For decades, surgeons have been at the forefront of the palliative care movement. From the historic utilization of palliative operations to relieve suffering to creation of the American College of Surgeons Palliative Care Task Force, surgeons are often first-line palliative care providers in the management of patients with advanced malignancy.

Palliative care involves paying attention to symptom distress, communicating with patients and families about goals of care in relation to prognosis and patient preferences, planning transitions, and engaging family support. Yet, despite a clear and established role, many surgeons are not prepared to effectively provide palliative care, and they are often resistant to the use of specialty palliative care services.

In my own training, I have witnessed apprehension and failure to use palliative care services. In one instance, I was managing an older patient after a complicated sarcoma resection. The patient suffered complications, which kept him hospitalized and returning to the hospital after short periods at a long-term acute care facility. I suggested that we call palliative care for assistance in management of the patient. He had pain, nausea, and poor oral intake, and he was depressed and anxious about his future. I was told "we don’t want the patient believing we were giving up on him."

After 3 weeks of minimal change, my attending relented. In a short time, the patient’s pain and nausea were better controlled, and we were able to have discussions with the patient and his family to clarify goals of care. Some of the symptom management techniques used methods that I had not yet encountered in my training and that seemed foreign and curious. But seeing the response left no question as to their utility. The patient was able to leave the hospital 2 weeks later with the palliative care service coordinating his management with the primary care provider and surgical team. This was a positive resolution to a significant problem. But what really hindered palliative care use?

Roadblocks include the term palliative having a negative connotation, being equated with "failure." Increased use of quality metrics may deincentivize palliative operations. Also, there is poor training and support for surgeons to provide primary palliative care services themselves. Yet, despite these barriers, there are opportunities for surgeons to improve care of patients with advanced malignancy by improving surgeon-patient communication and giving greater emphasis to advanced care planning prior to operative interventions.

As front-line providers for these patients, surgeons are an ideal conduit for delivery and improved use of early palliative care. My practice includes a discussion of advanced care planning with all of my cancer patients. I introduce this as a normal part of every discussion and refer the patient to the primary care provider or our Quality of Life service to facilitate further conversations and documentation. By destigmatizing the discussion for patients and families, a door is opened to an important part of comprehensive quality care. We must understand that diseases progress and complications occur. Failing to provide preemptive support to patients and families is true failure. With a preemptive approach, patients, families, and caregivers have a better understanding of the medical situation, and the latter can more effectively support the patient.

To standardize the role that surgeons routinely play in management of patients with advanced malignancy, efforts must focus on education and research. The role of education is twofold. First, surgical trainees need adequate tools to perform routine palliative care and an understanding of the appropriate timing to refer for specialized services. There have been multiple national efforts focused on teaching palliative care to varied practitioners. But given the aging population and the paucity of specialist palliative care providers, a renewed effort is needed. Second, surgeons must understand the role that palliative care plays and the benefits their patients can derive from it. Surgeons are routinely involved throughout the course of care of patients with malignancy from diagnosis to the end of life. Recognition of palliative care as a skill along the continuum of care already provided will improve outcomes.

Finally, research must focus on both models of use of palliative care and the quality of current practice. Palliative care as it pertains to surgeons is understudied: What teaching formats are most likely to affect clinical practice? What components of palliative care have an impact in surgical practice? What is the optimal timing and venue for providing palliative care in surgical practice? What health care system changes are needed to support surgeons to provide primary palliative care services?

We are uniquely aware of the complexities of care needed for management of patients with advanced malignancies. We are routinely called on to aid in the management of these patients. Surgical educators and researchers should focus their efforts on what is needed to fully integrate palliative care into patient-centered care already provided by trainees and surgeons.

Dr. Johnston is an assistant professor of surgery in the division of surgical oncology at the Medical College of Wisconsin, Milwaukee. He disclosed no conflicts.

For decades, surgeons have been at the forefront of the palliative care movement. From the historic utilization of palliative operations to relieve suffering to creation of the American College of Surgeons Palliative Care Task Force, surgeons are often first-line palliative care providers in the management of patients with advanced malignancy.

Palliative care involves paying attention to symptom distress, communicating with patients and families about goals of care in relation to prognosis and patient preferences, planning transitions, and engaging family support. Yet, despite a clear and established role, many surgeons are not prepared to effectively provide palliative care, and they are often resistant to the use of specialty palliative care services.

In my own training, I have witnessed apprehension and failure to use palliative care services. In one instance, I was managing an older patient after a complicated sarcoma resection. The patient suffered complications, which kept him hospitalized and returning to the hospital after short periods at a long-term acute care facility. I suggested that we call palliative care for assistance in management of the patient. He had pain, nausea, and poor oral intake, and he was depressed and anxious about his future. I was told "we don’t want the patient believing we were giving up on him."

After 3 weeks of minimal change, my attending relented. In a short time, the patient’s pain and nausea were better controlled, and we were able to have discussions with the patient and his family to clarify goals of care. Some of the symptom management techniques used methods that I had not yet encountered in my training and that seemed foreign and curious. But seeing the response left no question as to their utility. The patient was able to leave the hospital 2 weeks later with the palliative care service coordinating his management with the primary care provider and surgical team. This was a positive resolution to a significant problem. But what really hindered palliative care use?

Roadblocks include the term palliative having a negative connotation, being equated with "failure." Increased use of quality metrics may deincentivize palliative operations. Also, there is poor training and support for surgeons to provide primary palliative care services themselves. Yet, despite these barriers, there are opportunities for surgeons to improve care of patients with advanced malignancy by improving surgeon-patient communication and giving greater emphasis to advanced care planning prior to operative interventions.

As front-line providers for these patients, surgeons are an ideal conduit for delivery and improved use of early palliative care. My practice includes a discussion of advanced care planning with all of my cancer patients. I introduce this as a normal part of every discussion and refer the patient to the primary care provider or our Quality of Life service to facilitate further conversations and documentation. By destigmatizing the discussion for patients and families, a door is opened to an important part of comprehensive quality care. We must understand that diseases progress and complications occur. Failing to provide preemptive support to patients and families is true failure. With a preemptive approach, patients, families, and caregivers have a better understanding of the medical situation, and the latter can more effectively support the patient.

To standardize the role that surgeons routinely play in management of patients with advanced malignancy, efforts must focus on education and research. The role of education is twofold. First, surgical trainees need adequate tools to perform routine palliative care and an understanding of the appropriate timing to refer for specialized services. There have been multiple national efforts focused on teaching palliative care to varied practitioners. But given the aging population and the paucity of specialist palliative care providers, a renewed effort is needed. Second, surgeons must understand the role that palliative care plays and the benefits their patients can derive from it. Surgeons are routinely involved throughout the course of care of patients with malignancy from diagnosis to the end of life. Recognition of palliative care as a skill along the continuum of care already provided will improve outcomes.

Finally, research must focus on both models of use of palliative care and the quality of current practice. Palliative care as it pertains to surgeons is understudied: What teaching formats are most likely to affect clinical practice? What components of palliative care have an impact in surgical practice? What is the optimal timing and venue for providing palliative care in surgical practice? What health care system changes are needed to support surgeons to provide primary palliative care services?

We are uniquely aware of the complexities of care needed for management of patients with advanced malignancies. We are routinely called on to aid in the management of these patients. Surgical educators and researchers should focus their efforts on what is needed to fully integrate palliative care into patient-centered care already provided by trainees and surgeons.

Dr. Johnston is an assistant professor of surgery in the division of surgical oncology at the Medical College of Wisconsin, Milwaukee. He disclosed no conflicts.

For decades, surgeons have been at the forefront of the palliative care movement. From the historic utilization of palliative operations to relieve suffering to creation of the American College of Surgeons Palliative Care Task Force, surgeons are often first-line palliative care providers in the management of patients with advanced malignancy.

Palliative care involves paying attention to symptom distress, communicating with patients and families about goals of care in relation to prognosis and patient preferences, planning transitions, and engaging family support. Yet, despite a clear and established role, many surgeons are not prepared to effectively provide palliative care, and they are often resistant to the use of specialty palliative care services.

In my own training, I have witnessed apprehension and failure to use palliative care services. In one instance, I was managing an older patient after a complicated sarcoma resection. The patient suffered complications, which kept him hospitalized and returning to the hospital after short periods at a long-term acute care facility. I suggested that we call palliative care for assistance in management of the patient. He had pain, nausea, and poor oral intake, and he was depressed and anxious about his future. I was told "we don’t want the patient believing we were giving up on him."

After 3 weeks of minimal change, my attending relented. In a short time, the patient’s pain and nausea were better controlled, and we were able to have discussions with the patient and his family to clarify goals of care. Some of the symptom management techniques used methods that I had not yet encountered in my training and that seemed foreign and curious. But seeing the response left no question as to their utility. The patient was able to leave the hospital 2 weeks later with the palliative care service coordinating his management with the primary care provider and surgical team. This was a positive resolution to a significant problem. But what really hindered palliative care use?

Roadblocks include the term palliative having a negative connotation, being equated with "failure." Increased use of quality metrics may deincentivize palliative operations. Also, there is poor training and support for surgeons to provide primary palliative care services themselves. Yet, despite these barriers, there are opportunities for surgeons to improve care of patients with advanced malignancy by improving surgeon-patient communication and giving greater emphasis to advanced care planning prior to operative interventions.

As front-line providers for these patients, surgeons are an ideal conduit for delivery and improved use of early palliative care. My practice includes a discussion of advanced care planning with all of my cancer patients. I introduce this as a normal part of every discussion and refer the patient to the primary care provider or our Quality of Life service to facilitate further conversations and documentation. By destigmatizing the discussion for patients and families, a door is opened to an important part of comprehensive quality care. We must understand that diseases progress and complications occur. Failing to provide preemptive support to patients and families is true failure. With a preemptive approach, patients, families, and caregivers have a better understanding of the medical situation, and the latter can more effectively support the patient.

To standardize the role that surgeons routinely play in management of patients with advanced malignancy, efforts must focus on education and research. The role of education is twofold. First, surgical trainees need adequate tools to perform routine palliative care and an understanding of the appropriate timing to refer for specialized services. There have been multiple national efforts focused on teaching palliative care to varied practitioners. But given the aging population and the paucity of specialist palliative care providers, a renewed effort is needed. Second, surgeons must understand the role that palliative care plays and the benefits their patients can derive from it. Surgeons are routinely involved throughout the course of care of patients with malignancy from diagnosis to the end of life. Recognition of palliative care as a skill along the continuum of care already provided will improve outcomes.

Finally, research must focus on both models of use of palliative care and the quality of current practice. Palliative care as it pertains to surgeons is understudied: What teaching formats are most likely to affect clinical practice? What components of palliative care have an impact in surgical practice? What is the optimal timing and venue for providing palliative care in surgical practice? What health care system changes are needed to support surgeons to provide primary palliative care services?

We are uniquely aware of the complexities of care needed for management of patients with advanced malignancies. We are routinely called on to aid in the management of these patients. Surgical educators and researchers should focus their efforts on what is needed to fully integrate palliative care into patient-centered care already provided by trainees and surgeons.

Dr. Johnston is an assistant professor of surgery in the division of surgical oncology at the Medical College of Wisconsin, Milwaukee. He disclosed no conflicts.

Antihemophilic factor

The US Food and Drug Administration (FDA) has approved a new indication for the recombinant antihemophilic factor VIII product octocog alfa (Kogenate).

It is now approved for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults with hemophilia A.

Octocog alfa was already FDA-approved for the control and prevention of bleeding episodes in adults and children with hemophilia A, for perioperative management in adults and children with hemophilia A, as routine prophylaxis in children with hemophilia A, and to reduce the risk of joint damage in children without pre-existing joint damage.

The FDA’s latest approval is based on data from the SPINART study, in which patients were randomized to receive prophylactic octocog alfa or on-demand treatment. The study was sponsored by Bayer Healthcare, the company developing octocog alfa.

“In Bayer’s SPINART study, adult patients with hemophilia A on the prophylactic regimen experienced significantly fewer bleeding events than those using on-demand treatment,” said Marilyn Manco-Johnson, MD, principal investigator of the study and director at of the Mountain States Regional Hemophilia and Thrombosis Center at the University of Colorado at Denver and Health Sciences Center.

Results of the SPINART study were presented at the World Federation of Hemophilia 2012 World Congress and published in The Journal of Thrombosis and Haemostasis.

The study included 84 patients, ages 15 to 50, with hemophilia A. They were randomized to a prophylaxis regimen of 25 IU/kg 3 times per week (n=42) or on-demand treatment (n=42). Escalation by 5 IU/kg (to 30 or 35 IU/kg maximum) was allowed for subjects with 12 or more annual bleeds after 1 and 2 years.

Patients were stratified based on target joints (presence/absence) and the number of bleeding events in the previous 6 months (≥15 vs <15 annualized bleeds).

Patients who received prophylaxis experienced significantly fewer bleeds (P<0.0001) than patients treated on demand, regardless of factors such as age, bleeding history, and the presence or absence of target joints.

The ratio of the mean bleeding frequency was 15.2 (P<0.0001) for on-demand vs prophylaxis, indicating that patients who received on-demand treatment experienced, on average, 15.2 times as many bleeds as patients treated prophylactically.

The mean annualized bleed rates (bleeds/subject/year) were 37 in the on-demand group versus 2 in the prophylaxis group. The median annualized bleed rate in the on-demand group was 33 versus 0 in the prophylaxis group.

Fifty-two percent (22/42) of prophylaxis subjects experienced no bleeding, and 29% (12/42) of prophylaxis subjects experienced 1 to 2 bleeds during the follow-up period.

Adverse events were consistent with the existing safety profile for octocog alfa. The most common adverse reactions (≥4%) were inhibitor formation in previously untreated and minimally treated patients, skin-related hypersensitivity reactions (eg, rash, pruritus), infusion-site reactions (eg, inflammation, pain), and infections associated with a central venous access device.

Serious adverse reactions associated with octocog alfa include systemic hypersensitivity reactions—bronchospastic reactions and/or hypotension and anaphylaxis—and the development of high-titer inhibitors necessitating alternative treatments to factor VIII.

For more details on octocog alfa, see the full prescribing information.

Antihemophilic factor

The US Food and Drug Administration (FDA) has approved a new indication for the recombinant antihemophilic factor VIII product octocog alfa (Kogenate).

It is now approved for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults with hemophilia A.

Octocog alfa was already FDA-approved for the control and prevention of bleeding episodes in adults and children with hemophilia A, for perioperative management in adults and children with hemophilia A, as routine prophylaxis in children with hemophilia A, and to reduce the risk of joint damage in children without pre-existing joint damage.

The FDA’s latest approval is based on data from the SPINART study, in which patients were randomized to receive prophylactic octocog alfa or on-demand treatment. The study was sponsored by Bayer Healthcare, the company developing octocog alfa.

“In Bayer’s SPINART study, adult patients with hemophilia A on the prophylactic regimen experienced significantly fewer bleeding events than those using on-demand treatment,” said Marilyn Manco-Johnson, MD, principal investigator of the study and director at of the Mountain States Regional Hemophilia and Thrombosis Center at the University of Colorado at Denver and Health Sciences Center.

Results of the SPINART study were presented at the World Federation of Hemophilia 2012 World Congress and published in The Journal of Thrombosis and Haemostasis.

The study included 84 patients, ages 15 to 50, with hemophilia A. They were randomized to a prophylaxis regimen of 25 IU/kg 3 times per week (n=42) or on-demand treatment (n=42). Escalation by 5 IU/kg (to 30 or 35 IU/kg maximum) was allowed for subjects with 12 or more annual bleeds after 1 and 2 years.

Patients were stratified based on target joints (presence/absence) and the number of bleeding events in the previous 6 months (≥15 vs <15 annualized bleeds).

Patients who received prophylaxis experienced significantly fewer bleeds (P<0.0001) than patients treated on demand, regardless of factors such as age, bleeding history, and the presence or absence of target joints.

The ratio of the mean bleeding frequency was 15.2 (P<0.0001) for on-demand vs prophylaxis, indicating that patients who received on-demand treatment experienced, on average, 15.2 times as many bleeds as patients treated prophylactically.

The mean annualized bleed rates (bleeds/subject/year) were 37 in the on-demand group versus 2 in the prophylaxis group. The median annualized bleed rate in the on-demand group was 33 versus 0 in the prophylaxis group.

Fifty-two percent (22/42) of prophylaxis subjects experienced no bleeding, and 29% (12/42) of prophylaxis subjects experienced 1 to 2 bleeds during the follow-up period.

Adverse events were consistent with the existing safety profile for octocog alfa. The most common adverse reactions (≥4%) were inhibitor formation in previously untreated and minimally treated patients, skin-related hypersensitivity reactions (eg, rash, pruritus), infusion-site reactions (eg, inflammation, pain), and infections associated with a central venous access device.

Serious adverse reactions associated with octocog alfa include systemic hypersensitivity reactions—bronchospastic reactions and/or hypotension and anaphylaxis—and the development of high-titer inhibitors necessitating alternative treatments to factor VIII.

For more details on octocog alfa, see the full prescribing information.

Antihemophilic factor

The US Food and Drug Administration (FDA) has approved a new indication for the recombinant antihemophilic factor VIII product octocog alfa (Kogenate).

It is now approved for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults with hemophilia A.

Octocog alfa was already FDA-approved for the control and prevention of bleeding episodes in adults and children with hemophilia A, for perioperative management in adults and children with hemophilia A, as routine prophylaxis in children with hemophilia A, and to reduce the risk of joint damage in children without pre-existing joint damage.

The FDA’s latest approval is based on data from the SPINART study, in which patients were randomized to receive prophylactic octocog alfa or on-demand treatment. The study was sponsored by Bayer Healthcare, the company developing octocog alfa.

“In Bayer’s SPINART study, adult patients with hemophilia A on the prophylactic regimen experienced significantly fewer bleeding events than those using on-demand treatment,” said Marilyn Manco-Johnson, MD, principal investigator of the study and director at of the Mountain States Regional Hemophilia and Thrombosis Center at the University of Colorado at Denver and Health Sciences Center.

Results of the SPINART study were presented at the World Federation of Hemophilia 2012 World Congress and published in The Journal of Thrombosis and Haemostasis.

The study included 84 patients, ages 15 to 50, with hemophilia A. They were randomized to a prophylaxis regimen of 25 IU/kg 3 times per week (n=42) or on-demand treatment (n=42). Escalation by 5 IU/kg (to 30 or 35 IU/kg maximum) was allowed for subjects with 12 or more annual bleeds after 1 and 2 years.

Patients were stratified based on target joints (presence/absence) and the number of bleeding events in the previous 6 months (≥15 vs <15 annualized bleeds).

Patients who received prophylaxis experienced significantly fewer bleeds (P<0.0001) than patients treated on demand, regardless of factors such as age, bleeding history, and the presence or absence of target joints.

The ratio of the mean bleeding frequency was 15.2 (P<0.0001) for on-demand vs prophylaxis, indicating that patients who received on-demand treatment experienced, on average, 15.2 times as many bleeds as patients treated prophylactically.

The mean annualized bleed rates (bleeds/subject/year) were 37 in the on-demand group versus 2 in the prophylaxis group. The median annualized bleed rate in the on-demand group was 33 versus 0 in the prophylaxis group.

Fifty-two percent (22/42) of prophylaxis subjects experienced no bleeding, and 29% (12/42) of prophylaxis subjects experienced 1 to 2 bleeds during the follow-up period.

Adverse events were consistent with the existing safety profile for octocog alfa. The most common adverse reactions (≥4%) were inhibitor formation in previously untreated and minimally treated patients, skin-related hypersensitivity reactions (eg, rash, pruritus), infusion-site reactions (eg, inflammation, pain), and infections associated with a central venous access device.

Serious adverse reactions associated with octocog alfa include systemic hypersensitivity reactions—bronchospastic reactions and/or hypotension and anaphylaxis—and the development of high-titer inhibitors necessitating alternative treatments to factor VIII.

For more details on octocog alfa, see the full prescribing information.

Drug release in a cancer cell

Credit: PNAS

Researchers have discovered that a solvent used as a drug delivery vehicle has antimyeloma properties.

The team found that N-methyl-2-pyrrolidone (NMP)—long-regarded a basic, stable, and inactive solvent—affects the growth and survival of multiple myeloma (MM) cells and stimulates the immune system to kill these tumors.

Jake Shortt, MBChB, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia, described these findings in Cell Reports.

“[W]e found NMP effectively ‘reprograms’ myeloma cells by targeting a class of gene-regulating proteins,” Dr Shortt said. “This reprogramming reawakens thousands of genes that have been silenced in the cancer cells, immediately stopping the myeloma cells from growing, while activating the immune system to respond to the cancer.”

The researchers were surprised by this discovery because they had been using NMP as a vehicle to deliver drugs in mouse models of MM.

“In a routine experiment in 2010, Dr Shortt noticed our preclinical models of myeloma were responding to the control dose of NMP, which was surprising, as this control dose contained none of the novel cancer agents we were actually testing,” said study author Ricky Johnstone, PhD, also of the Peter MacCallum Cancer Centre.

Specifically, the researchers were using NMP as a drug delivery vehicle in mice transplanted with Vk*MYC MM tumors. And they consistently observed antitumor activity in vehicle-only control mice.

The team saw responses to NMP in mice transplanted with multiple, independently derived myelomas; namely, delayed paraprotein progression and improved survival in aggressive clones and sustained regressions in more indolent disease.

Further investigation revealed that NMP is an acetylated lysine mimetic and bromodomain ligand. And NMP shares molecular targets with lenalidomide, including cMYC and IRF4.

Unlike lenalidomide, NMP showed CRBN-independent activity. NMP induced similar growth arrest in CRBN-knockdown MM cells and lenalidomide-resistant MM cells.

Based on these findings, the researchers are planning a phase 1 trial of NMP, which is due to start later this year. The team noted that, because safe levels of NMP in humans are already well-established, the study is in the advanced planning stage.

“We’re at an advantage with this trial because we can immediately start at dosage levels within those recommended under occupational health and safety guidelines,” said David Ritchie, MBChB, PhD, a professor at the Peter MacCallum Cancer Centre and chief investigator of the phase 1 trial.

“It is extremely exciting to have this new insight into NMP, which is comparatively cost-effective and plentiful, compared to novel treatments developed by pharmaceutical companies, and hopefully holds promise for new or improved treatments in other cancer types.”

Drug release in a cancer cell

Credit: PNAS

Researchers have discovered that a solvent used as a drug delivery vehicle has antimyeloma properties.

The team found that N-methyl-2-pyrrolidone (NMP)—long-regarded a basic, stable, and inactive solvent—affects the growth and survival of multiple myeloma (MM) cells and stimulates the immune system to kill these tumors.

Jake Shortt, MBChB, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia, described these findings in Cell Reports.

“[W]e found NMP effectively ‘reprograms’ myeloma cells by targeting a class of gene-regulating proteins,” Dr Shortt said. “This reprogramming reawakens thousands of genes that have been silenced in the cancer cells, immediately stopping the myeloma cells from growing, while activating the immune system to respond to the cancer.”

The researchers were surprised by this discovery because they had been using NMP as a vehicle to deliver drugs in mouse models of MM.

“In a routine experiment in 2010, Dr Shortt noticed our preclinical models of myeloma were responding to the control dose of NMP, which was surprising, as this control dose contained none of the novel cancer agents we were actually testing,” said study author Ricky Johnstone, PhD, also of the Peter MacCallum Cancer Centre.

Specifically, the researchers were using NMP as a drug delivery vehicle in mice transplanted with Vk*MYC MM tumors. And they consistently observed antitumor activity in vehicle-only control mice.

The team saw responses to NMP in mice transplanted with multiple, independently derived myelomas; namely, delayed paraprotein progression and improved survival in aggressive clones and sustained regressions in more indolent disease.

Further investigation revealed that NMP is an acetylated lysine mimetic and bromodomain ligand. And NMP shares molecular targets with lenalidomide, including cMYC and IRF4.

Unlike lenalidomide, NMP showed CRBN-independent activity. NMP induced similar growth arrest in CRBN-knockdown MM cells and lenalidomide-resistant MM cells.

Based on these findings, the researchers are planning a phase 1 trial of NMP, which is due to start later this year. The team noted that, because safe levels of NMP in humans are already well-established, the study is in the advanced planning stage.

“We’re at an advantage with this trial because we can immediately start at dosage levels within those recommended under occupational health and safety guidelines,” said David Ritchie, MBChB, PhD, a professor at the Peter MacCallum Cancer Centre and chief investigator of the phase 1 trial.

“It is extremely exciting to have this new insight into NMP, which is comparatively cost-effective and plentiful, compared to novel treatments developed by pharmaceutical companies, and hopefully holds promise for new or improved treatments in other cancer types.”

Drug release in a cancer cell

Credit: PNAS

Researchers have discovered that a solvent used as a drug delivery vehicle has antimyeloma properties.

The team found that N-methyl-2-pyrrolidone (NMP)—long-regarded a basic, stable, and inactive solvent—affects the growth and survival of multiple myeloma (MM) cells and stimulates the immune system to kill these tumors.

Jake Shortt, MBChB, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia, described these findings in Cell Reports.

“[W]e found NMP effectively ‘reprograms’ myeloma cells by targeting a class of gene-regulating proteins,” Dr Shortt said. “This reprogramming reawakens thousands of genes that have been silenced in the cancer cells, immediately stopping the myeloma cells from growing, while activating the immune system to respond to the cancer.”

The researchers were surprised by this discovery because they had been using NMP as a vehicle to deliver drugs in mouse models of MM.

“In a routine experiment in 2010, Dr Shortt noticed our preclinical models of myeloma were responding to the control dose of NMP, which was surprising, as this control dose contained none of the novel cancer agents we were actually testing,” said study author Ricky Johnstone, PhD, also of the Peter MacCallum Cancer Centre.

Specifically, the researchers were using NMP as a drug delivery vehicle in mice transplanted with Vk*MYC MM tumors. And they consistently observed antitumor activity in vehicle-only control mice.

The team saw responses to NMP in mice transplanted with multiple, independently derived myelomas; namely, delayed paraprotein progression and improved survival in aggressive clones and sustained regressions in more indolent disease.

Further investigation revealed that NMP is an acetylated lysine mimetic and bromodomain ligand. And NMP shares molecular targets with lenalidomide, including cMYC and IRF4.

Unlike lenalidomide, NMP showed CRBN-independent activity. NMP induced similar growth arrest in CRBN-knockdown MM cells and lenalidomide-resistant MM cells.

Based on these findings, the researchers are planning a phase 1 trial of NMP, which is due to start later this year. The team noted that, because safe levels of NMP in humans are already well-established, the study is in the advanced planning stage.

“We’re at an advantage with this trial because we can immediately start at dosage levels within those recommended under occupational health and safety guidelines,” said David Ritchie, MBChB, PhD, a professor at the Peter MacCallum Cancer Centre and chief investigator of the phase 1 trial.

“It is extremely exciting to have this new insight into NMP, which is comparatively cost-effective and plentiful, compared to novel treatments developed by pharmaceutical companies, and hopefully holds promise for new or improved treatments in other cancer types.”

Lab mouse

Investigators have developed a technique that allowed them to track single tumor circulating in the blood of mice.

The method, described in Chemistry & Biology, involves photoswitchable fluorescent proteins that change color in response to light.

When one laser light hits the circulating tumor cells, they appear to be fluorescent green. A second laser makes the cells appear fluorescent red.

To label cells, the investigators use a violet laser beam aimed at small blood vessels.

The fluorescence from each cell is collected, detected, and reproduced on a computer monitor as real-time signal traces, allowing the team to count and track individual cells in the bloodstream.

“This technology allows for the labeling of just one circulating pathological cell among billions of other normal blood cells by ultrafast changing color of photosensitive proteins inside the cell in response to laser light,” said study author Ekaterina Galanzha, PhD, of the University of Arkansas for Medical Sciences in Little Rock.

In tumor-bearing mice, the investigators could monitor the real-time dynamics of circulating cancer cells released from a primary tumor.

They could also image the various final destinations of individual circulating cells and observe how these cells travel through circulation and colonize healthy tissue, existing sites of metastasis, or the site of the primary tumor.

“Therefore, the approach may give oncologists knowledge on how to intervene and stop circulating cancer cell dissemination that might prevent the development of metastasis,” Dr Galanzha said.

The investigators believe the approach might also prove useful for other areas of medicine—for example, tracking bacteria during infections or immune-related cells during the development of autoimmune disease.

Lab mouse

Investigators have developed a technique that allowed them to track single tumor circulating in the blood of mice.

The method, described in Chemistry & Biology, involves photoswitchable fluorescent proteins that change color in response to light.

When one laser light hits the circulating tumor cells, they appear to be fluorescent green. A second laser makes the cells appear fluorescent red.

To label cells, the investigators use a violet laser beam aimed at small blood vessels.

The fluorescence from each cell is collected, detected, and reproduced on a computer monitor as real-time signal traces, allowing the team to count and track individual cells in the bloodstream.

“This technology allows for the labeling of just one circulating pathological cell among billions of other normal blood cells by ultrafast changing color of photosensitive proteins inside the cell in response to laser light,” said study author Ekaterina Galanzha, PhD, of the University of Arkansas for Medical Sciences in Little Rock.

In tumor-bearing mice, the investigators could monitor the real-time dynamics of circulating cancer cells released from a primary tumor.

They could also image the various final destinations of individual circulating cells and observe how these cells travel through circulation and colonize healthy tissue, existing sites of metastasis, or the site of the primary tumor.

“Therefore, the approach may give oncologists knowledge on how to intervene and stop circulating cancer cell dissemination that might prevent the development of metastasis,” Dr Galanzha said.

The investigators believe the approach might also prove useful for other areas of medicine—for example, tracking bacteria during infections or immune-related cells during the development of autoimmune disease.

Lab mouse

Investigators have developed a technique that allowed them to track single tumor circulating in the blood of mice.

The method, described in Chemistry & Biology, involves photoswitchable fluorescent proteins that change color in response to light.

When one laser light hits the circulating tumor cells, they appear to be fluorescent green. A second laser makes the cells appear fluorescent red.

To label cells, the investigators use a violet laser beam aimed at small blood vessels.

The fluorescence from each cell is collected, detected, and reproduced on a computer monitor as real-time signal traces, allowing the team to count and track individual cells in the bloodstream.

“This technology allows for the labeling of just one circulating pathological cell among billions of other normal blood cells by ultrafast changing color of photosensitive proteins inside the cell in response to laser light,” said study author Ekaterina Galanzha, PhD, of the University of Arkansas for Medical Sciences in Little Rock.

In tumor-bearing mice, the investigators could monitor the real-time dynamics of circulating cancer cells released from a primary tumor.

They could also image the various final destinations of individual circulating cells and observe how these cells travel through circulation and colonize healthy tissue, existing sites of metastasis, or the site of the primary tumor.

“Therefore, the approach may give oncologists knowledge on how to intervene and stop circulating cancer cell dissemination that might prevent the development of metastasis,” Dr Galanzha said.

The investigators believe the approach might also prove useful for other areas of medicine—for example, tracking bacteria during infections or immune-related cells during the development of autoimmune disease.

Blood for transfusion

Credit: Elise Amendola

Results of a large study showed that black patients were more likely than white patients to receive perioperative blood transfusions for 2 of 3 common surgical procedures.

Researchers evaluated transfusion practices in these 2 racial groups for coronary artery bypass surgery (CABG), total hip replacement (THR), and colectomy.

And they found that black patients undergoing CABG or THR had a significantly higher incidence of transfusion than white patients undergoing these procedures.

Feng Qian, PhD, of the University at Albany School of Public Health, and his colleagues reported these findings in BMC Health Services Research.

The team examined the use of perioperative red blood cell transfusion using patient data from the University Health System Consortium, a network of academic medical centers and affiliated hospitals. The data included hospitalizations occurring from 2009 to 2011.

The researchers’ final sample included 42,933 patients who underwent THR (37,888 white and 5045 black), 25,849 patients who underwent CABG (23,113 white and 2736 black), and 8255 patients who underwent colectomy (6861 white and 1394 black).

Black patients tended to be younger than white patients, with the overall age ranging from 48 to 73 years. Blacks were also less well-insured than whites and more likely to have comorbidities such as diabetes, renal failure, and anemia.

Dr Qian and his colleagues adjusted for these differences in their analysis, as well as for patient gender, admission status, and severity of illness.

The analysis revealed that black patients undergoing CABG had a 41% higher incidence of perioperative transfusion than white patients (P=0.002).

For THR, the incidence of transfusion was 39% higher among blacks than whites (P<0.001). And for colectomy, the incidence was 8% higher among blacks than whites (P=0.40).

The researchers then performed an analysis adjusted for the aforementioned factors as well as for hospital-fixed effects.

This revealed that black patients undergoing CABG had a 42% higher incidence of transfusion than whites (P<0.001). Blacks undergoing THR had a 43% higher incidence of transfusion (P<0.001). And blacks undergoing colectomy had a 1% higher incidence of transfusion (P=0.92)

The researchers noted that, although blood transfusion is widely employed in surgery, the practice is associated with adverse outcomes. So overuse of transfusions may pose serious health risks, specifically in black patients undergoing CABG and THR.

Dr Qian added that recognizing racial disparities related to the use of perioperative red blood cell transfusion may help reduce potentially unnecessary transfusions in minority patients.

Blood for transfusion

Credit: Elise Amendola

Results of a large study showed that black patients were more likely than white patients to receive perioperative blood transfusions for 2 of 3 common surgical procedures.

Researchers evaluated transfusion practices in these 2 racial groups for coronary artery bypass surgery (CABG), total hip replacement (THR), and colectomy.

And they found that black patients undergoing CABG or THR had a significantly higher incidence of transfusion than white patients undergoing these procedures.

Feng Qian, PhD, of the University at Albany School of Public Health, and his colleagues reported these findings in BMC Health Services Research.

The team examined the use of perioperative red blood cell transfusion using patient data from the University Health System Consortium, a network of academic medical centers and affiliated hospitals. The data included hospitalizations occurring from 2009 to 2011.

The researchers’ final sample included 42,933 patients who underwent THR (37,888 white and 5045 black), 25,849 patients who underwent CABG (23,113 white and 2736 black), and 8255 patients who underwent colectomy (6861 white and 1394 black).

Black patients tended to be younger than white patients, with the overall age ranging from 48 to 73 years. Blacks were also less well-insured than whites and more likely to have comorbidities such as diabetes, renal failure, and anemia.

Dr Qian and his colleagues adjusted for these differences in their analysis, as well as for patient gender, admission status, and severity of illness.

The analysis revealed that black patients undergoing CABG had a 41% higher incidence of perioperative transfusion than white patients (P=0.002).

For THR, the incidence of transfusion was 39% higher among blacks than whites (P<0.001). And for colectomy, the incidence was 8% higher among blacks than whites (P=0.40).

The researchers then performed an analysis adjusted for the aforementioned factors as well as for hospital-fixed effects.

This revealed that black patients undergoing CABG had a 42% higher incidence of transfusion than whites (P<0.001). Blacks undergoing THR had a 43% higher incidence of transfusion (P<0.001). And blacks undergoing colectomy had a 1% higher incidence of transfusion (P=0.92)

The researchers noted that, although blood transfusion is widely employed in surgery, the practice is associated with adverse outcomes. So overuse of transfusions may pose serious health risks, specifically in black patients undergoing CABG and THR.

Dr Qian added that recognizing racial disparities related to the use of perioperative red blood cell transfusion may help reduce potentially unnecessary transfusions in minority patients.

Blood for transfusion

Credit: Elise Amendola

Results of a large study showed that black patients were more likely than white patients to receive perioperative blood transfusions for 2 of 3 common surgical procedures.

Researchers evaluated transfusion practices in these 2 racial groups for coronary artery bypass surgery (CABG), total hip replacement (THR), and colectomy.

And they found that black patients undergoing CABG or THR had a significantly higher incidence of transfusion than white patients undergoing these procedures.

Feng Qian, PhD, of the University at Albany School of Public Health, and his colleagues reported these findings in BMC Health Services Research.

The team examined the use of perioperative red blood cell transfusion using patient data from the University Health System Consortium, a network of academic medical centers and affiliated hospitals. The data included hospitalizations occurring from 2009 to 2011.

The researchers’ final sample included 42,933 patients who underwent THR (37,888 white and 5045 black), 25,849 patients who underwent CABG (23,113 white and 2736 black), and 8255 patients who underwent colectomy (6861 white and 1394 black).

Black patients tended to be younger than white patients, with the overall age ranging from 48 to 73 years. Blacks were also less well-insured than whites and more likely to have comorbidities such as diabetes, renal failure, and anemia.

Dr Qian and his colleagues adjusted for these differences in their analysis, as well as for patient gender, admission status, and severity of illness.

The analysis revealed that black patients undergoing CABG had a 41% higher incidence of perioperative transfusion than white patients (P=0.002).

For THR, the incidence of transfusion was 39% higher among blacks than whites (P<0.001). And for colectomy, the incidence was 8% higher among blacks than whites (P=0.40).

The researchers then performed an analysis adjusted for the aforementioned factors as well as for hospital-fixed effects.

This revealed that black patients undergoing CABG had a 42% higher incidence of transfusion than whites (P<0.001). Blacks undergoing THR had a 43% higher incidence of transfusion (P<0.001). And blacks undergoing colectomy had a 1% higher incidence of transfusion (P=0.92)

The researchers noted that, although blood transfusion is widely employed in surgery, the practice is associated with adverse outcomes. So overuse of transfusions may pose serious health risks, specifically in black patients undergoing CABG and THR.

Dr Qian added that recognizing racial disparities related to the use of perioperative red blood cell transfusion may help reduce potentially unnecessary transfusions in minority patients.

Blood for transfusion

Credit: UAB Hospital

Reinfusing the blood a patient loses during cardiopulmonary bypass surgery confers benefits over transfusing the patient with banked blood, results of a small study suggest.

Investigators noted that both the surgery and red blood cell (RBC) storage are associated with changes in RBCs that can adversely affect oxygen delivery.

However, their study revealed minimal effects on RBC structure and function among patients who received their own recycled blood during surgery.

On the other hand, patients who received banked RBCs along with their own blood experienced a dose-dependent decrease in RBC cell membrane deformability that could persist beyond 3 days.

Steven Frank, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues reported these findings in Anesthesia & Analgesia.

The team studied 32 patients undergoing cardiopulmonary bypass, categorizing them by their transfusion status: those who received their own RBCs (n=12), those who received their own blood plus fewer than 5 units of banked blood (n=10), and those who received their own RBCs plus 5 or more units of stored blood (n=10).

All patients had blood samples drawn before, during, and for 3 days after surgery. The investigators examined samples for blood cell membrane stiffness and flexibility.

In patients who received only their own recycled blood, their cells behaved normally right away, as if they had never been outside the body.

But the more banked blood a patient received, the less flexible their entire population of RBCs. Three days after surgery, RBCs in the group that received the largest number of transfused units still had not recovered their full function.

“We now have more evidence that fresh blood cells are of a higher quality than what comes from a blood bank,” Dr Frank said.

“If banked blood, which is stored for up to 6 weeks, is now shown to be of a lower quality, it makes more sense to use recycled blood that has only been outside the body for 1 or 2 hours. It’s always been the case that patients feel better about getting their own blood, and recycling is also more cost-effective.”

The investigators used a cell saver machine to collect the material a patient lost during surgery. They then rinsed away the unneeded fat and tissue, centrifuged and separated the red cells, and returned them to the patient.

Dr Frank and his colleagues noted that disposable parts of the cell saver, which can be used to process multiple units of blood, cost around $120, compared to $240 for each unit of banked blood. Additionally, recycling blood reduces a patient’s risk of contracting infections and experiencing transfusion-related adverse reactions.

Dr Frank pointed out, however, that cell saver machines are not appropriate for all operations, and not all hospitals have access to round-the-clock perfusionists to run them. For heart surgeries, a perfusionist is already in the operating room to run the heart-lung bypass machine.

Dr Frank also noted that many operations are considered to be a low risk for blood loss, in which case, the cell saver is unnecessary. Nevertheless, he advocates wider use of recycled blood.

“In any patient where you expect to give 1 unit of red blood cells or more, it’s cost-effective and beneficial to recycle,” he said.

Blood for transfusion

Credit: UAB Hospital

Reinfusing the blood a patient loses during cardiopulmonary bypass surgery confers benefits over transfusing the patient with banked blood, results of a small study suggest.

Investigators noted that both the surgery and red blood cell (RBC) storage are associated with changes in RBCs that can adversely affect oxygen delivery.

However, their study revealed minimal effects on RBC structure and function among patients who received their own recycled blood during surgery.

On the other hand, patients who received banked RBCs along with their own blood experienced a dose-dependent decrease in RBC cell membrane deformability that could persist beyond 3 days.

Steven Frank, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues reported these findings in Anesthesia & Analgesia.

The team studied 32 patients undergoing cardiopulmonary bypass, categorizing them by their transfusion status: those who received their own RBCs (n=12), those who received their own blood plus fewer than 5 units of banked blood (n=10), and those who received their own RBCs plus 5 or more units of stored blood (n=10).

All patients had blood samples drawn before, during, and for 3 days after surgery. The investigators examined samples for blood cell membrane stiffness and flexibility.

In patients who received only their own recycled blood, their cells behaved normally right away, as if they had never been outside the body.

But the more banked blood a patient received, the less flexible their entire population of RBCs. Three days after surgery, RBCs in the group that received the largest number of transfused units still had not recovered their full function.

“We now have more evidence that fresh blood cells are of a higher quality than what comes from a blood bank,” Dr Frank said.

“If banked blood, which is stored for up to 6 weeks, is now shown to be of a lower quality, it makes more sense to use recycled blood that has only been outside the body for 1 or 2 hours. It’s always been the case that patients feel better about getting their own blood, and recycling is also more cost-effective.”

The investigators used a cell saver machine to collect the material a patient lost during surgery. They then rinsed away the unneeded fat and tissue, centrifuged and separated the red cells, and returned them to the patient.

Dr Frank and his colleagues noted that disposable parts of the cell saver, which can be used to process multiple units of blood, cost around $120, compared to $240 for each unit of banked blood. Additionally, recycling blood reduces a patient’s risk of contracting infections and experiencing transfusion-related adverse reactions.

Dr Frank pointed out, however, that cell saver machines are not appropriate for all operations, and not all hospitals have access to round-the-clock perfusionists to run them. For heart surgeries, a perfusionist is already in the operating room to run the heart-lung bypass machine.

Dr Frank also noted that many operations are considered to be a low risk for blood loss, in which case, the cell saver is unnecessary. Nevertheless, he advocates wider use of recycled blood.

“In any patient where you expect to give 1 unit of red blood cells or more, it’s cost-effective and beneficial to recycle,” he said.

Blood for transfusion

Credit: UAB Hospital

Reinfusing the blood a patient loses during cardiopulmonary bypass surgery confers benefits over transfusing the patient with banked blood, results of a small study suggest.

Investigators noted that both the surgery and red blood cell (RBC) storage are associated with changes in RBCs that can adversely affect oxygen delivery.

However, their study revealed minimal effects on RBC structure and function among patients who received their own recycled blood during surgery.

On the other hand, patients who received banked RBCs along with their own blood experienced a dose-dependent decrease in RBC cell membrane deformability that could persist beyond 3 days.

Steven Frank, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues reported these findings in Anesthesia & Analgesia.

The team studied 32 patients undergoing cardiopulmonary bypass, categorizing them by their transfusion status: those who received their own RBCs (n=12), those who received their own blood plus fewer than 5 units of banked blood (n=10), and those who received their own RBCs plus 5 or more units of stored blood (n=10).

All patients had blood samples drawn before, during, and for 3 days after surgery. The investigators examined samples for blood cell membrane stiffness and flexibility.

In patients who received only their own recycled blood, their cells behaved normally right away, as if they had never been outside the body.

But the more banked blood a patient received, the less flexible their entire population of RBCs. Three days after surgery, RBCs in the group that received the largest number of transfused units still had not recovered their full function.

“We now have more evidence that fresh blood cells are of a higher quality than what comes from a blood bank,” Dr Frank said.

“If banked blood, which is stored for up to 6 weeks, is now shown to be of a lower quality, it makes more sense to use recycled blood that has only been outside the body for 1 or 2 hours. It’s always been the case that patients feel better about getting their own blood, and recycling is also more cost-effective.”

The investigators used a cell saver machine to collect the material a patient lost during surgery. They then rinsed away the unneeded fat and tissue, centrifuged and separated the red cells, and returned them to the patient.

Dr Frank and his colleagues noted that disposable parts of the cell saver, which can be used to process multiple units of blood, cost around $120, compared to $240 for each unit of banked blood. Additionally, recycling blood reduces a patient’s risk of contracting infections and experiencing transfusion-related adverse reactions.

Dr Frank pointed out, however, that cell saver machines are not appropriate for all operations, and not all hospitals have access to round-the-clock perfusionists to run them. For heart surgeries, a perfusionist is already in the operating room to run the heart-lung bypass machine.

Dr Frank also noted that many operations are considered to be a low risk for blood loss, in which case, the cell saver is unnecessary. Nevertheless, he advocates wider use of recycled blood.

“In any patient where you expect to give 1 unit of red blood cells or more, it’s cost-effective and beneficial to recycle,” he said.

Thrombus

Credit: Andre E.X. Brown

The US Food and Drug Administration (FDA) has approved the antiplatelet agent vorapaxar (Zontivity) to reduce the risk of thrombotic cardiovascular events in patients with a history of myocardial infarction or peripheral arterial disease.

Results of a large study suggested the drug can be effective as prophylaxis but may also increase the risk of bleeding.

Vorapaxar’s label has a black box warning describing this risk, which includes intracranial hemorrhage and fatal bleeding.

The warning also states that vorapaxar should not be given to patients with a history of stroke, transient ischemic attack, intracranial hemorrhage, or active pathological bleeding.

The drug will be dispensed with an FDA-approved patient medication guide that provides instructions for its use and important safety information.

Vorapaxar tablets are intended to be given once daily, along with aspirin and/or clopidogrel, according to their indications or the standard of care.

“In patients who have had a heart attack or who have peripheral arterial disease, this drug will lower the risk of heart attack, stroke, and cardiovascular death,” said Ellis Unger, MD, director of the Office of Drug Evaluation in the FDA’s Center for Drug Evaluation and Research.

“In the study that supported the drug’s approval, [vorapaxar] lowered this risk from 9.5% to 7.9% over a 3-year period—about 0.5% per year.”

The study, which was published in NEJM, included 26,449 patients with a history of myocardial infarction (n=17,779), ischemic stroke (n=4883), or peripheral arterial disease (n=3787).

The patients were randomized to receive vorapaxar at 2.5 mg daily or matching placebo, in addition to standard antiplatelet therapy.

The study’s primary efficacy endpoint was the composite of death from cardiovascular causes, myocardial infarction, or stroke. At 3 years, 1028 patients (9.3%) in the vorapaxar group and 1176 patients (10.5%) in the placebo group reached the primary endpoint.

Both moderate and severe bleeding events were significantly higher in patients on vorapaxar than in the placebo group. Bleeding occurred in 4.2% and 2.5% of patients, respectively. And intracranial hemorrhage occurred in 1.0% and 0.5%, respectively.

The risk of intracranial bleeding was highest among patients with a history of stroke, so these patients were taken off of vorapaxar early.

Vorapaxar is made by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., of Whitehouse Station, New Jersey. For more information on the drug, see the full prescribing information.

Thrombus

Credit: Andre E.X. Brown

The US Food and Drug Administration (FDA) has approved the antiplatelet agent vorapaxar (Zontivity) to reduce the risk of thrombotic cardiovascular events in patients with a history of myocardial infarction or peripheral arterial disease.

Results of a large study suggested the drug can be effective as prophylaxis but may also increase the risk of bleeding.

Vorapaxar’s label has a black box warning describing this risk, which includes intracranial hemorrhage and fatal bleeding.

The warning also states that vorapaxar should not be given to patients with a history of stroke, transient ischemic attack, intracranial hemorrhage, or active pathological bleeding.

The drug will be dispensed with an FDA-approved patient medication guide that provides instructions for its use and important safety information.

Vorapaxar tablets are intended to be given once daily, along with aspirin and/or clopidogrel, according to their indications or the standard of care.

“In patients who have had a heart attack or who have peripheral arterial disease, this drug will lower the risk of heart attack, stroke, and cardiovascular death,” said Ellis Unger, MD, director of the Office of Drug Evaluation in the FDA’s Center for Drug Evaluation and Research.

“In the study that supported the drug’s approval, [vorapaxar] lowered this risk from 9.5% to 7.9% over a 3-year period—about 0.5% per year.”

The study, which was published in NEJM, included 26,449 patients with a history of myocardial infarction (n=17,779), ischemic stroke (n=4883), or peripheral arterial disease (n=3787).

The patients were randomized to receive vorapaxar at 2.5 mg daily or matching placebo, in addition to standard antiplatelet therapy.

The study’s primary efficacy endpoint was the composite of death from cardiovascular causes, myocardial infarction, or stroke. At 3 years, 1028 patients (9.3%) in the vorapaxar group and 1176 patients (10.5%) in the placebo group reached the primary endpoint.

Both moderate and severe bleeding events were significantly higher in patients on vorapaxar than in the placebo group. Bleeding occurred in 4.2% and 2.5% of patients, respectively. And intracranial hemorrhage occurred in 1.0% and 0.5%, respectively.

The risk of intracranial bleeding was highest among patients with a history of stroke, so these patients were taken off of vorapaxar early.

Vorapaxar is made by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., of Whitehouse Station, New Jersey. For more information on the drug, see the full prescribing information.

Thrombus

Credit: Andre E.X. Brown

The US Food and Drug Administration (FDA) has approved the antiplatelet agent vorapaxar (Zontivity) to reduce the risk of thrombotic cardiovascular events in patients with a history of myocardial infarction or peripheral arterial disease.

Results of a large study suggested the drug can be effective as prophylaxis but may also increase the risk of bleeding.

Vorapaxar’s label has a black box warning describing this risk, which includes intracranial hemorrhage and fatal bleeding.

The warning also states that vorapaxar should not be given to patients with a history of stroke, transient ischemic attack, intracranial hemorrhage, or active pathological bleeding.

The drug will be dispensed with an FDA-approved patient medication guide that provides instructions for its use and important safety information.

Vorapaxar tablets are intended to be given once daily, along with aspirin and/or clopidogrel, according to their indications or the standard of care.

“In patients who have had a heart attack or who have peripheral arterial disease, this drug will lower the risk of heart attack, stroke, and cardiovascular death,” said Ellis Unger, MD, director of the Office of Drug Evaluation in the FDA’s Center for Drug Evaluation and Research.

“In the study that supported the drug’s approval, [vorapaxar] lowered this risk from 9.5% to 7.9% over a 3-year period—about 0.5% per year.”

The study, which was published in NEJM, included 26,449 patients with a history of myocardial infarction (n=17,779), ischemic stroke (n=4883), or peripheral arterial disease (n=3787).

The patients were randomized to receive vorapaxar at 2.5 mg daily or matching placebo, in addition to standard antiplatelet therapy.

The study’s primary efficacy endpoint was the composite of death from cardiovascular causes, myocardial infarction, or stroke. At 3 years, 1028 patients (9.3%) in the vorapaxar group and 1176 patients (10.5%) in the placebo group reached the primary endpoint.

Both moderate and severe bleeding events were significantly higher in patients on vorapaxar than in the placebo group. Bleeding occurred in 4.2% and 2.5% of patients, respectively. And intracranial hemorrhage occurred in 1.0% and 0.5%, respectively.

The risk of intracranial bleeding was highest among patients with a history of stroke, so these patients were taken off of vorapaxar early.

Vorapaxar is made by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., of Whitehouse Station, New Jersey. For more information on the drug, see the full prescribing information.

Researcher in the lab

Credit: NIH

A group of researchers who tried, and failed, to replicate the STAP cell phenomenon have detailed their work in F1000Research.

Kenneth Ka Ho Lee, PhD, of the Chinese University of Hong Kong, and his colleagues attempted to create STAP (stimulus-triggered acquisition of pluripotency) cells using the method described in a recent Nature paper.

The paper’s authors had reported they could induce pluripotency in somatic cells by bathing them in acid.

However, not long after the paper and a related letter were published, members of the scientific community voiced concerns about the publications—such as suspicions of plagiarism and the possibility of doctored images—and began to question the findings.

Then, an investigation by the Japanese research institute RIKEN (where many of the researchers are employed) suggested that at least some of the paper’s authors were guilty of misconduct and/or negligence.

However, the study’s lead author, Haruko Obokata, PhD, has maintained that, despite errors in the paper, STAP cells can be created.

Dr Lee’s experiments suggest otherwise—or at least that the cells cannot be created using the methods outlined in the Nature paper.

Dr Lee and his colleagues reported that carefully replicating the original acid-treatment method does not induce pluripotency in 2 types of mouse somatic cells.

Using both white blood cells isolated from the spleen of neonatal mice—the same cells used in the original study—and lung fibroblasts, the team was unable to replicate the original findings.

They’ve published a full account of this work in F1000Research. The journal also employs open peer review by invited experts, which occurs after publication and is published in full online alongside the paper.

Dr Lee’s study will now undergo this process, and readers interested to see referees’ views as they come in can follow the paper by clicking “Track” on the published article.

Researcher in the lab

Credit: NIH

A group of researchers who tried, and failed, to replicate the STAP cell phenomenon have detailed their work in F1000Research.

Kenneth Ka Ho Lee, PhD, of the Chinese University of Hong Kong, and his colleagues attempted to create STAP (stimulus-triggered acquisition of pluripotency) cells using the method described in a recent Nature paper.

The paper’s authors had reported they could induce pluripotency in somatic cells by bathing them in acid.

However, not long after the paper and a related letter were published, members of the scientific community voiced concerns about the publications—such as suspicions of plagiarism and the possibility of doctored images—and began to question the findings.

Then, an investigation by the Japanese research institute RIKEN (where many of the researchers are employed) suggested that at least some of the paper’s authors were guilty of misconduct and/or negligence.

However, the study’s lead author, Haruko Obokata, PhD, has maintained that, despite errors in the paper, STAP cells can be created.

Dr Lee’s experiments suggest otherwise—or at least that the cells cannot be created using the methods outlined in the Nature paper.

Dr Lee and his colleagues reported that carefully replicating the original acid-treatment method does not induce pluripotency in 2 types of mouse somatic cells.

Using both white blood cells isolated from the spleen of neonatal mice—the same cells used in the original study—and lung fibroblasts, the team was unable to replicate the original findings.

They’ve published a full account of this work in F1000Research. The journal also employs open peer review by invited experts, which occurs after publication and is published in full online alongside the paper.

Dr Lee’s study will now undergo this process, and readers interested to see referees’ views as they come in can follow the paper by clicking “Track” on the published article.

Researcher in the lab

Credit: NIH

A group of researchers who tried, and failed, to replicate the STAP cell phenomenon have detailed their work in F1000Research.

Kenneth Ka Ho Lee, PhD, of the Chinese University of Hong Kong, and his colleagues attempted to create STAP (stimulus-triggered acquisition of pluripotency) cells using the method described in a recent Nature paper.

The paper’s authors had reported they could induce pluripotency in somatic cells by bathing them in acid.

However, not long after the paper and a related letter were published, members of the scientific community voiced concerns about the publications—such as suspicions of plagiarism and the possibility of doctored images—and began to question the findings.

Then, an investigation by the Japanese research institute RIKEN (where many of the researchers are employed) suggested that at least some of the paper’s authors were guilty of misconduct and/or negligence.

However, the study’s lead author, Haruko Obokata, PhD, has maintained that, despite errors in the paper, STAP cells can be created.

Dr Lee’s experiments suggest otherwise—or at least that the cells cannot be created using the methods outlined in the Nature paper.

Dr Lee and his colleagues reported that carefully replicating the original acid-treatment method does not induce pluripotency in 2 types of mouse somatic cells.

Using both white blood cells isolated from the spleen of neonatal mice—the same cells used in the original study—and lung fibroblasts, the team was unable to replicate the original findings.

They’ve published a full account of this work in F1000Research. The journal also employs open peer review by invited experts, which occurs after publication and is published in full online alongside the paper.

Dr Lee’s study will now undergo this process, and readers interested to see referees’ views as they come in can follow the paper by clicking “Track” on the published article.

RIKEN President Ryoji Noyori

Credit: RIKEN

The Japanese research institute RIKEN has announced that it will not re-investigate the allegations of misconduct levelled against the researcher who claimed to have discovered a new method for inducing pluripotency in somatic cells.

In January, Haruko Obokata, PhD, and her colleagues reported the creation of stimulus-triggered acquisition of pluripotency (STAP) cells.

The team said they could induce pluripotency by exposing somatic cells to a low-pH environment.

But members of the scientific community voiced concerns about the research, so RIKEN launched an investigation.

In April, the investigative committee concluded that Dr Obokata and some of her colleagues were guilty of misconduct and/or negligence.

Dr Obokata appealed the findings, but the committee has decided another investigation is not warranted. RIKEN has also called for a retraction of the Nature paper in which the committee found evidence of misconduct.

Another RIKEN committee has already met to discuss possible disciplinary action for Dr Obokata and some of her colleagues. Potential punishments range from pay cuts to temporary suspension to disciplinary discharge.

In the meantime, a group headed by Shinichi Aizawa, PhD, special advisor to RIKEN, is attempting to verify the results of the STAP experiments and determine if the STAP phenomenon is, in fact, real.

As the events of this case unfolded, another possible case of misconduct surfaced at RIKEN.

The institute recently announced that Shunsuke Ishii, PhD, chairperson of the committee investigating misconduct in the STAP papers, had resigned from the committee amid concerns about one of his own papers.

RIKEN replaced Dr Ishii with Jun Watanabe, a lawyer already on the committee. And the institute has launched an investigation into Dr Ishii’s work.

Furthermore, RIKEN’s office for internal reform, headed by President Ryoji Noyori, PhD, has commissioned a committee of outside experts to deliberate and recommend measures to prevent research misconduct in the future.

RIKEN President Ryoji Noyori

Credit: RIKEN

The Japanese research institute RIKEN has announced that it will not re-investigate the allegations of misconduct levelled against the researcher who claimed to have discovered a new method for inducing pluripotency in somatic cells.

In January, Haruko Obokata, PhD, and her colleagues reported the creation of stimulus-triggered acquisition of pluripotency (STAP) cells.

The team said they could induce pluripotency by exposing somatic cells to a low-pH environment.

But members of the scientific community voiced concerns about the research, so RIKEN launched an investigation.

In April, the investigative committee concluded that Dr Obokata and some of her colleagues were guilty of misconduct and/or negligence.

Dr Obokata appealed the findings, but the committee has decided another investigation is not warranted. RIKEN has also called for a retraction of the Nature paper in which the committee found evidence of misconduct.

Another RIKEN committee has already met to discuss possible disciplinary action for Dr Obokata and some of her colleagues. Potential punishments range from pay cuts to temporary suspension to disciplinary discharge.

In the meantime, a group headed by Shinichi Aizawa, PhD, special advisor to RIKEN, is attempting to verify the results of the STAP experiments and determine if the STAP phenomenon is, in fact, real.

As the events of this case unfolded, another possible case of misconduct surfaced at RIKEN.

The institute recently announced that Shunsuke Ishii, PhD, chairperson of the committee investigating misconduct in the STAP papers, had resigned from the committee amid concerns about one of his own papers.

RIKEN replaced Dr Ishii with Jun Watanabe, a lawyer already on the committee. And the institute has launched an investigation into Dr Ishii’s work.

Furthermore, RIKEN’s office for internal reform, headed by President Ryoji Noyori, PhD, has commissioned a committee of outside experts to deliberate and recommend measures to prevent research misconduct in the future.

RIKEN President Ryoji Noyori

Credit: RIKEN

The Japanese research institute RIKEN has announced that it will not re-investigate the allegations of misconduct levelled against the researcher who claimed to have discovered a new method for inducing pluripotency in somatic cells.

In January, Haruko Obokata, PhD, and her colleagues reported the creation of stimulus-triggered acquisition of pluripotency (STAP) cells.

The team said they could induce pluripotency by exposing somatic cells to a low-pH environment.

But members of the scientific community voiced concerns about the research, so RIKEN launched an investigation.

In April, the investigative committee concluded that Dr Obokata and some of her colleagues were guilty of misconduct and/or negligence.

Dr Obokata appealed the findings, but the committee has decided another investigation is not warranted. RIKEN has also called for a retraction of the Nature paper in which the committee found evidence of misconduct.

Another RIKEN committee has already met to discuss possible disciplinary action for Dr Obokata and some of her colleagues. Potential punishments range from pay cuts to temporary suspension to disciplinary discharge.

In the meantime, a group headed by Shinichi Aizawa, PhD, special advisor to RIKEN, is attempting to verify the results of the STAP experiments and determine if the STAP phenomenon is, in fact, real.

As the events of this case unfolded, another possible case of misconduct surfaced at RIKEN.

The institute recently announced that Shunsuke Ishii, PhD, chairperson of the committee investigating misconduct in the STAP papers, had resigned from the committee amid concerns about one of his own papers.

RIKEN replaced Dr Ishii with Jun Watanabe, a lawyer already on the committee. And the institute has launched an investigation into Dr Ishii’s work.

Furthermore, RIKEN’s office for internal reform, headed by President Ryoji Noyori, PhD, has commissioned a committee of outside experts to deliberate and recommend measures to prevent research misconduct in the future.

The Diagnosis: Carotenemia

Laboratory parameters including thyroid function testing as well as total protein and bilirubin levels were within reference range. Testing revealed multiple food allergies to almonds, oranges, cashews, garlic, peanuts, and cantaloupe. The patient was treated with a dietary expansion based on his allergy testing.

ß-Carotene converts to vitamin A in the intestine and acts as a lipochrome. Lack of conversion can be noted as an inborn error of metabolism.¹ Many green, yellow, and orange fruits and vegetables contain ß-carotene, including carrots, sweet potatoes, squash, green beans, papayas, and pumpkins.^1-3 ß-Carotene also is used as a vitamin supplement⁴ or therapeutic agent in photosensitive disorders such as genetic porphyrias.⁵

ß-Carotene can accumulate in the stratum corneum and impart a yellow color to the skin when the circulating levels are high; this coloration is termed carotenemia.^1,4 Carotenemia is common in infants and young children who have diets rich in green and orange vegetable purees.⁶ Carotenemia limited to thick areas of the skin, such as the palms and soles, can be seen in adults who eat large amounts of carrots; generalized carotenemia is rare.^1,4

Carotenemia is a benign condition of excess cutaneous buildup of ß-carotene through excessive intake of carotene-rich foods^1-4 or nutritional supplements⁷ or through association with anorexia, liver disease, renal disease, hypothyroidism, or diabetes mellitus.^1,4,8,9 Carotene deposits usually are most notable in areas with thick stratum corneum, such as the nasolabial folds, palms, and soles, as opposed to areas such as the conjunctivae and mucosa.^1,4

Carotenemia may mimic jaundice and should be differentiated through scleral examination for icterus and bilirubin levels. Carotene levels can be tested but generally are unnecessary. Carotenemia can be seen in liver or renal disease and can exacerbate the yellow coloration seen in jaundiced individuals.^1,4,9

Because it is a benign condition, the pathology usually is limited to skin discoloration, as seen in our patient. Although this condition can be reversed with a modified diet, our patient had multiple food allergies that further restricted his vegetarian diet, thereby limiting the modifications that he was willing to make to his diet.

The Diagnosis: Carotenemia

Laboratory parameters including thyroid function testing as well as total protein and bilirubin levels were within reference range. Testing revealed multiple food allergies to almonds, oranges, cashews, garlic, peanuts, and cantaloupe. The patient was treated with a dietary expansion based on his allergy testing.

ß-Carotene converts to vitamin A in the intestine and acts as a lipochrome. Lack of conversion can be noted as an inborn error of metabolism.¹ Many green, yellow, and orange fruits and vegetables contain ß-carotene, including carrots, sweet potatoes, squash, green beans, papayas, and pumpkins.^1-3 ß-Carotene also is used as a vitamin supplement⁴ or therapeutic agent in photosensitive disorders such as genetic porphyrias.⁵

ß-Carotene can accumulate in the stratum corneum and impart a yellow color to the skin when the circulating levels are high; this coloration is termed carotenemia.^1,4 Carotenemia is common in infants and young children who have diets rich in green and orange vegetable purees.⁶ Carotenemia limited to thick areas of the skin, such as the palms and soles, can be seen in adults who eat large amounts of carrots; generalized carotenemia is rare.^1,4

Carotenemia is a benign condition of excess cutaneous buildup of ß-carotene through excessive intake of carotene-rich foods^1-4 or nutritional supplements⁷ or through association with anorexia, liver disease, renal disease, hypothyroidism, or diabetes mellitus.^1,4,8,9 Carotene deposits usually are most notable in areas with thick stratum corneum, such as the nasolabial folds, palms, and soles, as opposed to areas such as the conjunctivae and mucosa.^1,4

Carotenemia may mimic jaundice and should be differentiated through scleral examination for icterus and bilirubin levels. Carotene levels can be tested but generally are unnecessary. Carotenemia can be seen in liver or renal disease and can exacerbate the yellow coloration seen in jaundiced individuals.^1,4,9

Because it is a benign condition, the pathology usually is limited to skin discoloration, as seen in our patient. Although this condition can be reversed with a modified diet, our patient had multiple food allergies that further restricted his vegetarian diet, thereby limiting the modifications that he was willing to make to his diet.

The Diagnosis: Carotenemia

Laboratory parameters including thyroid function testing as well as total protein and bilirubin levels were within reference range. Testing revealed multiple food allergies to almonds, oranges, cashews, garlic, peanuts, and cantaloupe. The patient was treated with a dietary expansion based on his allergy testing.

ß-Carotene converts to vitamin A in the intestine and acts as a lipochrome. Lack of conversion can be noted as an inborn error of metabolism.¹ Many green, yellow, and orange fruits and vegetables contain ß-carotene, including carrots, sweet potatoes, squash, green beans, papayas, and pumpkins.^1-3 ß-Carotene also is used as a vitamin supplement⁴ or therapeutic agent in photosensitive disorders such as genetic porphyrias.⁵

ß-Carotene can accumulate in the stratum corneum and impart a yellow color to the skin when the circulating levels are high; this coloration is termed carotenemia.^1,4 Carotenemia is common in infants and young children who have diets rich in green and orange vegetable purees.⁶ Carotenemia limited to thick areas of the skin, such as the palms and soles, can be seen in adults who eat large amounts of carrots; generalized carotenemia is rare.^1,4

Carotenemia is a benign condition of excess cutaneous buildup of ß-carotene through excessive intake of carotene-rich foods^1-4 or nutritional supplements⁷ or through association with anorexia, liver disease, renal disease, hypothyroidism, or diabetes mellitus.^1,4,8,9 Carotene deposits usually are most notable in areas with thick stratum corneum, such as the nasolabial folds, palms, and soles, as opposed to areas such as the conjunctivae and mucosa.^1,4

Carotenemia may mimic jaundice and should be differentiated through scleral examination for icterus and bilirubin levels. Carotene levels can be tested but generally are unnecessary. Carotenemia can be seen in liver or renal disease and can exacerbate the yellow coloration seen in jaundiced individuals.^1,4,9

Because it is a benign condition, the pathology usually is limited to skin discoloration, as seen in our patient. Although this condition can be reversed with a modified diet, our patient had multiple food allergies that further restricted his vegetarian diet, thereby limiting the modifications that he was willing to make to his diet.