times higher risk of morbidity, and longer hospital stays (17.9 versus 3.6 days) compared with those without CDI. Further studies with a larger population size will confirm the findings of this study.

The study was conducted on middle-aged to elderly male veterans, and it can only be assumed that these results will translate to other populations. Nevertheless, CDI can lead to significant morbidity and mortality, and the study reinforces the importance of infection control and prevention to reduce CDI incidence and disease severity.

Bottom line: Postoperative CDI is significantly associated with the number of postoperative antibiotics, surgical procedure complexity, preoperative length of stay, and patient comorbidities.

Citation: Li X, Wilson M, Nylander W, Smith T, Lynn M, Gunnar W. Analysis of morbidity and mortality outcomes in postoperative Clostridium difficile infection in the Veterans Health Administration. JAMA Surg. 2015;25:1-9.

Clinical question: What are the factors that increase risk of Clostridium difficile infection (CDI) in postoperative patients?

Background: CDI has become an important infectious etiology for morbidity, lengthy and costly hospital admissions, and mortality. This study focused on the risks for postoperative patients to be infected with C. diff. Awareness of the risk factors for CDI allows for processes to be implemented that can decrease the rate of infection.

Study design: Retrospective, observational study.

Setting: Multiple Veterans Health Administration surgery programs.

Synopsis: The study investigated 468,386 surgical procedures in 134 surgical programs in 12 subspecialties over a four-year period. Overall, the postoperative CDI rate was 0.4% per year. Rates were higher in emergency or complex procedures, older patients, patients with longer preoperative hospital stays, and those who received three or more classes of antibiotics. CDI in postoperative patients was associated with five times higher risk of mortality, a 12 times higher risk of morbidity, and longer hospital stays (17.9 versus 3.6 days) compared with those without CDI. Further studies with a larger population size will confirm the findings of this study.

The study was conducted on middle-aged to elderly male veterans, and it can only be assumed that these results will translate to other populations. Nevertheless, CDI can lead to significant morbidity and mortality, and the study reinforces the importance of infection control and prevention to reduce CDI incidence and disease severity.

Bottom line: Postoperative CDI is significantly associated with the number of postoperative antibiotics, surgical procedure complexity, preoperative length of stay, and patient comorbidities.

Citation: Li X, Wilson M, Nylander W, Smith T, Lynn M, Gunnar W. Analysis of morbidity and mortality outcomes in postoperative Clostridium difficile infection in the Veterans Health Administration. JAMA Surg. 2015;25:1-9.

Clinical question: What is the etiology of 30-day readmissions in postoperative patients?

Background: As the focus of healthcare changes to a quality-focused model, readmissions impact physicians, reimbursements, and patients. Understanding the cause of readmissions becomes essential to preventing them. The etiology of 30-day readmissions in postoperative patients has not specifically been studied.

Study design: Retrospective analysis.

Setting: Academic tertiary-care center.

Synopsis: Using administrative claims data, an analysis of 22,559 patients who underwent a major surgical procedure between 2009 and 2013 was performed. A total of 56 surgeons within eight surgical subspecialties were analyzed, showing that variation in 30-day readmissions was largely due to patient-specific factors (82.8%) while only a minority were attributable to surgical subspecialty (14.5%) and individual surgeon levels (2.8%). Factors associated with readmission included race/ethnicity, comorbidities, postoperative complications, and extended length of stay.

Further studies within this area will need to be conducted focusing on one specific subspecialty and one surgeon to exclude confounding factors. Additional meta-analysis can then compare these individual studies. A larger population and multiple care centers will also further validate the findings. Understanding the cause of the readmissions in postoperative patients can prevent further readmissions, improve quality of care, and decrease healthcare costs. If patient factors are identified as a major cause for readmissions in postoperative patients, changes in preoperative management may need to be made.

Bottom line: Postoperative readmissions are more dependent on patient factors than surgeon- or surgical subspecialty-specific factors.

Citation: Gani F, Lucas DJ, Kim Y, Schneider EB, Pawlik TM. Understanding variation in 30-day surgical readmission in the era of accountable care: effect of the patient, surgeon, and surgical subspecialties. JAMA Surg. 2015;150(11):1042-1049.

Clinical question: What is the etiology of 30-day readmissions in postoperative patients?

Background: As the focus of healthcare changes to a quality-focused model, readmissions impact physicians, reimbursements, and patients. Understanding the cause of readmissions becomes essential to preventing them. The etiology of 30-day readmissions in postoperative patients has not specifically been studied.

Study design: Retrospective analysis.

Setting: Academic tertiary-care center.

Synopsis: Using administrative claims data, an analysis of 22,559 patients who underwent a major surgical procedure between 2009 and 2013 was performed. A total of 56 surgeons within eight surgical subspecialties were analyzed, showing that variation in 30-day readmissions was largely due to patient-specific factors (82.8%) while only a minority were attributable to surgical subspecialty (14.5%) and individual surgeon levels (2.8%). Factors associated with readmission included race/ethnicity, comorbidities, postoperative complications, and extended length of stay.

Further studies within this area will need to be conducted focusing on one specific subspecialty and one surgeon to exclude confounding factors. Additional meta-analysis can then compare these individual studies. A larger population and multiple care centers will also further validate the findings. Understanding the cause of the readmissions in postoperative patients can prevent further readmissions, improve quality of care, and decrease healthcare costs. If patient factors are identified as a major cause for readmissions in postoperative patients, changes in preoperative management may need to be made.

Bottom line: Postoperative readmissions are more dependent on patient factors than surgeon- or surgical subspecialty-specific factors.

Citation: Gani F, Lucas DJ, Kim Y, Schneider EB, Pawlik TM. Understanding variation in 30-day surgical readmission in the era of accountable care: effect of the patient, surgeon, and surgical subspecialties. JAMA Surg. 2015;150(11):1042-1049.

Clinical question: What is the etiology of 30-day readmissions in postoperative patients?

Background: As the focus of healthcare changes to a quality-focused model, readmissions impact physicians, reimbursements, and patients. Understanding the cause of readmissions becomes essential to preventing them. The etiology of 30-day readmissions in postoperative patients has not specifically been studied.

Study design: Retrospective analysis.

Setting: Academic tertiary-care center.

Synopsis: Using administrative claims data, an analysis of 22,559 patients who underwent a major surgical procedure between 2009 and 2013 was performed. A total of 56 surgeons within eight surgical subspecialties were analyzed, showing that variation in 30-day readmissions was largely due to patient-specific factors (82.8%) while only a minority were attributable to surgical subspecialty (14.5%) and individual surgeon levels (2.8%). Factors associated with readmission included race/ethnicity, comorbidities, postoperative complications, and extended length of stay.

Further studies within this area will need to be conducted focusing on one specific subspecialty and one surgeon to exclude confounding factors. Additional meta-analysis can then compare these individual studies. A larger population and multiple care centers will also further validate the findings. Understanding the cause of the readmissions in postoperative patients can prevent further readmissions, improve quality of care, and decrease healthcare costs. If patient factors are identified as a major cause for readmissions in postoperative patients, changes in preoperative management may need to be made.

Bottom line: Postoperative readmissions are more dependent on patient factors than surgeon- or surgical subspecialty-specific factors.

Citation: Gani F, Lucas DJ, Kim Y, Schneider EB, Pawlik TM. Understanding variation in 30-day surgical readmission in the era of accountable care: effect of the patient, surgeon, and surgical subspecialties. JAMA Surg. 2015;150(11):1042-1049.

(Reuters) - U.S. hospitals should brace for a surge in "ransomware" attacks by cyber criminals who infect and shut down computer networks, then demand payment in return for unlocking them, a non-profit healthcare group warned on Friday.

The Health Information Trust Alliance conducted a study of some 30 mid-sized U.S. hospitals late last year and found that 52 percent of them were infected with malicious software, HITRUST Chief Executive Daniel Nutkis told Reuters.

The most common type of malware was ransomware, Nutkis said, which was present in 35 percent of the hospitals included in the study of network traffic conducted by security software maker Trend Micro Inc.

Ransomware is malicious software that locks up data in computers and leaves messages demanding payment to recover the data. Last month, Hollywood Presbyterian Hospital in Los Angeles paid a ransom of $17,000 to regain access to its systems.

This week, an attack on MedStar Health forced the largest healthcare provider in Washington, D.C., to shut down much of its computer network. The Baltimore Sun reported a ransom of $18,500 was sought. MedStar declined to comment.

HITRUST said it expects such attacks to become more frequent because ransomware has turned into a profitable business for cyber criminals.

The results of the study, which HITRUST has yet to share with the public, demonstrate that hackers have moved away from focusing on stealing patient data, Nutkis said.

"If stuff isn't working, they move on. If stuff is working, they keep doing it," said Nutkis. "Organizations that are paying have considered their options, and unfortunately they don't have a lot of options."

Extortion has become more popular with cyber criminals because it is seen as a way to generate fast money, said Larry Whiteside, a healthcare expert with cyber security firm Optiv.

Stealing healthcare data is far more labour intensive, requiring attackers to keep their presence in a victim's network undetected for months as they steal data, then they need to find buyers, he added.

"With ransomware I'm going to get paid immediately," Whiteside said.

Frisco, Texas-based HITRUST's board includes executives from Anthem, Health Care Services, Humana, UnitedHealth and Walgreens.

(Reuters) - U.S. hospitals should brace for a surge in "ransomware" attacks by cyber criminals who infect and shut down computer networks, then demand payment in return for unlocking them, a non-profit healthcare group warned on Friday.

The Health Information Trust Alliance conducted a study of some 30 mid-sized U.S. hospitals late last year and found that 52 percent of them were infected with malicious software, HITRUST Chief Executive Daniel Nutkis told Reuters.

The most common type of malware was ransomware, Nutkis said, which was present in 35 percent of the hospitals included in the study of network traffic conducted by security software maker Trend Micro Inc.

Ransomware is malicious software that locks up data in computers and leaves messages demanding payment to recover the data. Last month, Hollywood Presbyterian Hospital in Los Angeles paid a ransom of $17,000 to regain access to its systems.

This week, an attack on MedStar Health forced the largest healthcare provider in Washington, D.C., to shut down much of its computer network. The Baltimore Sun reported a ransom of $18,500 was sought. MedStar declined to comment.

HITRUST said it expects such attacks to become more frequent because ransomware has turned into a profitable business for cyber criminals.

The results of the study, which HITRUST has yet to share with the public, demonstrate that hackers have moved away from focusing on stealing patient data, Nutkis said.

"If stuff isn't working, they move on. If stuff is working, they keep doing it," said Nutkis. "Organizations that are paying have considered their options, and unfortunately they don't have a lot of options."

Extortion has become more popular with cyber criminals because it is seen as a way to generate fast money, said Larry Whiteside, a healthcare expert with cyber security firm Optiv.

Stealing healthcare data is far more labour intensive, requiring attackers to keep their presence in a victim's network undetected for months as they steal data, then they need to find buyers, he added.

"With ransomware I'm going to get paid immediately," Whiteside said.

Frisco, Texas-based HITRUST's board includes executives from Anthem, Health Care Services, Humana, UnitedHealth and Walgreens.

(Reuters) - U.S. hospitals should brace for a surge in "ransomware" attacks by cyber criminals who infect and shut down computer networks, then demand payment in return for unlocking them, a non-profit healthcare group warned on Friday.

The Health Information Trust Alliance conducted a study of some 30 mid-sized U.S. hospitals late last year and found that 52 percent of them were infected with malicious software, HITRUST Chief Executive Daniel Nutkis told Reuters.

The most common type of malware was ransomware, Nutkis said, which was present in 35 percent of the hospitals included in the study of network traffic conducted by security software maker Trend Micro Inc.

Ransomware is malicious software that locks up data in computers and leaves messages demanding payment to recover the data. Last month, Hollywood Presbyterian Hospital in Los Angeles paid a ransom of $17,000 to regain access to its systems.

This week, an attack on MedStar Health forced the largest healthcare provider in Washington, D.C., to shut down much of its computer network. The Baltimore Sun reported a ransom of $18,500 was sought. MedStar declined to comment.

HITRUST said it expects such attacks to become more frequent because ransomware has turned into a profitable business for cyber criminals.

The results of the study, which HITRUST has yet to share with the public, demonstrate that hackers have moved away from focusing on stealing patient data, Nutkis said.

"If stuff isn't working, they move on. If stuff is working, they keep doing it," said Nutkis. "Organizations that are paying have considered their options, and unfortunately they don't have a lot of options."

Extortion has become more popular with cyber criminals because it is seen as a way to generate fast money, said Larry Whiteside, a healthcare expert with cyber security firm Optiv.

Stealing healthcare data is far more labour intensive, requiring attackers to keep their presence in a victim's network undetected for months as they steal data, then they need to find buyers, he added.

"With ransomware I'm going to get paid immediately," Whiteside said.

Frisco, Texas-based HITRUST's board includes executives from Anthem, Health Care Services, Humana, UnitedHealth and Walgreens.

Cells from a mouse with SCD

Image courtesy of the

University of Michigan

Activating the antioxidant regulator Nrf2 may slow the progression of sickle cell disease (SCD), according to preclinical research published in JCI Insight.

Investigators found the severity of hemolytic anemia, vascular inflammation, and lung injury increased with age in mice with SCD.

However, activating Nrf2 in young animals had a prophylactic effect, reducing the severity of these adverse effects and improving survival.

To uncover these findings, Solomon Ofori-Acquah, PhD, of the University of Pittsburgh in Pennsylvania, and his colleagues conducted a 10-month longitudinal observational study of mice with SCD.

The team found that, in mice with homozygous SCD (SS), there was a link between intravascular hemolysis, vascular inflammation, lung injury, and early death.

Mice as young as 2 months showed exacerbation of intravascular hemolysis. And additional investigation linked worsening intravascular hemolysis and oxidative stress to the release of VE-cadherin and progressive lung damage in aging SS mice.

The investigators knew that Nrf2 regulates the expression of genes that protect against the effects of intravascular hemolysis. So they decided to see if activating Nrf2 in young mice with SCD would slow the disease progression that occurs with age.

The team took SS mice that were about a month old and randomized them to receive 3H-1, 2-dithiole-3-thione (D3T) or a DMSO vehicle for 3 months or longer.

Treatment with D3T stabilized the concentration of hemoglobin, increased white blood cell counts, increased reticulocyte counts (though not significantly), kept HO-1 levels stable, increased levels of NQO1 and ferritin, and impeded the progression of endothelial dysfunction.

The investigators also looked at the role of Nrf2 in nonhematopoietic tissues and were surprised to find that Nrf2 deficiency in nonhematopoietic tissues exacerbated anemia and caused premature pulmonary edema in mice with SCD.

The team said this suggests a dominant protective role for nonhematopoietic Nrf2 against tissue damage in both erythroid and nonerythroid tissues in SCD.

And, when taken together, the results of this research indicate that activating Nrf2 can impede the onset of the severe adult phenotype of SCD in mice.

Cells from a mouse with SCD

Image courtesy of the

University of Michigan

Activating the antioxidant regulator Nrf2 may slow the progression of sickle cell disease (SCD), according to preclinical research published in JCI Insight.

Investigators found the severity of hemolytic anemia, vascular inflammation, and lung injury increased with age in mice with SCD.

However, activating Nrf2 in young animals had a prophylactic effect, reducing the severity of these adverse effects and improving survival.

To uncover these findings, Solomon Ofori-Acquah, PhD, of the University of Pittsburgh in Pennsylvania, and his colleagues conducted a 10-month longitudinal observational study of mice with SCD.

The team found that, in mice with homozygous SCD (SS), there was a link between intravascular hemolysis, vascular inflammation, lung injury, and early death.

Mice as young as 2 months showed exacerbation of intravascular hemolysis. And additional investigation linked worsening intravascular hemolysis and oxidative stress to the release of VE-cadherin and progressive lung damage in aging SS mice.

The investigators knew that Nrf2 regulates the expression of genes that protect against the effects of intravascular hemolysis. So they decided to see if activating Nrf2 in young mice with SCD would slow the disease progression that occurs with age.

The team took SS mice that were about a month old and randomized them to receive 3H-1, 2-dithiole-3-thione (D3T) or a DMSO vehicle for 3 months or longer.

Treatment with D3T stabilized the concentration of hemoglobin, increased white blood cell counts, increased reticulocyte counts (though not significantly), kept HO-1 levels stable, increased levels of NQO1 and ferritin, and impeded the progression of endothelial dysfunction.

The investigators also looked at the role of Nrf2 in nonhematopoietic tissues and were surprised to find that Nrf2 deficiency in nonhematopoietic tissues exacerbated anemia and caused premature pulmonary edema in mice with SCD.

The team said this suggests a dominant protective role for nonhematopoietic Nrf2 against tissue damage in both erythroid and nonerythroid tissues in SCD.

And, when taken together, the results of this research indicate that activating Nrf2 can impede the onset of the severe adult phenotype of SCD in mice.

Cells from a mouse with SCD

Image courtesy of the

University of Michigan

Activating the antioxidant regulator Nrf2 may slow the progression of sickle cell disease (SCD), according to preclinical research published in JCI Insight.

Investigators found the severity of hemolytic anemia, vascular inflammation, and lung injury increased with age in mice with SCD.

However, activating Nrf2 in young animals had a prophylactic effect, reducing the severity of these adverse effects and improving survival.

To uncover these findings, Solomon Ofori-Acquah, PhD, of the University of Pittsburgh in Pennsylvania, and his colleagues conducted a 10-month longitudinal observational study of mice with SCD.

The team found that, in mice with homozygous SCD (SS), there was a link between intravascular hemolysis, vascular inflammation, lung injury, and early death.

Mice as young as 2 months showed exacerbation of intravascular hemolysis. And additional investigation linked worsening intravascular hemolysis and oxidative stress to the release of VE-cadherin and progressive lung damage in aging SS mice.

The investigators knew that Nrf2 regulates the expression of genes that protect against the effects of intravascular hemolysis. So they decided to see if activating Nrf2 in young mice with SCD would slow the disease progression that occurs with age.

The team took SS mice that were about a month old and randomized them to receive 3H-1, 2-dithiole-3-thione (D3T) or a DMSO vehicle for 3 months or longer.

Treatment with D3T stabilized the concentration of hemoglobin, increased white blood cell counts, increased reticulocyte counts (though not significantly), kept HO-1 levels stable, increased levels of NQO1 and ferritin, and impeded the progression of endothelial dysfunction.

The investigators also looked at the role of Nrf2 in nonhematopoietic tissues and were surprised to find that Nrf2 deficiency in nonhematopoietic tissues exacerbated anemia and caused premature pulmonary edema in mice with SCD.

The team said this suggests a dominant protective role for nonhematopoietic Nrf2 against tissue damage in both erythroid and nonerythroid tissues in SCD.

And, when taken together, the results of this research indicate that activating Nrf2 can impede the onset of the severe adult phenotype of SCD in mice.

Doctor examines child

Photo by Logan Tuttle

The European Commission (EC) has approved eltrombopag (Revolade), a once-daily oral thrombopoietin receptor agonist, to treat pediatric patients (age 1 and older) with chronic immune thrombocytopenia (ITP) that is refractory to other therapies.

This approval includes the use of tablets and a new oral suspension formulation of eltrombopag, which is designed for younger children who may not be able to swallow tablets.

The approval applies to all 28 member states of the European Union plus Iceland, Norway, and Liechtenstein.

Eltrombopag was previously approved by the EC for use in adults with refractory chronic ITP. The drug is also approved in the EC to treat adults with severe aplastic anemia and adults with chronic hepatitis C virus infection who have thrombocytopenia.

Eltrombopag is made by Novartis. For more details on the drug, see the full Summary of Product Characteristics, available on the European Medicines Agency’s website.

The EC’s latest approval of eltrombopag was based on data from 2 double-blind, placebo-controlled trials—the phase 2 PETIT trial and the phase 3 PETIT2 trial.

PETIT trials: Efficacy

The PETIT trial included 67 ITP patients stratified by age cohort (12-17 years, 6-11 years, and 1-5 years). They were randomized (2:1) to receive eltrombopag or placebo for 7 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects achieving platelet counts of 50 x 10⁹/L or higher at least once between days 8 and 43 of the randomized period of the study.

Significantly more patients in the eltrombopag arm met this endpoint—62.2%—compared to 31.8% in the placebo arm (P=0.011).

The PETIT2 trial enrolled 92 patients with chronic ITP who were randomized (2:1) to receive eltrombopag or placebo for 13 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects who achieved platelet counts of 50 x 10⁹/L or higher for at least 6 out of 8 weeks, between weeks 5 and 12 of the randomized period.

Significantly more patients in the eltrombopag arm met this endpoint—41.3%—compared to 3.4% of patients in the placebo arm (P<0.001).

PETIT trials: Safety

For both trials, there were 107 eltrombopag-treated patients evaluable for safety.

The most common adverse events that occurred more frequently in the eltrombopag arms than the placebo arms were upper respiratory tract infection, nasopharyngitis, cough, diarrhea, pyrexia, rhinitis, abdominal pain, oropharyngeal pain, toothache, increased ALT/AST, rash, and rhinorrhea.

Serious adverse events were reported in 8% of patients during the randomized part of both trials, although no serious adverse event occurred in more than 1 patient.

An ALT elevation of at least 3 times the upper limit of normal occurred in 5% of eltrombopag-treated patients. Of those patients, 2% had ALT increases of at least 5 times the upper limit of normal.

There were no deaths or thromboembolic events during either study.

Doctor examines child

Photo by Logan Tuttle

The European Commission (EC) has approved eltrombopag (Revolade), a once-daily oral thrombopoietin receptor agonist, to treat pediatric patients (age 1 and older) with chronic immune thrombocytopenia (ITP) that is refractory to other therapies.

This approval includes the use of tablets and a new oral suspension formulation of eltrombopag, which is designed for younger children who may not be able to swallow tablets.

The approval applies to all 28 member states of the European Union plus Iceland, Norway, and Liechtenstein.

Eltrombopag was previously approved by the EC for use in adults with refractory chronic ITP. The drug is also approved in the EC to treat adults with severe aplastic anemia and adults with chronic hepatitis C virus infection who have thrombocytopenia.

Eltrombopag is made by Novartis. For more details on the drug, see the full Summary of Product Characteristics, available on the European Medicines Agency’s website.

The EC’s latest approval of eltrombopag was based on data from 2 double-blind, placebo-controlled trials—the phase 2 PETIT trial and the phase 3 PETIT2 trial.

PETIT trials: Efficacy

The PETIT trial included 67 ITP patients stratified by age cohort (12-17 years, 6-11 years, and 1-5 years). They were randomized (2:1) to receive eltrombopag or placebo for 7 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects achieving platelet counts of 50 x 10⁹/L or higher at least once between days 8 and 43 of the randomized period of the study.

Significantly more patients in the eltrombopag arm met this endpoint—62.2%—compared to 31.8% in the placebo arm (P=0.011).

The PETIT2 trial enrolled 92 patients with chronic ITP who were randomized (2:1) to receive eltrombopag or placebo for 13 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects who achieved platelet counts of 50 x 10⁹/L or higher for at least 6 out of 8 weeks, between weeks 5 and 12 of the randomized period.

Significantly more patients in the eltrombopag arm met this endpoint—41.3%—compared to 3.4% of patients in the placebo arm (P<0.001).

PETIT trials: Safety

For both trials, there were 107 eltrombopag-treated patients evaluable for safety.

The most common adverse events that occurred more frequently in the eltrombopag arms than the placebo arms were upper respiratory tract infection, nasopharyngitis, cough, diarrhea, pyrexia, rhinitis, abdominal pain, oropharyngeal pain, toothache, increased ALT/AST, rash, and rhinorrhea.

Serious adverse events were reported in 8% of patients during the randomized part of both trials, although no serious adverse event occurred in more than 1 patient.

An ALT elevation of at least 3 times the upper limit of normal occurred in 5% of eltrombopag-treated patients. Of those patients, 2% had ALT increases of at least 5 times the upper limit of normal.

There were no deaths or thromboembolic events during either study.

Doctor examines child

Photo by Logan Tuttle

The European Commission (EC) has approved eltrombopag (Revolade), a once-daily oral thrombopoietin receptor agonist, to treat pediatric patients (age 1 and older) with chronic immune thrombocytopenia (ITP) that is refractory to other therapies.

This approval includes the use of tablets and a new oral suspension formulation of eltrombopag, which is designed for younger children who may not be able to swallow tablets.

The approval applies to all 28 member states of the European Union plus Iceland, Norway, and Liechtenstein.

Eltrombopag was previously approved by the EC for use in adults with refractory chronic ITP. The drug is also approved in the EC to treat adults with severe aplastic anemia and adults with chronic hepatitis C virus infection who have thrombocytopenia.

Eltrombopag is made by Novartis. For more details on the drug, see the full Summary of Product Characteristics, available on the European Medicines Agency’s website.

The EC’s latest approval of eltrombopag was based on data from 2 double-blind, placebo-controlled trials—the phase 2 PETIT trial and the phase 3 PETIT2 trial.

PETIT trials: Efficacy

The PETIT trial included 67 ITP patients stratified by age cohort (12-17 years, 6-11 years, and 1-5 years). They were randomized (2:1) to receive eltrombopag or placebo for 7 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects achieving platelet counts of 50 x 10⁹/L or higher at least once between days 8 and 43 of the randomized period of the study.

Significantly more patients in the eltrombopag arm met this endpoint—62.2%—compared to 31.8% in the placebo arm (P=0.011).

The PETIT2 trial enrolled 92 patients with chronic ITP who were randomized (2:1) to receive eltrombopag or placebo for 13 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects who achieved platelet counts of 50 x 10⁹/L or higher for at least 6 out of 8 weeks, between weeks 5 and 12 of the randomized period.

Significantly more patients in the eltrombopag arm met this endpoint—41.3%—compared to 3.4% of patients in the placebo arm (P<0.001).

PETIT trials: Safety

For both trials, there were 107 eltrombopag-treated patients evaluable for safety.

The most common adverse events that occurred more frequently in the eltrombopag arms than the placebo arms were upper respiratory tract infection, nasopharyngitis, cough, diarrhea, pyrexia, rhinitis, abdominal pain, oropharyngeal pain, toothache, increased ALT/AST, rash, and rhinorrhea.

Serious adverse events were reported in 8% of patients during the randomized part of both trials, although no serious adverse event occurred in more than 1 patient.

An ALT elevation of at least 3 times the upper limit of normal occurred in 5% of eltrombopag-treated patients. Of those patients, 2% had ALT increases of at least 5 times the upper limit of normal.

There were no deaths or thromboembolic events during either study.

Colony of iPSCs

Image from the Salk Institute

In tracking the mutational history of somatic cells and induced pluripotent stem cells (iPSCs), researchers found that somatic cells accumulate mutations more frequently than iPSCs.

And none of the mutations found in iPSCs were associated with cancers.

“None of the mutations we found in induced pluripotent stem cells were cancer-driver mutations or mutations in cancer-causing genes,” said Foad Rouhani, of the Wellcome Trust Sanger Institute in the UK.

“We didn’t find anything that would preclude the use of [iPSCs] in therapeutic medicine.”

Rouhani and his colleagues reported these findings in PLOS Genetics.

The researchers generated iPSCs using cells from healthy individuals, then sequenced the genomes of the somatic cells and the derived iPSCs.

They found that somatic cells had a mutation rate of 14 single nucleotide variants per cell per generation, and the mutation rate for iPSCs was 10-fold lower.

The researchers said this is the first time that mutation rates of both types of cells, the donor cell and iPSC, have been calculated and compared.

“Until now, the question of whether generating [iPSCs] and growing them in cell culture creates mutations has not been addressed in detail,” said study author Allan Bradley, PhD, of the Wellcome Trust Sanger Institute.

“If human cells are really to be reprogrammed on a large scale for use in regenerative medicine, then understanding the mutations the donor cells carry will be a crucial step. We now have the tools to do this.”

The researchers also used the iPSCs to trace the history of every mutation that one endothelial progenitor cell had developed from the time it was a fertilized egg to the moment it was taken out of the body.

They said the ability to track the genetic changes in cells over a lifetime could improve scientists’ understanding of how, when, and why mutations lead to cancer.

Colony of iPSCs

Image from the Salk Institute

In tracking the mutational history of somatic cells and induced pluripotent stem cells (iPSCs), researchers found that somatic cells accumulate mutations more frequently than iPSCs.

And none of the mutations found in iPSCs were associated with cancers.

“None of the mutations we found in induced pluripotent stem cells were cancer-driver mutations or mutations in cancer-causing genes,” said Foad Rouhani, of the Wellcome Trust Sanger Institute in the UK.

“We didn’t find anything that would preclude the use of [iPSCs] in therapeutic medicine.”

Rouhani and his colleagues reported these findings in PLOS Genetics.

The researchers generated iPSCs using cells from healthy individuals, then sequenced the genomes of the somatic cells and the derived iPSCs.

They found that somatic cells had a mutation rate of 14 single nucleotide variants per cell per generation, and the mutation rate for iPSCs was 10-fold lower.

The researchers said this is the first time that mutation rates of both types of cells, the donor cell and iPSC, have been calculated and compared.

“Until now, the question of whether generating [iPSCs] and growing them in cell culture creates mutations has not been addressed in detail,” said study author Allan Bradley, PhD, of the Wellcome Trust Sanger Institute.

“If human cells are really to be reprogrammed on a large scale for use in regenerative medicine, then understanding the mutations the donor cells carry will be a crucial step. We now have the tools to do this.”

The researchers also used the iPSCs to trace the history of every mutation that one endothelial progenitor cell had developed from the time it was a fertilized egg to the moment it was taken out of the body.

They said the ability to track the genetic changes in cells over a lifetime could improve scientists’ understanding of how, when, and why mutations lead to cancer.

Colony of iPSCs

Image from the Salk Institute

In tracking the mutational history of somatic cells and induced pluripotent stem cells (iPSCs), researchers found that somatic cells accumulate mutations more frequently than iPSCs.

And none of the mutations found in iPSCs were associated with cancers.

“None of the mutations we found in induced pluripotent stem cells were cancer-driver mutations or mutations in cancer-causing genes,” said Foad Rouhani, of the Wellcome Trust Sanger Institute in the UK.

“We didn’t find anything that would preclude the use of [iPSCs] in therapeutic medicine.”

Rouhani and his colleagues reported these findings in PLOS Genetics.

The researchers generated iPSCs using cells from healthy individuals, then sequenced the genomes of the somatic cells and the derived iPSCs.

They found that somatic cells had a mutation rate of 14 single nucleotide variants per cell per generation, and the mutation rate for iPSCs was 10-fold lower.

The researchers said this is the first time that mutation rates of both types of cells, the donor cell and iPSC, have been calculated and compared.

“Until now, the question of whether generating [iPSCs] and growing them in cell culture creates mutations has not been addressed in detail,” said study author Allan Bradley, PhD, of the Wellcome Trust Sanger Institute.

“If human cells are really to be reprogrammed on a large scale for use in regenerative medicine, then understanding the mutations the donor cells carry will be a crucial step. We now have the tools to do this.”

The researchers also used the iPSCs to trace the history of every mutation that one endothelial progenitor cell had developed from the time it was a fertilized egg to the moment it was taken out of the body.

They said the ability to track the genetic changes in cells over a lifetime could improve scientists’ understanding of how, when, and why mutations lead to cancer.