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Findings could aid treatment of resistant T-ALL
(blue and purple) invaded
by leukemia cells (yellow).
Image courtesy of Edwin
Hawkins, Delfim Duarte,
and Imperial College London
Preclinical research has shed light on how certain leukemia cells survive treatment and could pave the way for better therapeutic targeting of these resistant cells.
Researchers have speculated that some leukemia cells survive treatment by hiding out in specific niches in the bone marrow.
Results of the new research, conducted in mouse models and human samples of T-cell acute lymphoblastic leukemia (T-ALL), contradict that theory.
The experiments showed that resistant T-ALL cells move rapidly through the bone marrow before, during, and after treatment, interacting with—and sometimes killing—healthy cells.
“We expected the cells that survived treatment to be sat in particular niches, but, instead, they are very active throughout the bone marrow,” said Cristina Lo Celso, PhD, of Imperial College London in the UK.
“We now know that it would be ineffective to target particular niches in the bone marrow to tackle treatment-resistant leukemia. Now that we know that the cells don’t hide, we can explore why that is and how their movement helps them to survive. Ultimately, we want to find out whether we can stop the movement and whether this could kill the treatment-resistant cells.”
Dr Lo Celso and her colleagues described these findings in a letter to Nature.
The researchers used intravital microscopy to track the movement of T-ALL cells in mice—before, during, and after treatment. Treatment consisted of dexamethasone alone, vincristine alone, or combination dexamethasone, vincristine, and L-asparaginase.
The team found that T-ALL cells moved around rapidly, not showing any preference for bone marrow subcompartments. The cells’ behavior was consistent over time—from the earliest bone marrow seeding through to treatment response and resistance.
However, the researchers noted that surviving T-ALL cells were “highly migratory” and travelled at significantly faster speeds than early infiltrating cells. In addition, resistant T-ALL cells were still capable of undergoing division at times when other T-ALL cells were dying.
The team suggested that the act of moving may help T-ALL cells to survive, possibly through short-lived interactions with other cells.
This theory was supported by the discovery that T-ALL cells actively attack osteoblasts. The researchers noted that osteoblasts are associated with hematopoietic fitness. So the loss of osteoblasts may contribute to the loss of healthy hematopoiesis observed in leukemia patients.
The team believes this insight could aid the development of treatments to safeguard the production of healthy blood cells in T-ALL patients.
“Our study supports the idea that, at least in this leukemia, new therapies should target the cancer cells themselves instead of the surrounding normal stromal cells to better eradicate the disease,” said study author Delfim Duarte, MD, a PhD student at Imperial College London.
“Our work also suggests that protecting normal stromal bone cells from the attack of leukemia cells can have wide implications in the support of healthy blood cell production,” said Edwin Hawkins, PhD, of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Victoria, Australia.
“Keeping blood cell levels up would prevent anemia, infection, and bleeding.” 
(blue and purple) invaded
by leukemia cells (yellow).
Image courtesy of Edwin
Hawkins, Delfim Duarte,
and Imperial College London
Preclinical research has shed light on how certain leukemia cells survive treatment and could pave the way for better therapeutic targeting of these resistant cells.
Researchers have speculated that some leukemia cells survive treatment by hiding out in specific niches in the bone marrow.
Results of the new research, conducted in mouse models and human samples of T-cell acute lymphoblastic leukemia (T-ALL), contradict that theory.
The experiments showed that resistant T-ALL cells move rapidly through the bone marrow before, during, and after treatment, interacting with—and sometimes killing—healthy cells.
“We expected the cells that survived treatment to be sat in particular niches, but, instead, they are very active throughout the bone marrow,” said Cristina Lo Celso, PhD, of Imperial College London in the UK.
“We now know that it would be ineffective to target particular niches in the bone marrow to tackle treatment-resistant leukemia. Now that we know that the cells don’t hide, we can explore why that is and how their movement helps them to survive. Ultimately, we want to find out whether we can stop the movement and whether this could kill the treatment-resistant cells.”
Dr Lo Celso and her colleagues described these findings in a letter to Nature.
The researchers used intravital microscopy to track the movement of T-ALL cells in mice—before, during, and after treatment. Treatment consisted of dexamethasone alone, vincristine alone, or combination dexamethasone, vincristine, and L-asparaginase.
The team found that T-ALL cells moved around rapidly, not showing any preference for bone marrow subcompartments. The cells’ behavior was consistent over time—from the earliest bone marrow seeding through to treatment response and resistance.
However, the researchers noted that surviving T-ALL cells were “highly migratory” and travelled at significantly faster speeds than early infiltrating cells. In addition, resistant T-ALL cells were still capable of undergoing division at times when other T-ALL cells were dying.
The team suggested that the act of moving may help T-ALL cells to survive, possibly through short-lived interactions with other cells.
This theory was supported by the discovery that T-ALL cells actively attack osteoblasts. The researchers noted that osteoblasts are associated with hematopoietic fitness. So the loss of osteoblasts may contribute to the loss of healthy hematopoiesis observed in leukemia patients.
The team believes this insight could aid the development of treatments to safeguard the production of healthy blood cells in T-ALL patients.
“Our study supports the idea that, at least in this leukemia, new therapies should target the cancer cells themselves instead of the surrounding normal stromal cells to better eradicate the disease,” said study author Delfim Duarte, MD, a PhD student at Imperial College London.
“Our work also suggests that protecting normal stromal bone cells from the attack of leukemia cells can have wide implications in the support of healthy blood cell production,” said Edwin Hawkins, PhD, of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Victoria, Australia.
“Keeping blood cell levels up would prevent anemia, infection, and bleeding.”
(blue and purple) invaded
by leukemia cells (yellow).
Image courtesy of Edwin
Hawkins, Delfim Duarte,
and Imperial College London
Preclinical research has shed light on how certain leukemia cells survive treatment and could pave the way for better therapeutic targeting of these resistant cells.
Researchers have speculated that some leukemia cells survive treatment by hiding out in specific niches in the bone marrow.
Results of the new research, conducted in mouse models and human samples of T-cell acute lymphoblastic leukemia (T-ALL), contradict that theory.
The experiments showed that resistant T-ALL cells move rapidly through the bone marrow before, during, and after treatment, interacting with—and sometimes killing—healthy cells.
“We expected the cells that survived treatment to be sat in particular niches, but, instead, they are very active throughout the bone marrow,” said Cristina Lo Celso, PhD, of Imperial College London in the UK.
“We now know that it would be ineffective to target particular niches in the bone marrow to tackle treatment-resistant leukemia. Now that we know that the cells don’t hide, we can explore why that is and how their movement helps them to survive. Ultimately, we want to find out whether we can stop the movement and whether this could kill the treatment-resistant cells.”
Dr Lo Celso and her colleagues described these findings in a letter to Nature.
The researchers used intravital microscopy to track the movement of T-ALL cells in mice—before, during, and after treatment. Treatment consisted of dexamethasone alone, vincristine alone, or combination dexamethasone, vincristine, and L-asparaginase.
The team found that T-ALL cells moved around rapidly, not showing any preference for bone marrow subcompartments. The cells’ behavior was consistent over time—from the earliest bone marrow seeding through to treatment response and resistance.
However, the researchers noted that surviving T-ALL cells were “highly migratory” and travelled at significantly faster speeds than early infiltrating cells. In addition, resistant T-ALL cells were still capable of undergoing division at times when other T-ALL cells were dying.
The team suggested that the act of moving may help T-ALL cells to survive, possibly through short-lived interactions with other cells.
This theory was supported by the discovery that T-ALL cells actively attack osteoblasts. The researchers noted that osteoblasts are associated with hematopoietic fitness. So the loss of osteoblasts may contribute to the loss of healthy hematopoiesis observed in leukemia patients.
The team believes this insight could aid the development of treatments to safeguard the production of healthy blood cells in T-ALL patients.
“Our study supports the idea that, at least in this leukemia, new therapies should target the cancer cells themselves instead of the surrounding normal stromal cells to better eradicate the disease,” said study author Delfim Duarte, MD, a PhD student at Imperial College London.
“Our work also suggests that protecting normal stromal bone cells from the attack of leukemia cells can have wide implications in the support of healthy blood cell production,” said Edwin Hawkins, PhD, of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Victoria, Australia.
“Keeping blood cell levels up would prevent anemia, infection, and bleeding.”
The mesh tradeoff: Lower recurrence risk vs. complicaitons
Among patients undergoing elective incisional repair of abdominal wall hernias, the use of mesh reinforcement decreases the short-term recurrence rate by 5% but increases major complications by approximately the same amount over the subsequent 5 years, Dunja Kokotovic, MB, reported at the annual clinical congress of the American College of Surgeons.
“Given the continuously increasing incidence of mesh-related complications with time, it is expected that, with even longer follow-up up than the 5 years observed in this study, mesh-related complications continue to accrue,” said Dr. Kokotovic of the Center for Surgical Science, Zealand University Hospital, Koge, Denmark. The findings of this observational registry-based cohort study were presented at the congress and simultaneously published online in JAMA (2016 Oct 17. doi: 10.1001/jama.2016.15217).
These results highlight the need to assess the long-term safety of interventions before making definitive conclusions about their benefits and widely adopting them. In the United States, manufacturers are required to demonstrate the long-term safety of drugs but not of some devices, including hernia meshes. There were approximately 190,000 such hernia repairs performed in the United States alone during the most recent year for which data are available, and mesh is estimated to have been used in at least half, Dr. Kokotovic noted.
She and her associates analyzed the 5-year outcomes for virtually all incisional hernia repairs performed in Denmark from 2007 through 2010 using data in a mandatory national registry. Their analysis included 3,242 patients (mean age, 58 years): 1,119 (34.5%) who had open mesh repair, 1,757 (54.2%) who had laparoscopic mesh repair, and 366 (11.3%) who had nonmesh repair.
The cumulative risk of reoperation for hernia recurrence was significantly lower for patients who had open mesh repair (12.3%) or laparoscopic mesh repair (10.6%) than for those who had nonmesh repair (17.1%). However, this benefit was offset by the rate of major mesh-related complications requiring surgical intervention – including surgical site infection, formation of a chronic sinus tract, late-onset intra-abdominal abscess, enterocutaneous fistula, bowel obstruction, and bowel perforation – which progressively increased over time. The cumulative incidence of such complications was 5.6% for open mesh repair and 3.7% for laparoscopic mesh repair.
This study was limited in that it was observational rather than being based on randomized data, so selection bias and imbalances among the study groups couldn’t be fully controlled for. However, two strengths of this study were that it reflects the real-world experience of an entire country and all the surgeons performing hernia repairs there, and it had 100% follow-up, the researchers said.
This study was partly funded by the Edgar Schnohr and Wife Gilberte Schnohr’s Foundation supporting independent surgical and anesthesiological research. Dr. Kokotovic reported having no relevant financial disclosures; one investigator reported receiving personal fees from Bard and Etichon for educational presentations.
These study findings suggest that the risk-benefit ratio of mesh reinforcement is not as clear as previously thought and call into question the current widespread use of mesh, even for repair of small hernias, when mesh is the norm for all incisional hernia repairs of any size.
Although the study by Kokotovic and colleagues is one of the most comprehensive long-term studies in hernia surgery, many questions remain about the optimal approach for repairing ventral hernia. To provide more rigorous data to better understand optimal approaches to this common clinical problem, surgeons will need to design large multicenter pragmatic trials with long-term follow-up.
Kamal M. F. Itani, MD, is at the VA Boston Health Care System, Boston University, West Roxbury, Mass., and Harvard Medical School in Boston. He reported having served as a research consultant to Davol 4 years ago regarding an antibiotic-coated mesh product. These remarks are excerpted from an editorial accompanying Dr. Kokotovic’s report (JAMA 2016 Oct 17. doi: 10.1001/jama.2016.15722).
These study findings suggest that the risk-benefit ratio of mesh reinforcement is not as clear as previously thought and call into question the current widespread use of mesh, even for repair of small hernias, when mesh is the norm for all incisional hernia repairs of any size.
Although the study by Kokotovic and colleagues is one of the most comprehensive long-term studies in hernia surgery, many questions remain about the optimal approach for repairing ventral hernia. To provide more rigorous data to better understand optimal approaches to this common clinical problem, surgeons will need to design large multicenter pragmatic trials with long-term follow-up.
Kamal M. F. Itani, MD, is at the VA Boston Health Care System, Boston University, West Roxbury, Mass., and Harvard Medical School in Boston. He reported having served as a research consultant to Davol 4 years ago regarding an antibiotic-coated mesh product. These remarks are excerpted from an editorial accompanying Dr. Kokotovic’s report (JAMA 2016 Oct 17. doi: 10.1001/jama.2016.15722).
These study findings suggest that the risk-benefit ratio of mesh reinforcement is not as clear as previously thought and call into question the current widespread use of mesh, even for repair of small hernias, when mesh is the norm for all incisional hernia repairs of any size.
Although the study by Kokotovic and colleagues is one of the most comprehensive long-term studies in hernia surgery, many questions remain about the optimal approach for repairing ventral hernia. To provide more rigorous data to better understand optimal approaches to this common clinical problem, surgeons will need to design large multicenter pragmatic trials with long-term follow-up.
Kamal M. F. Itani, MD, is at the VA Boston Health Care System, Boston University, West Roxbury, Mass., and Harvard Medical School in Boston. He reported having served as a research consultant to Davol 4 years ago regarding an antibiotic-coated mesh product. These remarks are excerpted from an editorial accompanying Dr. Kokotovic’s report (JAMA 2016 Oct 17. doi: 10.1001/jama.2016.15722).
Among patients undergoing elective incisional repair of abdominal wall hernias, the use of mesh reinforcement decreases the short-term recurrence rate by 5% but increases major complications by approximately the same amount over the subsequent 5 years, Dunja Kokotovic, MB, reported at the annual clinical congress of the American College of Surgeons.
“Given the continuously increasing incidence of mesh-related complications with time, it is expected that, with even longer follow-up up than the 5 years observed in this study, mesh-related complications continue to accrue,” said Dr. Kokotovic of the Center for Surgical Science, Zealand University Hospital, Koge, Denmark. The findings of this observational registry-based cohort study were presented at the congress and simultaneously published online in JAMA (2016 Oct 17. doi: 10.1001/jama.2016.15217).
These results highlight the need to assess the long-term safety of interventions before making definitive conclusions about their benefits and widely adopting them. In the United States, manufacturers are required to demonstrate the long-term safety of drugs but not of some devices, including hernia meshes. There were approximately 190,000 such hernia repairs performed in the United States alone during the most recent year for which data are available, and mesh is estimated to have been used in at least half, Dr. Kokotovic noted.
She and her associates analyzed the 5-year outcomes for virtually all incisional hernia repairs performed in Denmark from 2007 through 2010 using data in a mandatory national registry. Their analysis included 3,242 patients (mean age, 58 years): 1,119 (34.5%) who had open mesh repair, 1,757 (54.2%) who had laparoscopic mesh repair, and 366 (11.3%) who had nonmesh repair.
The cumulative risk of reoperation for hernia recurrence was significantly lower for patients who had open mesh repair (12.3%) or laparoscopic mesh repair (10.6%) than for those who had nonmesh repair (17.1%). However, this benefit was offset by the rate of major mesh-related complications requiring surgical intervention – including surgical site infection, formation of a chronic sinus tract, late-onset intra-abdominal abscess, enterocutaneous fistula, bowel obstruction, and bowel perforation – which progressively increased over time. The cumulative incidence of such complications was 5.6% for open mesh repair and 3.7% for laparoscopic mesh repair.
This study was limited in that it was observational rather than being based on randomized data, so selection bias and imbalances among the study groups couldn’t be fully controlled for. However, two strengths of this study were that it reflects the real-world experience of an entire country and all the surgeons performing hernia repairs there, and it had 100% follow-up, the researchers said.
This study was partly funded by the Edgar Schnohr and Wife Gilberte Schnohr’s Foundation supporting independent surgical and anesthesiological research. Dr. Kokotovic reported having no relevant financial disclosures; one investigator reported receiving personal fees from Bard and Etichon for educational presentations.
Among patients undergoing elective incisional repair of abdominal wall hernias, the use of mesh reinforcement decreases the short-term recurrence rate by 5% but increases major complications by approximately the same amount over the subsequent 5 years, Dunja Kokotovic, MB, reported at the annual clinical congress of the American College of Surgeons.
“Given the continuously increasing incidence of mesh-related complications with time, it is expected that, with even longer follow-up up than the 5 years observed in this study, mesh-related complications continue to accrue,” said Dr. Kokotovic of the Center for Surgical Science, Zealand University Hospital, Koge, Denmark. The findings of this observational registry-based cohort study were presented at the congress and simultaneously published online in JAMA (2016 Oct 17. doi: 10.1001/jama.2016.15217).
These results highlight the need to assess the long-term safety of interventions before making definitive conclusions about their benefits and widely adopting them. In the United States, manufacturers are required to demonstrate the long-term safety of drugs but not of some devices, including hernia meshes. There were approximately 190,000 such hernia repairs performed in the United States alone during the most recent year for which data are available, and mesh is estimated to have been used in at least half, Dr. Kokotovic noted.
She and her associates analyzed the 5-year outcomes for virtually all incisional hernia repairs performed in Denmark from 2007 through 2010 using data in a mandatory national registry. Their analysis included 3,242 patients (mean age, 58 years): 1,119 (34.5%) who had open mesh repair, 1,757 (54.2%) who had laparoscopic mesh repair, and 366 (11.3%) who had nonmesh repair.
The cumulative risk of reoperation for hernia recurrence was significantly lower for patients who had open mesh repair (12.3%) or laparoscopic mesh repair (10.6%) than for those who had nonmesh repair (17.1%). However, this benefit was offset by the rate of major mesh-related complications requiring surgical intervention – including surgical site infection, formation of a chronic sinus tract, late-onset intra-abdominal abscess, enterocutaneous fistula, bowel obstruction, and bowel perforation – which progressively increased over time. The cumulative incidence of such complications was 5.6% for open mesh repair and 3.7% for laparoscopic mesh repair.
This study was limited in that it was observational rather than being based on randomized data, so selection bias and imbalances among the study groups couldn’t be fully controlled for. However, two strengths of this study were that it reflects the real-world experience of an entire country and all the surgeons performing hernia repairs there, and it had 100% follow-up, the researchers said.
This study was partly funded by the Edgar Schnohr and Wife Gilberte Schnohr’s Foundation supporting independent surgical and anesthesiological research. Dr. Kokotovic reported having no relevant financial disclosures; one investigator reported receiving personal fees from Bard and Etichon for educational presentations.
FROM THE ACS CLINICAL CONGRESS
Key clinical point: Among patients undergoing elective incisional repair of abdominal wall hernias, the use of mesh reinforcement decreases the short-term recurrence rate by 5% but increases major complications by 5.6% over the subsequent 5 years.
Major finding: The cumulative rate of major mesh-related complications requiring surgical intervention was 5.6% for open mesh repair and 3.7% for laparoscopic mesh repair, compared with 0% for nonmesh repair.
Data source: A nationwide observational registry-based cohort study involving virtually all incisional hernia repairs (3,242) performed in Denmark from 2007 through 2010.
Disclosures: This study was partly funded by the Edgar Schnohr and Wife Gilberte Schnohr’s Foundation supporting independent surgical and anesthesiological research. Dr. Kokotovic reported having no relevant financial disclosures; one investigator reported receiving personal fees from Bard and Etichon for educational presentations.
Hepatitis infection raises non-Hodgkin lymphoma risk in HIV patients
HIV-infected individuals on antiretroviral therapy who also have chronic coinfection with hepatitis B or C virus have an increased risk of developing non-Hodgkin lymphoma, according to new research published in Annals of Internal Medicine.
Lead author Qing Wang, PhD, of the Basel Institute for Clinical Epidemiology & Biostatistics at University Hospital Basel, Switzerland, and her coauthors said there is growing evidence of an association between both chronic hepatitis B virus infection (HBV) and chronic hepatitis C virus infection (HCV), and non-Hodgkin lymphoma, with chronic immune activation and B cell proliferation suggested as potential mechanisms. However, the impact of chronic coinfection in individuals with HIV is unclear.
Researchers undertook a cohort study of 52,479 treatment-naive individuals with HIV infection, using 18 of 33 cohorts from the Collaboration of Observational HIV Epidemiological Research Europe. Of these participants, 1,336 had chronic HBV and 7,506 had chronic HCV infection, and more than three-quarters (77%) later started treatment with antiretroviral therapy.
After 13 months of follow-up in the treatment-naive group and 50 months in the antiretroviral group, there were 252 cases of non-Hodgkin lymphoma in the treatment-naive group and 310 cases in the treated group (Ann Intern Med. 2016 Oct 17. doi: 10.7326/M16-0240).
Antiretroviral-treated patients with chronic hepatitis B showed a significant 74% greater risk (95% confidence interval, 1.08-2.82) and those with hepatitis C showed a 73% greater risk (95% CI, 1.21-2.46) of non-Hodgkin lymphoma compared to treated individuals with neither coinfection. However, the differences in non-Hodgkin lymphoma rates in treatment-naive HBV and HCV coinfected individuals were not significant, which the authors suggested could be due to lower numbers of events and limited follow-up.
“The median CD4 count at the time of NHL diagnosis was less than 0.250 x 109 cells/L in both ART-naive and treated patients coinfected with HBV and HCV, indicating that coinfected patients with NHL initiate ART late or have insufficient HIV viral control and immune recovery that may be due to multiple reasons,” the authors wrote. “This unfavorable constellation is aggravated by the fact that chronic HBV infection attenuates immune recovery in ART-treated patients; whether this is also the case for chronic HCV infection is less clear.”
The authors said routine screening for chronic HBV and HCV infection, in conjunction with early diagnosis and treatment of HIV infection, was essential to reduce morbidity and mortality from non-Hodgkin lymphoma.
“Our findings provide strong evidence that HCV coinfected patients with poor immune status or restoration (CD4 count lower than 0.250 x 109 cells/L) are at high risk for NHL and death and deserve high priority for access to well-tolerated, interferon-free, direct-acting antiviral treatment programs similar to those for patients with advanced liver fibrosis or cirrhosis.”
The study was supported by the European Union Seventh Framework Programme, Schweizerische Krebsliga, Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS), Paris; the HIV Monitoring Foundation, Amsterdam; and the Augustinus Foundation, Copenhagen. Eleven authors declared grants, personal fees, and other support from pharmaceutical companies including those involved in the manufacture of HIV and hepatitis drugs. No other conflicts of interest were reported.
HIV-infected individuals on antiretroviral therapy who also have chronic coinfection with hepatitis B or C virus have an increased risk of developing non-Hodgkin lymphoma, according to new research published in Annals of Internal Medicine.
Lead author Qing Wang, PhD, of the Basel Institute for Clinical Epidemiology & Biostatistics at University Hospital Basel, Switzerland, and her coauthors said there is growing evidence of an association between both chronic hepatitis B virus infection (HBV) and chronic hepatitis C virus infection (HCV), and non-Hodgkin lymphoma, with chronic immune activation and B cell proliferation suggested as potential mechanisms. However, the impact of chronic coinfection in individuals with HIV is unclear.
Researchers undertook a cohort study of 52,479 treatment-naive individuals with HIV infection, using 18 of 33 cohorts from the Collaboration of Observational HIV Epidemiological Research Europe. Of these participants, 1,336 had chronic HBV and 7,506 had chronic HCV infection, and more than three-quarters (77%) later started treatment with antiretroviral therapy.
After 13 months of follow-up in the treatment-naive group and 50 months in the antiretroviral group, there were 252 cases of non-Hodgkin lymphoma in the treatment-naive group and 310 cases in the treated group (Ann Intern Med. 2016 Oct 17. doi: 10.7326/M16-0240).
Antiretroviral-treated patients with chronic hepatitis B showed a significant 74% greater risk (95% confidence interval, 1.08-2.82) and those with hepatitis C showed a 73% greater risk (95% CI, 1.21-2.46) of non-Hodgkin lymphoma compared to treated individuals with neither coinfection. However, the differences in non-Hodgkin lymphoma rates in treatment-naive HBV and HCV coinfected individuals were not significant, which the authors suggested could be due to lower numbers of events and limited follow-up.
“The median CD4 count at the time of NHL diagnosis was less than 0.250 x 109 cells/L in both ART-naive and treated patients coinfected with HBV and HCV, indicating that coinfected patients with NHL initiate ART late or have insufficient HIV viral control and immune recovery that may be due to multiple reasons,” the authors wrote. “This unfavorable constellation is aggravated by the fact that chronic HBV infection attenuates immune recovery in ART-treated patients; whether this is also the case for chronic HCV infection is less clear.”
The authors said routine screening for chronic HBV and HCV infection, in conjunction with early diagnosis and treatment of HIV infection, was essential to reduce morbidity and mortality from non-Hodgkin lymphoma.
“Our findings provide strong evidence that HCV coinfected patients with poor immune status or restoration (CD4 count lower than 0.250 x 109 cells/L) are at high risk for NHL and death and deserve high priority for access to well-tolerated, interferon-free, direct-acting antiviral treatment programs similar to those for patients with advanced liver fibrosis or cirrhosis.”
The study was supported by the European Union Seventh Framework Programme, Schweizerische Krebsliga, Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS), Paris; the HIV Monitoring Foundation, Amsterdam; and the Augustinus Foundation, Copenhagen. Eleven authors declared grants, personal fees, and other support from pharmaceutical companies including those involved in the manufacture of HIV and hepatitis drugs. No other conflicts of interest were reported.
HIV-infected individuals on antiretroviral therapy who also have chronic coinfection with hepatitis B or C virus have an increased risk of developing non-Hodgkin lymphoma, according to new research published in Annals of Internal Medicine.
Lead author Qing Wang, PhD, of the Basel Institute for Clinical Epidemiology & Biostatistics at University Hospital Basel, Switzerland, and her coauthors said there is growing evidence of an association between both chronic hepatitis B virus infection (HBV) and chronic hepatitis C virus infection (HCV), and non-Hodgkin lymphoma, with chronic immune activation and B cell proliferation suggested as potential mechanisms. However, the impact of chronic coinfection in individuals with HIV is unclear.
Researchers undertook a cohort study of 52,479 treatment-naive individuals with HIV infection, using 18 of 33 cohorts from the Collaboration of Observational HIV Epidemiological Research Europe. Of these participants, 1,336 had chronic HBV and 7,506 had chronic HCV infection, and more than three-quarters (77%) later started treatment with antiretroviral therapy.
After 13 months of follow-up in the treatment-naive group and 50 months in the antiretroviral group, there were 252 cases of non-Hodgkin lymphoma in the treatment-naive group and 310 cases in the treated group (Ann Intern Med. 2016 Oct 17. doi: 10.7326/M16-0240).
Antiretroviral-treated patients with chronic hepatitis B showed a significant 74% greater risk (95% confidence interval, 1.08-2.82) and those with hepatitis C showed a 73% greater risk (95% CI, 1.21-2.46) of non-Hodgkin lymphoma compared to treated individuals with neither coinfection. However, the differences in non-Hodgkin lymphoma rates in treatment-naive HBV and HCV coinfected individuals were not significant, which the authors suggested could be due to lower numbers of events and limited follow-up.
“The median CD4 count at the time of NHL diagnosis was less than 0.250 x 109 cells/L in both ART-naive and treated patients coinfected with HBV and HCV, indicating that coinfected patients with NHL initiate ART late or have insufficient HIV viral control and immune recovery that may be due to multiple reasons,” the authors wrote. “This unfavorable constellation is aggravated by the fact that chronic HBV infection attenuates immune recovery in ART-treated patients; whether this is also the case for chronic HCV infection is less clear.”
The authors said routine screening for chronic HBV and HCV infection, in conjunction with early diagnosis and treatment of HIV infection, was essential to reduce morbidity and mortality from non-Hodgkin lymphoma.
“Our findings provide strong evidence that HCV coinfected patients with poor immune status or restoration (CD4 count lower than 0.250 x 109 cells/L) are at high risk for NHL and death and deserve high priority for access to well-tolerated, interferon-free, direct-acting antiviral treatment programs similar to those for patients with advanced liver fibrosis or cirrhosis.”
The study was supported by the European Union Seventh Framework Programme, Schweizerische Krebsliga, Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS), Paris; the HIV Monitoring Foundation, Amsterdam; and the Augustinus Foundation, Copenhagen. Eleven authors declared grants, personal fees, and other support from pharmaceutical companies including those involved in the manufacture of HIV and hepatitis drugs. No other conflicts of interest were reported.
FROM ANNALS OF INTERNAL MEDICINE
Key clinical point: HIV-infected individuals on antiretroviral therapy who also have chronic coinfection with hepatitis B or C virus have an increased risk of developing non-Hodgkin lymphoma.
Major finding: Antiretroviral-treated patients with chronic hepatitis B showed a significant 74% greater risk and those with hepatitis C showed a 73% greater risk of non-Hodgkin lymphoma, compared to treated individuals with neither coinfection.
Data source: A cohort study of 52,479 treatment-naive individuals with HIV infection, using 18 of 33 cohorts from the Collaboration of Observational HIV Epidemiological Research Europe.
Disclosures: The study was supported by the European Union Seventh Framework Programme, Schweizerische Krebsliga, Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS), Paris; the HIV Monitoring Foundation, Amsterdam; and the Augustinus Foundation, Copenhagen. Eleven authors declared grants, personal fees, and other support from pharmaceutical companies including those involved in the manufacture of HIV and hepatitis drugs. No other conflicts of interest were reported.
Reslizumab performance tied to eosinophil count
Reslizumab was most effective in patients with high baseline eosinophil counts, two randomized, placebo-controlled studies have determined. The companion studies were simultaneously published in the October issue of Chest.
The drug reslizumab, an anti–interleukin-5 monoclonal antibody, is made by Teva Branded Pharmaceutical Products R&D, who sponsored both studies.
The larger study, comprising 492 patients, found no significant benefit of reslizumab over placebo, Jonathan Corren, MD, and his colleagues wrote (Chest. 2016;150:799-810). But this study didn’t stratify patients by baseline eosinophil levels; a post-hoc subanalysis found a significant benefit in forced expiratory volume in 69 of the patients who had at least 400 eosinophils/microliter (mcL) when treatment began.
In these patients, the drug significantly improved not only lung function, but asthma symptoms and asthma-related quality of life scores.
“These efficacy findings are consistent with results from other reslizumab trials and combined with the favorable safety profile observed, support the use of reslizumab in patients with asthma and elevated blood eosinophils, uncontrolled by an inhaled corticosteroid-based regimen,” Dr. Bjermer and his coauthors wrote.
The unstratified trial was conducted at 66 sites in the U.S. All of the patients had poorly controlled asthma despite using at least a medium-dosed inhaled corticosteroid. They were randomized to infusions of reslizumab 3.0 mg/kg or placebo given once every 4 weeks for 16 weeks.*
The primary endpoint was the change in forced expiratory volume in one second (FEV1); secondary endpoints included quality of life scores; the need for rescue medication; forced vital capacity; and eosinophil count.
Patients in the placebo and reslizumab groups were an average age of 45.1 years and 44.9 years, respectively. The mean disease duration of patients in both groups was 26 years.
At week 16, the mean change in FEV1 from baseline was 255 ml in the active group and 187 ml in the placebo group – not a significant difference.
The team performed a post-hoc subgroup analysis that dichotomized the cohort based on baseline eosinophil levels. For the 343 with counts of less than 400 cells/mcL, there was no difference in FEV1 at 16 weeks, between the patients who received treatment and the patients who received a placebo. The FEV1s of these two groups were separated by just 33 mL.
The story was different for the 82 patients with at least 400 cells/mcL, with 69 of such patients receiving the drug and 13 of such patients receiving the placebo. At 16 weeks, the difference in FEV1 change was 270 mL, in favor of the active group. The strength of these findings may be weakened by the large difference in size between the treatment and placebo groups and the “near complete lack of response in the small number of placebo-treated patients.”
“Interpretation of the results in the [400 or more cells/mcL] subgroup is limited as the study was not designed or statistically powered to specifically test this group of patients,” the team wrote. Nevertheless, they concluded that reslizumab is a reasonable treatment option for this group. “These findings support an acceptable benefit-risk profile for reslizumab in asthma patients with a blood eosinophil threshold” of at least 400 cells/mcL.
The stratified study examined more endpoints: pre-bronchodilator spirometry (forced expiratory volume in one second FEV1, forced vital capacity, and forced expiratory flow), asthma symptoms, quality of life, rescue inhaler use, and blood eosinophil levels.
The 315 patients in this study all had a baseline eosinophil count of at least 400 cells/mcL. They were randomized to placebo or to 0.3 or 3.0 mg/kg reslizumab dose once every 4 weeks for 16 weeks. The mean ages for the patients taking the placebo, reslizumab 0.3 mg/kg, and reslizumab 3.0 mg/kg were 44.2, 44.5, and 43.0, respectively. The range of average disease durations for patients in the placebo group and two reslizumab groups was 20 to 20.7 years.
The final FEV1 was significantly improved over placebo in both active groups, although the change was much more pronounced in those taking 3.0 mg/kg, compared with those taking 0.3 mg/kg (160 mL and 115 mL, respectively, relative to placebo). Forced vital capacity also improved significantly in the 3.0 mg/kg dose group (130 mL relative to placebo).
Reslizumab was generally well tolerated in both studies. The most frequent adverse events in the stratified study were asthma worsening, headache, nasopharyngitis, upper respiratory infections, and sinusitis.
In the unstratified study, there were two anaphylactic reactions, but only one was related to the study drug. No deaths occurred in either treatment group of this study.
Both trials were sponsored by Teva. Dr. Bjermer has served on advisory boards or provided lectures for Aerocrine, Airsonett, ALK, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Meda, Mundipharma, Nigaard, Novartis, Regeneron, Sanofi-Aventis, Takeda, and Teva. Dr. Corren has been involved in speaker bureau activities for Genentech and Merck; he has served on advisory boards for Genentech, Merck, Novartis, and Vectura.
*CORRECTION 12/9/16: An earlier version of this article misstated the infusion frequency.
[email protected]
On Twitter @Alz_Gal
Persistent eosinophilic inflammation is present in about half of patients with severe asthma, and the studies by Corren and Bjermer represent important advances in learning how to target this inflammatory pathway, Richard Russell, MBBS, MRCP, and Christopher Brightling, PhD, FCCP, wrote in an accompanying editorial (Chest. 2016;150:766-8).
“The most advanced therapeutic target is IL-5, which is an attractive target because it is an obligate cytokine for eosinophil maturation and survival. Its inhibition is thus predicted to reduce bone marrow production of eosinophils and promote apoptosis,” wrote Dr. Russell, a clinical research fellow, and Dr. Brightling, a professor, both at the University of Leicester (England).
“These findings support the view that an elevated blood eosinophil count is associated with a good clinical response [to the antibody reslizumab] but [the studies] did not find a clear correlation between the intensity of the baseline eosinophil count and response,” the colleagues wrote. “Thus, the best cut-off for the blood eosinophil count to apply clinically remains uncertain.”
Clinicians and patients may find a different answer to this riddle than do payers.
“From a patient perspective there is an argument to select a low or no cut-off as there is some benefit even with low baseline eosinophil counts, whereas from a payer’s perspective the health economic benefit is better with a higher cut-off.”
As is often the case, more study will help clarify these new concerns.
“We are moving into a new era of Type-2 immunity-mediated therapies that will bring new opportunities for clinicians and our patients, but with this opportunity comes new challenges. Biomarkers will increase in importance to help drive precision medicine, but we need to understand how to use them, and, in particular, what cut-points to apply. For anti-IL-5 approaches, we probably need to look towards elevated blood eosinophil counts, as aiming for a high cut-off is most likely the best way we shall achieve success.”
Dr. Russell had no financial disclosures. Mr. Brightling reported financial relationships with several pharmaceutical companies, but not with Teva.
Persistent eosinophilic inflammation is present in about half of patients with severe asthma, and the studies by Corren and Bjermer represent important advances in learning how to target this inflammatory pathway, Richard Russell, MBBS, MRCP, and Christopher Brightling, PhD, FCCP, wrote in an accompanying editorial (Chest. 2016;150:766-8).
“The most advanced therapeutic target is IL-5, which is an attractive target because it is an obligate cytokine for eosinophil maturation and survival. Its inhibition is thus predicted to reduce bone marrow production of eosinophils and promote apoptosis,” wrote Dr. Russell, a clinical research fellow, and Dr. Brightling, a professor, both at the University of Leicester (England).
“These findings support the view that an elevated blood eosinophil count is associated with a good clinical response [to the antibody reslizumab] but [the studies] did not find a clear correlation between the intensity of the baseline eosinophil count and response,” the colleagues wrote. “Thus, the best cut-off for the blood eosinophil count to apply clinically remains uncertain.”
Clinicians and patients may find a different answer to this riddle than do payers.
“From a patient perspective there is an argument to select a low or no cut-off as there is some benefit even with low baseline eosinophil counts, whereas from a payer’s perspective the health economic benefit is better with a higher cut-off.”
As is often the case, more study will help clarify these new concerns.
“We are moving into a new era of Type-2 immunity-mediated therapies that will bring new opportunities for clinicians and our patients, but with this opportunity comes new challenges. Biomarkers will increase in importance to help drive precision medicine, but we need to understand how to use them, and, in particular, what cut-points to apply. For anti-IL-5 approaches, we probably need to look towards elevated blood eosinophil counts, as aiming for a high cut-off is most likely the best way we shall achieve success.”
Dr. Russell had no financial disclosures. Mr. Brightling reported financial relationships with several pharmaceutical companies, but not with Teva.
Persistent eosinophilic inflammation is present in about half of patients with severe asthma, and the studies by Corren and Bjermer represent important advances in learning how to target this inflammatory pathway, Richard Russell, MBBS, MRCP, and Christopher Brightling, PhD, FCCP, wrote in an accompanying editorial (Chest. 2016;150:766-8).
“The most advanced therapeutic target is IL-5, which is an attractive target because it is an obligate cytokine for eosinophil maturation and survival. Its inhibition is thus predicted to reduce bone marrow production of eosinophils and promote apoptosis,” wrote Dr. Russell, a clinical research fellow, and Dr. Brightling, a professor, both at the University of Leicester (England).
“These findings support the view that an elevated blood eosinophil count is associated with a good clinical response [to the antibody reslizumab] but [the studies] did not find a clear correlation between the intensity of the baseline eosinophil count and response,” the colleagues wrote. “Thus, the best cut-off for the blood eosinophil count to apply clinically remains uncertain.”
Clinicians and patients may find a different answer to this riddle than do payers.
“From a patient perspective there is an argument to select a low or no cut-off as there is some benefit even with low baseline eosinophil counts, whereas from a payer’s perspective the health economic benefit is better with a higher cut-off.”
As is often the case, more study will help clarify these new concerns.
“We are moving into a new era of Type-2 immunity-mediated therapies that will bring new opportunities for clinicians and our patients, but with this opportunity comes new challenges. Biomarkers will increase in importance to help drive precision medicine, but we need to understand how to use them, and, in particular, what cut-points to apply. For anti-IL-5 approaches, we probably need to look towards elevated blood eosinophil counts, as aiming for a high cut-off is most likely the best way we shall achieve success.”
Dr. Russell had no financial disclosures. Mr. Brightling reported financial relationships with several pharmaceutical companies, but not with Teva.
Reslizumab was most effective in patients with high baseline eosinophil counts, two randomized, placebo-controlled studies have determined. The companion studies were simultaneously published in the October issue of Chest.
The drug reslizumab, an anti–interleukin-5 monoclonal antibody, is made by Teva Branded Pharmaceutical Products R&D, who sponsored both studies.
The larger study, comprising 492 patients, found no significant benefit of reslizumab over placebo, Jonathan Corren, MD, and his colleagues wrote (Chest. 2016;150:799-810). But this study didn’t stratify patients by baseline eosinophil levels; a post-hoc subanalysis found a significant benefit in forced expiratory volume in 69 of the patients who had at least 400 eosinophils/microliter (mcL) when treatment began.
In these patients, the drug significantly improved not only lung function, but asthma symptoms and asthma-related quality of life scores.
“These efficacy findings are consistent with results from other reslizumab trials and combined with the favorable safety profile observed, support the use of reslizumab in patients with asthma and elevated blood eosinophils, uncontrolled by an inhaled corticosteroid-based regimen,” Dr. Bjermer and his coauthors wrote.
The unstratified trial was conducted at 66 sites in the U.S. All of the patients had poorly controlled asthma despite using at least a medium-dosed inhaled corticosteroid. They were randomized to infusions of reslizumab 3.0 mg/kg or placebo given once every 4 weeks for 16 weeks.*
The primary endpoint was the change in forced expiratory volume in one second (FEV1); secondary endpoints included quality of life scores; the need for rescue medication; forced vital capacity; and eosinophil count.
Patients in the placebo and reslizumab groups were an average age of 45.1 years and 44.9 years, respectively. The mean disease duration of patients in both groups was 26 years.
At week 16, the mean change in FEV1 from baseline was 255 ml in the active group and 187 ml in the placebo group – not a significant difference.
The team performed a post-hoc subgroup analysis that dichotomized the cohort based on baseline eosinophil levels. For the 343 with counts of less than 400 cells/mcL, there was no difference in FEV1 at 16 weeks, between the patients who received treatment and the patients who received a placebo. The FEV1s of these two groups were separated by just 33 mL.
The story was different for the 82 patients with at least 400 cells/mcL, with 69 of such patients receiving the drug and 13 of such patients receiving the placebo. At 16 weeks, the difference in FEV1 change was 270 mL, in favor of the active group. The strength of these findings may be weakened by the large difference in size between the treatment and placebo groups and the “near complete lack of response in the small number of placebo-treated patients.”
“Interpretation of the results in the [400 or more cells/mcL] subgroup is limited as the study was not designed or statistically powered to specifically test this group of patients,” the team wrote. Nevertheless, they concluded that reslizumab is a reasonable treatment option for this group. “These findings support an acceptable benefit-risk profile for reslizumab in asthma patients with a blood eosinophil threshold” of at least 400 cells/mcL.
The stratified study examined more endpoints: pre-bronchodilator spirometry (forced expiratory volume in one second FEV1, forced vital capacity, and forced expiratory flow), asthma symptoms, quality of life, rescue inhaler use, and blood eosinophil levels.
The 315 patients in this study all had a baseline eosinophil count of at least 400 cells/mcL. They were randomized to placebo or to 0.3 or 3.0 mg/kg reslizumab dose once every 4 weeks for 16 weeks. The mean ages for the patients taking the placebo, reslizumab 0.3 mg/kg, and reslizumab 3.0 mg/kg were 44.2, 44.5, and 43.0, respectively. The range of average disease durations for patients in the placebo group and two reslizumab groups was 20 to 20.7 years.
The final FEV1 was significantly improved over placebo in both active groups, although the change was much more pronounced in those taking 3.0 mg/kg, compared with those taking 0.3 mg/kg (160 mL and 115 mL, respectively, relative to placebo). Forced vital capacity also improved significantly in the 3.0 mg/kg dose group (130 mL relative to placebo).
Reslizumab was generally well tolerated in both studies. The most frequent adverse events in the stratified study were asthma worsening, headache, nasopharyngitis, upper respiratory infections, and sinusitis.
In the unstratified study, there were two anaphylactic reactions, but only one was related to the study drug. No deaths occurred in either treatment group of this study.
Both trials were sponsored by Teva. Dr. Bjermer has served on advisory boards or provided lectures for Aerocrine, Airsonett, ALK, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Meda, Mundipharma, Nigaard, Novartis, Regeneron, Sanofi-Aventis, Takeda, and Teva. Dr. Corren has been involved in speaker bureau activities for Genentech and Merck; he has served on advisory boards for Genentech, Merck, Novartis, and Vectura.
*CORRECTION 12/9/16: An earlier version of this article misstated the infusion frequency.
[email protected]
On Twitter @Alz_Gal
Reslizumab was most effective in patients with high baseline eosinophil counts, two randomized, placebo-controlled studies have determined. The companion studies were simultaneously published in the October issue of Chest.
The drug reslizumab, an anti–interleukin-5 monoclonal antibody, is made by Teva Branded Pharmaceutical Products R&D, who sponsored both studies.
The larger study, comprising 492 patients, found no significant benefit of reslizumab over placebo, Jonathan Corren, MD, and his colleagues wrote (Chest. 2016;150:799-810). But this study didn’t stratify patients by baseline eosinophil levels; a post-hoc subanalysis found a significant benefit in forced expiratory volume in 69 of the patients who had at least 400 eosinophils/microliter (mcL) when treatment began.
In these patients, the drug significantly improved not only lung function, but asthma symptoms and asthma-related quality of life scores.
“These efficacy findings are consistent with results from other reslizumab trials and combined with the favorable safety profile observed, support the use of reslizumab in patients with asthma and elevated blood eosinophils, uncontrolled by an inhaled corticosteroid-based regimen,” Dr. Bjermer and his coauthors wrote.
The unstratified trial was conducted at 66 sites in the U.S. All of the patients had poorly controlled asthma despite using at least a medium-dosed inhaled corticosteroid. They were randomized to infusions of reslizumab 3.0 mg/kg or placebo given once every 4 weeks for 16 weeks.*
The primary endpoint was the change in forced expiratory volume in one second (FEV1); secondary endpoints included quality of life scores; the need for rescue medication; forced vital capacity; and eosinophil count.
Patients in the placebo and reslizumab groups were an average age of 45.1 years and 44.9 years, respectively. The mean disease duration of patients in both groups was 26 years.
At week 16, the mean change in FEV1 from baseline was 255 ml in the active group and 187 ml in the placebo group – not a significant difference.
The team performed a post-hoc subgroup analysis that dichotomized the cohort based on baseline eosinophil levels. For the 343 with counts of less than 400 cells/mcL, there was no difference in FEV1 at 16 weeks, between the patients who received treatment and the patients who received a placebo. The FEV1s of these two groups were separated by just 33 mL.
The story was different for the 82 patients with at least 400 cells/mcL, with 69 of such patients receiving the drug and 13 of such patients receiving the placebo. At 16 weeks, the difference in FEV1 change was 270 mL, in favor of the active group. The strength of these findings may be weakened by the large difference in size between the treatment and placebo groups and the “near complete lack of response in the small number of placebo-treated patients.”
“Interpretation of the results in the [400 or more cells/mcL] subgroup is limited as the study was not designed or statistically powered to specifically test this group of patients,” the team wrote. Nevertheless, they concluded that reslizumab is a reasonable treatment option for this group. “These findings support an acceptable benefit-risk profile for reslizumab in asthma patients with a blood eosinophil threshold” of at least 400 cells/mcL.
The stratified study examined more endpoints: pre-bronchodilator spirometry (forced expiratory volume in one second FEV1, forced vital capacity, and forced expiratory flow), asthma symptoms, quality of life, rescue inhaler use, and blood eosinophil levels.
The 315 patients in this study all had a baseline eosinophil count of at least 400 cells/mcL. They were randomized to placebo or to 0.3 or 3.0 mg/kg reslizumab dose once every 4 weeks for 16 weeks. The mean ages for the patients taking the placebo, reslizumab 0.3 mg/kg, and reslizumab 3.0 mg/kg were 44.2, 44.5, and 43.0, respectively. The range of average disease durations for patients in the placebo group and two reslizumab groups was 20 to 20.7 years.
The final FEV1 was significantly improved over placebo in both active groups, although the change was much more pronounced in those taking 3.0 mg/kg, compared with those taking 0.3 mg/kg (160 mL and 115 mL, respectively, relative to placebo). Forced vital capacity also improved significantly in the 3.0 mg/kg dose group (130 mL relative to placebo).
Reslizumab was generally well tolerated in both studies. The most frequent adverse events in the stratified study were asthma worsening, headache, nasopharyngitis, upper respiratory infections, and sinusitis.
In the unstratified study, there were two anaphylactic reactions, but only one was related to the study drug. No deaths occurred in either treatment group of this study.
Both trials were sponsored by Teva. Dr. Bjermer has served on advisory boards or provided lectures for Aerocrine, Airsonett, ALK, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Meda, Mundipharma, Nigaard, Novartis, Regeneron, Sanofi-Aventis, Takeda, and Teva. Dr. Corren has been involved in speaker bureau activities for Genentech and Merck; he has served on advisory boards for Genentech, Merck, Novartis, and Vectura.
*CORRECTION 12/9/16: An earlier version of this article misstated the infusion frequency.
[email protected]
On Twitter @Alz_Gal
FROM CHEST
Key clinical point:
Major finding: Forced expiratory volume in 1 second (FEV1) improved by 160 mL with reslizumab 3.0 mg/kg relative to placebo.
Data source: The two randomized, placebo-controlled studies comprised about 800 patients.
Disclosures: Both trials were sponsored by Teva Branded Pharmaceutical Products R&D. Dr. Bjermer has served on an advisory board or provided lectures for Teva. Dr. Corren has served on advisory boards and has been involved in speaker bureau activities for various pharmaceutical companies.
Pembrolizumab ‘new standard of care’ in advanced PD-L1-rich NSCLC
COPENHAGEN – Chalk up another one for immunotherapy: the PD-1 checkpoint inhibitor pembrolizumab cut the risk of disease progression or death in half among select patients with non–small cell lung cancer (NSCLC), compared with standard platinum doublet chemotherapy, in the first-line setting.
Among 305 patients with non–small cell lung cancers with 50% or greater expression of the programmed death ligand 1 (PD-L1), median progression-free survival (PFS) for patients treated with pembrolizumab (Keytruda) was 10.3 months, compared with 6 months for patients assigned to receive platinum-based chemotherapy at the investigators discretion (hazard ratio, 0.50, P less than .001), reported Martin Reck, MD, from the department of thoracic oncology at the Lung Clinic Grosshansdorf, in Germany.
Results of the KEYNOTE-024 study were also published online in the New England Journal of Medicine (2016 Oct 9. doi: 10.1056/NEJMoa1606774). Approximately 23%-30% of patients with advanced non–small cell lung cancers have tumors that express PD-L1 on the membrane of at least 50% of tumor cells, making them attractive targets for pembrolizumab, which is a monoclonal antibody directed against programmed death 1 (PD-1). Pembrolizumab disengages the brake on the immune system caused by the interaction of receptor PD-1 with the PD-L1 and PD-L2 ligands.
The study was conducted to compare upfront pembrolizumab with platinum-based chemotherapy in patients with newly diagnosed advanced NSCLC that did not carry targetable EGFR-activating mutations or ALK translocations.
A total of 305 patients from 16 countries with untreated stage IV NSCLC, good performance status, and tumors with a 50% or greater expression of PD-L1 were enrolled and randomized to either pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Or four to six cycles of platinum-doublet chemotherapy at the investigator’s discretion. The combinations included carboplatin plus pemetrexed, cisplatin plus pemetrexed, carboplatin plus gemcitabine, cisplatin plus gemcitabine, or carboplatin plus paclitaxel.
At a median follow-up of 11.2 months, 48.1% of patients assigned to pembrolizumab were still on treatment, as were 10% of those assigned to standard chemotherapy.
As noted before, PFS, the primary endpoint, was significantly better with pembrolizumab, as was the secondary endpoint of overall survival at 6 months. In all, 80% of patients treated with pembrolizumab were still alive at 6 months, compared with 72% of patients on chemotherapy (HR, 0.60; P = .005).
The confirmed response rate was also higher in the pembrolizumab arm, at 44.8% vs. 27.8%(P = .0011), and the median duration of response was longer (not reached vs. 6.3 months). There were six complete responses in the pembrolizumab arm.
Pembrolizumab also demonstrated a generally more favorable safety profile, with adverse events of any grade occurring in 73.4% of patients, compared with 90% of those treated with chemotherapy.
Grade 3 or 4 adverse events and treatment-related deaths were also lower in the pembrolizumab arm, at 26.6% vs. 53.3%.
Jean-Charles Soria, MD, chair of drug development at Gustave Roussy Cancer Center in Paris, the invited discussant, noted that the “45% objective response rate in first-line non–small cell lung cancer is unheard of, and is achieved with a monotherapy.”
“Pembrolizumab clearly leads to a higher objective response, a longer duration of response, a lower frequency of adverse events, better PFS, better OS, compared to chemotherapy.”
“We have, probably, a new standard of care” for patients with high PD-L1 expression and no targetable mutations,” he said.
COPENHAGEN – Chalk up another one for immunotherapy: the PD-1 checkpoint inhibitor pembrolizumab cut the risk of disease progression or death in half among select patients with non–small cell lung cancer (NSCLC), compared with standard platinum doublet chemotherapy, in the first-line setting.
Among 305 patients with non–small cell lung cancers with 50% or greater expression of the programmed death ligand 1 (PD-L1), median progression-free survival (PFS) for patients treated with pembrolizumab (Keytruda) was 10.3 months, compared with 6 months for patients assigned to receive platinum-based chemotherapy at the investigators discretion (hazard ratio, 0.50, P less than .001), reported Martin Reck, MD, from the department of thoracic oncology at the Lung Clinic Grosshansdorf, in Germany.
Results of the KEYNOTE-024 study were also published online in the New England Journal of Medicine (2016 Oct 9. doi: 10.1056/NEJMoa1606774). Approximately 23%-30% of patients with advanced non–small cell lung cancers have tumors that express PD-L1 on the membrane of at least 50% of tumor cells, making them attractive targets for pembrolizumab, which is a monoclonal antibody directed against programmed death 1 (PD-1). Pembrolizumab disengages the brake on the immune system caused by the interaction of receptor PD-1 with the PD-L1 and PD-L2 ligands.
The study was conducted to compare upfront pembrolizumab with platinum-based chemotherapy in patients with newly diagnosed advanced NSCLC that did not carry targetable EGFR-activating mutations or ALK translocations.
A total of 305 patients from 16 countries with untreated stage IV NSCLC, good performance status, and tumors with a 50% or greater expression of PD-L1 were enrolled and randomized to either pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Or four to six cycles of platinum-doublet chemotherapy at the investigator’s discretion. The combinations included carboplatin plus pemetrexed, cisplatin plus pemetrexed, carboplatin plus gemcitabine, cisplatin plus gemcitabine, or carboplatin plus paclitaxel.
At a median follow-up of 11.2 months, 48.1% of patients assigned to pembrolizumab were still on treatment, as were 10% of those assigned to standard chemotherapy.
As noted before, PFS, the primary endpoint, was significantly better with pembrolizumab, as was the secondary endpoint of overall survival at 6 months. In all, 80% of patients treated with pembrolizumab were still alive at 6 months, compared with 72% of patients on chemotherapy (HR, 0.60; P = .005).
The confirmed response rate was also higher in the pembrolizumab arm, at 44.8% vs. 27.8%(P = .0011), and the median duration of response was longer (not reached vs. 6.3 months). There were six complete responses in the pembrolizumab arm.
Pembrolizumab also demonstrated a generally more favorable safety profile, with adverse events of any grade occurring in 73.4% of patients, compared with 90% of those treated with chemotherapy.
Grade 3 or 4 adverse events and treatment-related deaths were also lower in the pembrolizumab arm, at 26.6% vs. 53.3%.
Jean-Charles Soria, MD, chair of drug development at Gustave Roussy Cancer Center in Paris, the invited discussant, noted that the “45% objective response rate in first-line non–small cell lung cancer is unheard of, and is achieved with a monotherapy.”
“Pembrolizumab clearly leads to a higher objective response, a longer duration of response, a lower frequency of adverse events, better PFS, better OS, compared to chemotherapy.”
“We have, probably, a new standard of care” for patients with high PD-L1 expression and no targetable mutations,” he said.
COPENHAGEN – Chalk up another one for immunotherapy: the PD-1 checkpoint inhibitor pembrolizumab cut the risk of disease progression or death in half among select patients with non–small cell lung cancer (NSCLC), compared with standard platinum doublet chemotherapy, in the first-line setting.
Among 305 patients with non–small cell lung cancers with 50% or greater expression of the programmed death ligand 1 (PD-L1), median progression-free survival (PFS) for patients treated with pembrolizumab (Keytruda) was 10.3 months, compared with 6 months for patients assigned to receive platinum-based chemotherapy at the investigators discretion (hazard ratio, 0.50, P less than .001), reported Martin Reck, MD, from the department of thoracic oncology at the Lung Clinic Grosshansdorf, in Germany.
Results of the KEYNOTE-024 study were also published online in the New England Journal of Medicine (2016 Oct 9. doi: 10.1056/NEJMoa1606774). Approximately 23%-30% of patients with advanced non–small cell lung cancers have tumors that express PD-L1 on the membrane of at least 50% of tumor cells, making them attractive targets for pembrolizumab, which is a monoclonal antibody directed against programmed death 1 (PD-1). Pembrolizumab disengages the brake on the immune system caused by the interaction of receptor PD-1 with the PD-L1 and PD-L2 ligands.
The study was conducted to compare upfront pembrolizumab with platinum-based chemotherapy in patients with newly diagnosed advanced NSCLC that did not carry targetable EGFR-activating mutations or ALK translocations.
A total of 305 patients from 16 countries with untreated stage IV NSCLC, good performance status, and tumors with a 50% or greater expression of PD-L1 were enrolled and randomized to either pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Or four to six cycles of platinum-doublet chemotherapy at the investigator’s discretion. The combinations included carboplatin plus pemetrexed, cisplatin plus pemetrexed, carboplatin plus gemcitabine, cisplatin plus gemcitabine, or carboplatin plus paclitaxel.
At a median follow-up of 11.2 months, 48.1% of patients assigned to pembrolizumab were still on treatment, as were 10% of those assigned to standard chemotherapy.
As noted before, PFS, the primary endpoint, was significantly better with pembrolizumab, as was the secondary endpoint of overall survival at 6 months. In all, 80% of patients treated with pembrolizumab were still alive at 6 months, compared with 72% of patients on chemotherapy (HR, 0.60; P = .005).
The confirmed response rate was also higher in the pembrolizumab arm, at 44.8% vs. 27.8%(P = .0011), and the median duration of response was longer (not reached vs. 6.3 months). There were six complete responses in the pembrolizumab arm.
Pembrolizumab also demonstrated a generally more favorable safety profile, with adverse events of any grade occurring in 73.4% of patients, compared with 90% of those treated with chemotherapy.
Grade 3 or 4 adverse events and treatment-related deaths were also lower in the pembrolizumab arm, at 26.6% vs. 53.3%.
Jean-Charles Soria, MD, chair of drug development at Gustave Roussy Cancer Center in Paris, the invited discussant, noted that the “45% objective response rate in first-line non–small cell lung cancer is unheard of, and is achieved with a monotherapy.”
“Pembrolizumab clearly leads to a higher objective response, a longer duration of response, a lower frequency of adverse events, better PFS, better OS, compared to chemotherapy.”
“We have, probably, a new standard of care” for patients with high PD-L1 expression and no targetable mutations,” he said.
AT ESMO 2016
Key clinical point: Pembrolizumab was superior to chemotherapy in stage IV NSCLC with PD-L1 expression of 50% or more.
Major finding: The hazard ratio for progression-free survival was 0.50 for pembrolizumab vs. platinum-based chemotherapy.
Data source: Randomized phase III trial in 305 patients with untreated stage IV NSCLC with 50% or more of tumor cells expressing PD-L1
Disclosures: The study was sponsored by Merck, Sharp & Dohme. Dr. Reck and Dr. Soria disclosed financial relationships (consulting/honoraria, research funding, etc.) with several companies, but not Merck.
Tooth Decay Is the Most Prevalent Disease
There are 2 leading types of dental diseases: tooth decay (dental caries or cavities) and gum disease (periodontal disease). Tooth decay is by far the more prevalent of the 2, causing a greater, needless loss in the quality of life.
Prevalence of Tooth Decay
Dental caries is a major public health problem. Even though in the past 50 years there has been a significant decline in dental caries, it is the most common ailment in the U.S., and large segments of the population experience various barriers to care. Among children and adolescents, dental caries is 4 to 5 times more common than asthma.1,2 Data from the National Health and Nutrition Examination Survey, 2011-2012, show that among children aged 2 to 8 years, 37% had dental caries in their primary teeth. Among adolescents aged 12 to 19 years, the prevalence of dental caries in the permanent teeth was 58%. About 90% of adults aged ≥ 20 years had dental caries.3,4
Unmet Dental Needs
The real disease burden of dental caries is the amount of unmet needs or untreated decay. In recent years, there has been a shift in the peak prevalence of untreated tooth decay from children to adults, possibly attributable to socioecologic factors.3,5 The prevalence of untreated decay in children and adolescents was about 15%. However, the prevalence of untreated decay among adults aged 20 to 64 years was higher: 27% of the adults had decayed teeth that were left untreated.3,4
The rates of untreated decay among these adults were higher among Hispanics (36%) and non-Hispanic blacks (42%) than among non-Hispanic whites (22%) and non-Hispanic Asians (17%).3,4 Despite the decline in dental caries, disparities persist among different racial, ethnic, educational, and income groups; it remains a modern curse for large segments of the population.
Basics of Tooth Decay
Tooth decay is caused by Streptococcus mutans (S mutans) bacterial infection. The cariogenic bacteria are transmissible from mother or caregiver to children.6 After tooth eruption, the mouth is quickly colonized by S mutans. Even though the bacteria are ubiquitous, the disease burden is more concentrated in some populations.
What makes some people more susceptible to tooth decay? Contrary to popular belief, it is not caused by childbirth or low dietary intake of calcium.7,8 Tooth decay typically starts on the chewing surfaces or proximal contacts of teeth.
S mutans is introduced into the mouth principally from another person. The bacteria colonize the mouth and with the formation of plaques, adhere to the teeth. Plaque is the soft, sticky film formed on teeth from food degradation. The biofilm is conducive to bacterial proliferation and teeming with bacteria.
The S mutans bacteria break down sugars and produce lactic acids, which cause tooth decay—a process of demineralization, or loss of calcium phosphate, from the tooth structure.2,9 As a result, the tooth “softens” and eventually collapses on itself, forming a cavity. Tooth decay most commonly occurs at the occlusal (chewing) surfaces and the proximal contacts of teeth. The occlusal aspects of teeth have a natural pit-and-fissure morphology that facilitates bacterial adherence and colonization. The proximal contacts of teeth also facilitate adherence of plaque and bacteria.
A tooth is made up of 3 layers. The outermost layer of the tooth crown is the enamel, which is the hardest or most mineralized part of the tooth—it is harder than bone. The next layer is the dentin, which has a higher percentage of organic material (collagen) and water than the enamel has and is softer. In the center of the tooth is the pulp (consisting of nerves and blood vessels), which keeps the tooth alive and provides sensation to the tooth. The outermost layer of the tooth root is cementum (instead of enamel), followed by dentin, which encases the pulp tissues contained within the root canals (Figure). 
Process of Tooth Loss
At the early stage of tooth decay, when the decay is confined to the enamel, the tooth is asymptomatic, and the damage is reversible. When the decay extends into the dentin, restorations are a consideration. The further the decay extends toward the pulp, the greater the risk of tooth sensitivity and pain. Decay naturally progresses faster in the (less mineralized) dentin than when the decay is still confined to the enamel. If left unchecked, the decay may progress, and the bacteria eventually invade the pulp. At that point, there is risk of not only pain, but also swelling and tooth loss.
At the earlier stage of decay, a tooth may be treated with restorations, which are typically made of dental amalgam, resin (composite), glass ionomer, porcelain, or gold. When the bacteria have invaded the pulp, a dental restoration will not treat the pain and infection. Root canal therapy is needed to remove the infected tissues in the pulp chamber and root canals. Further, if the tooth is too compromised with extensive destruction from the decay or if there are financial or other barriers to root canal therapy, extraction is likely the only option.
Key to Oral Health
Personal daily oral hygiene (brushing and flossing) helps remove plaque from accumulating on tooth surfaces—especially the occlusal surfaces and proximal contacts, which are most prone to decay. Brushing teeth is of limited benefit without the use of fluoride toothpaste.8 The most important time for brushing is before bedtime, because less salivation occurs during sleep. Saliva helps clear fermented bacterial products, buffers the drop in pH, prevents demineralization, and enhances remineralizaton.10
Fluoride benefits children and adults of all ages, and comes in the form of fluoridated tap water, toothpaste, mouth rinse, and professionally applied gel and varnish. Fluoride occurs naturally in the environment, too. Its effect is mainly topical—fluoride gets incorporated into the tooth as fluorapatite, replacing the hydroxyapatite. Fluorapatite is harder than the hydroxyapatite; hence, the tooth is better able to resist demineralization by bacterial acid attacks.11 Professionally applied fluoride is generally recommended for high-risk patients, typically patients with high caries burden, ie, many decayed teeth. The best predictor of future caries is the past caries experience.
Sealants are thin, plastic coatings that are painted on to tooth occlusal surfaces, obliterating the pits and fissures normally found on posterior teeth. The smooth sealants effectively inhibit the colonization of S mutans on the occlusal aspects of teeth.12 Sealants are applied in dental offices (by the dentists or dental hygienists) or in school-based programs.
1. U.S. Department of Health and Human Services. Oral health in America: a report of the Surgeon General. http://www.nidcr.nih.gov/DataStatistics/SurgeonGeneral/Report/ExecutiveSummary.htm. Updated March 7, 2014. Accessed August 22, 2016.
2. Centers for Disease Control and Prevention. Hygiene-related diseases. http://www.cdc.gov/healthywater/hygiene/disease/dental_caries.html. Updated December 16, 2014. Accessed August 22, 2016.
3. Dye BA, Thornton-Evan G, Xianfen L, Iafolla TJ. Dental caries and sealant prevalence in children and adolescents in the United States, 2011-2012. http://www.cdc.gov/nchs/data/databriefs/db191.pdf. Published March 2015. NCHS Data Brief. Accessed August 22, 2016.
4. Dye BA, Thornton-Evan G, Xianfen L, Iafolla TJ. Dental caries and tooth loss in adults in the United States, 2011-2012. http://www.cdc.gov/nchs/data/databriefs/db197.pdf. NCHS Data Brief. Published May 2015. Accessed August 22, 2016.
5. Kassebaum NJ, Bernabé E, Dahiya M, Bhandari B, Murray CJ, Marcenes W. Global burden of untreated caries: a systematic review and metaregression. J Dent Res. 2015;94(5):650-658.
6. Smith RE, Badner VM, Morse DE, Freeman K. Maternal risk indicators for childhood caries in an inner city population. Community Dent Oral Epidemiol. 2002;30(3):176-181.
7. Boggess KA, Urlaub DM, Moos MK, Polinkovsky M, El-Khorazaty J, Lorenz C. Knowledge and beliefs regarding oral health among pregnant women. J Am Dent Assoc. 2011;142(11):1275-1282.
8. Roberts-Thomson KF, Spencer AJ. Public knowledge of the prevention of dental decay and gum diseases. Aust Dent J. 1999;44(4):253-258.
9. Cochrane NJ, Cai F, Hug NL, Burrow MF, Reynolds EC. New approaches to enhanced remineralization of tooth enamel. J Dent Res. 2010;89(11):1187-1197.
10. Prabhakar AR, Dodawad R, Os R. Evaluation of flow Rate, pH, buffering capacity, calcium, total protein and total antioxidant levels of saliva in caries free and caries active children—an in vivo study. Int J Clin Pediatr Dent. 2009;2(1):9-12.
11. Hicks J, Garcia-Godoy F, Flaitz C. Biological factors in dental caries: role of remineralization and fluoride in the dynamic process of demineralization and remuneration (part 3). J Clin Pediatr Dent. 2004;28(3):203-214.
12. Azarpazhooh A, Main PA. Pit and fissure sealants in the prevention of dental caries in children and adolescents: a systematic review. J Can Dent Assoc. 2008;74(2):171-177.
There are 2 leading types of dental diseases: tooth decay (dental caries or cavities) and gum disease (periodontal disease). Tooth decay is by far the more prevalent of the 2, causing a greater, needless loss in the quality of life.
Prevalence of Tooth Decay
Dental caries is a major public health problem. Even though in the past 50 years there has been a significant decline in dental caries, it is the most common ailment in the U.S., and large segments of the population experience various barriers to care. Among children and adolescents, dental caries is 4 to 5 times more common than asthma.1,2 Data from the National Health and Nutrition Examination Survey, 2011-2012, show that among children aged 2 to 8 years, 37% had dental caries in their primary teeth. Among adolescents aged 12 to 19 years, the prevalence of dental caries in the permanent teeth was 58%. About 90% of adults aged ≥ 20 years had dental caries.3,4
Unmet Dental Needs
The real disease burden of dental caries is the amount of unmet needs or untreated decay. In recent years, there has been a shift in the peak prevalence of untreated tooth decay from children to adults, possibly attributable to socioecologic factors.3,5 The prevalence of untreated decay in children and adolescents was about 15%. However, the prevalence of untreated decay among adults aged 20 to 64 years was higher: 27% of the adults had decayed teeth that were left untreated.3,4
The rates of untreated decay among these adults were higher among Hispanics (36%) and non-Hispanic blacks (42%) than among non-Hispanic whites (22%) and non-Hispanic Asians (17%).3,4 Despite the decline in dental caries, disparities persist among different racial, ethnic, educational, and income groups; it remains a modern curse for large segments of the population.
Basics of Tooth Decay
Tooth decay is caused by Streptococcus mutans (S mutans) bacterial infection. The cariogenic bacteria are transmissible from mother or caregiver to children.6 After tooth eruption, the mouth is quickly colonized by S mutans. Even though the bacteria are ubiquitous, the disease burden is more concentrated in some populations.
What makes some people more susceptible to tooth decay? Contrary to popular belief, it is not caused by childbirth or low dietary intake of calcium.7,8 Tooth decay typically starts on the chewing surfaces or proximal contacts of teeth.
S mutans is introduced into the mouth principally from another person. The bacteria colonize the mouth and with the formation of plaques, adhere to the teeth. Plaque is the soft, sticky film formed on teeth from food degradation. The biofilm is conducive to bacterial proliferation and teeming with bacteria.
The S mutans bacteria break down sugars and produce lactic acids, which cause tooth decay—a process of demineralization, or loss of calcium phosphate, from the tooth structure.2,9 As a result, the tooth “softens” and eventually collapses on itself, forming a cavity. Tooth decay most commonly occurs at the occlusal (chewing) surfaces and the proximal contacts of teeth. The occlusal aspects of teeth have a natural pit-and-fissure morphology that facilitates bacterial adherence and colonization. The proximal contacts of teeth also facilitate adherence of plaque and bacteria.
A tooth is made up of 3 layers. The outermost layer of the tooth crown is the enamel, which is the hardest or most mineralized part of the tooth—it is harder than bone. The next layer is the dentin, which has a higher percentage of organic material (collagen) and water than the enamel has and is softer. In the center of the tooth is the pulp (consisting of nerves and blood vessels), which keeps the tooth alive and provides sensation to the tooth. The outermost layer of the tooth root is cementum (instead of enamel), followed by dentin, which encases the pulp tissues contained within the root canals (Figure).
Process of Tooth Loss
At the early stage of tooth decay, when the decay is confined to the enamel, the tooth is asymptomatic, and the damage is reversible. When the decay extends into the dentin, restorations are a consideration. The further the decay extends toward the pulp, the greater the risk of tooth sensitivity and pain. Decay naturally progresses faster in the (less mineralized) dentin than when the decay is still confined to the enamel. If left unchecked, the decay may progress, and the bacteria eventually invade the pulp. At that point, there is risk of not only pain, but also swelling and tooth loss.
At the earlier stage of decay, a tooth may be treated with restorations, which are typically made of dental amalgam, resin (composite), glass ionomer, porcelain, or gold. When the bacteria have invaded the pulp, a dental restoration will not treat the pain and infection. Root canal therapy is needed to remove the infected tissues in the pulp chamber and root canals. Further, if the tooth is too compromised with extensive destruction from the decay or if there are financial or other barriers to root canal therapy, extraction is likely the only option.
Key to Oral Health
Personal daily oral hygiene (brushing and flossing) helps remove plaque from accumulating on tooth surfaces—especially the occlusal surfaces and proximal contacts, which are most prone to decay. Brushing teeth is of limited benefit without the use of fluoride toothpaste.8 The most important time for brushing is before bedtime, because less salivation occurs during sleep. Saliva helps clear fermented bacterial products, buffers the drop in pH, prevents demineralization, and enhances remineralizaton.10
Fluoride benefits children and adults of all ages, and comes in the form of fluoridated tap water, toothpaste, mouth rinse, and professionally applied gel and varnish. Fluoride occurs naturally in the environment, too. Its effect is mainly topical—fluoride gets incorporated into the tooth as fluorapatite, replacing the hydroxyapatite. Fluorapatite is harder than the hydroxyapatite; hence, the tooth is better able to resist demineralization by bacterial acid attacks.11 Professionally applied fluoride is generally recommended for high-risk patients, typically patients with high caries burden, ie, many decayed teeth. The best predictor of future caries is the past caries experience.
Sealants are thin, plastic coatings that are painted on to tooth occlusal surfaces, obliterating the pits and fissures normally found on posterior teeth. The smooth sealants effectively inhibit the colonization of S mutans on the occlusal aspects of teeth.12 Sealants are applied in dental offices (by the dentists or dental hygienists) or in school-based programs.
There are 2 leading types of dental diseases: tooth decay (dental caries or cavities) and gum disease (periodontal disease). Tooth decay is by far the more prevalent of the 2, causing a greater, needless loss in the quality of life.
Prevalence of Tooth Decay
Dental caries is a major public health problem. Even though in the past 50 years there has been a significant decline in dental caries, it is the most common ailment in the U.S., and large segments of the population experience various barriers to care. Among children and adolescents, dental caries is 4 to 5 times more common than asthma.1,2 Data from the National Health and Nutrition Examination Survey, 2011-2012, show that among children aged 2 to 8 years, 37% had dental caries in their primary teeth. Among adolescents aged 12 to 19 years, the prevalence of dental caries in the permanent teeth was 58%. About 90% of adults aged ≥ 20 years had dental caries.3,4
Unmet Dental Needs
The real disease burden of dental caries is the amount of unmet needs or untreated decay. In recent years, there has been a shift in the peak prevalence of untreated tooth decay from children to adults, possibly attributable to socioecologic factors.3,5 The prevalence of untreated decay in children and adolescents was about 15%. However, the prevalence of untreated decay among adults aged 20 to 64 years was higher: 27% of the adults had decayed teeth that were left untreated.3,4
The rates of untreated decay among these adults were higher among Hispanics (36%) and non-Hispanic blacks (42%) than among non-Hispanic whites (22%) and non-Hispanic Asians (17%).3,4 Despite the decline in dental caries, disparities persist among different racial, ethnic, educational, and income groups; it remains a modern curse for large segments of the population.
Basics of Tooth Decay
Tooth decay is caused by Streptococcus mutans (S mutans) bacterial infection. The cariogenic bacteria are transmissible from mother or caregiver to children.6 After tooth eruption, the mouth is quickly colonized by S mutans. Even though the bacteria are ubiquitous, the disease burden is more concentrated in some populations.
What makes some people more susceptible to tooth decay? Contrary to popular belief, it is not caused by childbirth or low dietary intake of calcium.7,8 Tooth decay typically starts on the chewing surfaces or proximal contacts of teeth.
S mutans is introduced into the mouth principally from another person. The bacteria colonize the mouth and with the formation of plaques, adhere to the teeth. Plaque is the soft, sticky film formed on teeth from food degradation. The biofilm is conducive to bacterial proliferation and teeming with bacteria.
The S mutans bacteria break down sugars and produce lactic acids, which cause tooth decay—a process of demineralization, or loss of calcium phosphate, from the tooth structure.2,9 As a result, the tooth “softens” and eventually collapses on itself, forming a cavity. Tooth decay most commonly occurs at the occlusal (chewing) surfaces and the proximal contacts of teeth. The occlusal aspects of teeth have a natural pit-and-fissure morphology that facilitates bacterial adherence and colonization. The proximal contacts of teeth also facilitate adherence of plaque and bacteria.
A tooth is made up of 3 layers. The outermost layer of the tooth crown is the enamel, which is the hardest or most mineralized part of the tooth—it is harder than bone. The next layer is the dentin, which has a higher percentage of organic material (collagen) and water than the enamel has and is softer. In the center of the tooth is the pulp (consisting of nerves and blood vessels), which keeps the tooth alive and provides sensation to the tooth. The outermost layer of the tooth root is cementum (instead of enamel), followed by dentin, which encases the pulp tissues contained within the root canals (Figure).
Process of Tooth Loss
At the early stage of tooth decay, when the decay is confined to the enamel, the tooth is asymptomatic, and the damage is reversible. When the decay extends into the dentin, restorations are a consideration. The further the decay extends toward the pulp, the greater the risk of tooth sensitivity and pain. Decay naturally progresses faster in the (less mineralized) dentin than when the decay is still confined to the enamel. If left unchecked, the decay may progress, and the bacteria eventually invade the pulp. At that point, there is risk of not only pain, but also swelling and tooth loss.
At the earlier stage of decay, a tooth may be treated with restorations, which are typically made of dental amalgam, resin (composite), glass ionomer, porcelain, or gold. When the bacteria have invaded the pulp, a dental restoration will not treat the pain and infection. Root canal therapy is needed to remove the infected tissues in the pulp chamber and root canals. Further, if the tooth is too compromised with extensive destruction from the decay or if there are financial or other barriers to root canal therapy, extraction is likely the only option.
Key to Oral Health
Personal daily oral hygiene (brushing and flossing) helps remove plaque from accumulating on tooth surfaces—especially the occlusal surfaces and proximal contacts, which are most prone to decay. Brushing teeth is of limited benefit without the use of fluoride toothpaste.8 The most important time for brushing is before bedtime, because less salivation occurs during sleep. Saliva helps clear fermented bacterial products, buffers the drop in pH, prevents demineralization, and enhances remineralizaton.10
Fluoride benefits children and adults of all ages, and comes in the form of fluoridated tap water, toothpaste, mouth rinse, and professionally applied gel and varnish. Fluoride occurs naturally in the environment, too. Its effect is mainly topical—fluoride gets incorporated into the tooth as fluorapatite, replacing the hydroxyapatite. Fluorapatite is harder than the hydroxyapatite; hence, the tooth is better able to resist demineralization by bacterial acid attacks.11 Professionally applied fluoride is generally recommended for high-risk patients, typically patients with high caries burden, ie, many decayed teeth. The best predictor of future caries is the past caries experience.
Sealants are thin, plastic coatings that are painted on to tooth occlusal surfaces, obliterating the pits and fissures normally found on posterior teeth. The smooth sealants effectively inhibit the colonization of S mutans on the occlusal aspects of teeth.12 Sealants are applied in dental offices (by the dentists or dental hygienists) or in school-based programs.
1. U.S. Department of Health and Human Services. Oral health in America: a report of the Surgeon General. http://www.nidcr.nih.gov/DataStatistics/SurgeonGeneral/Report/ExecutiveSummary.htm. Updated March 7, 2014. Accessed August 22, 2016.
2. Centers for Disease Control and Prevention. Hygiene-related diseases. http://www.cdc.gov/healthywater/hygiene/disease/dental_caries.html. Updated December 16, 2014. Accessed August 22, 2016.
3. Dye BA, Thornton-Evan G, Xianfen L, Iafolla TJ. Dental caries and sealant prevalence in children and adolescents in the United States, 2011-2012. http://www.cdc.gov/nchs/data/databriefs/db191.pdf. Published March 2015. NCHS Data Brief. Accessed August 22, 2016.
4. Dye BA, Thornton-Evan G, Xianfen L, Iafolla TJ. Dental caries and tooth loss in adults in the United States, 2011-2012. http://www.cdc.gov/nchs/data/databriefs/db197.pdf. NCHS Data Brief. Published May 2015. Accessed August 22, 2016.
5. Kassebaum NJ, Bernabé E, Dahiya M, Bhandari B, Murray CJ, Marcenes W. Global burden of untreated caries: a systematic review and metaregression. J Dent Res. 2015;94(5):650-658.
6. Smith RE, Badner VM, Morse DE, Freeman K. Maternal risk indicators for childhood caries in an inner city population. Community Dent Oral Epidemiol. 2002;30(3):176-181.
7. Boggess KA, Urlaub DM, Moos MK, Polinkovsky M, El-Khorazaty J, Lorenz C. Knowledge and beliefs regarding oral health among pregnant women. J Am Dent Assoc. 2011;142(11):1275-1282.
8. Roberts-Thomson KF, Spencer AJ. Public knowledge of the prevention of dental decay and gum diseases. Aust Dent J. 1999;44(4):253-258.
9. Cochrane NJ, Cai F, Hug NL, Burrow MF, Reynolds EC. New approaches to enhanced remineralization of tooth enamel. J Dent Res. 2010;89(11):1187-1197.
10. Prabhakar AR, Dodawad R, Os R. Evaluation of flow Rate, pH, buffering capacity, calcium, total protein and total antioxidant levels of saliva in caries free and caries active children—an in vivo study. Int J Clin Pediatr Dent. 2009;2(1):9-12.
11. Hicks J, Garcia-Godoy F, Flaitz C. Biological factors in dental caries: role of remineralization and fluoride in the dynamic process of demineralization and remuneration (part 3). J Clin Pediatr Dent. 2004;28(3):203-214.
12. Azarpazhooh A, Main PA. Pit and fissure sealants in the prevention of dental caries in children and adolescents: a systematic review. J Can Dent Assoc. 2008;74(2):171-177.
1. U.S. Department of Health and Human Services. Oral health in America: a report of the Surgeon General. http://www.nidcr.nih.gov/DataStatistics/SurgeonGeneral/Report/ExecutiveSummary.htm. Updated March 7, 2014. Accessed August 22, 2016.
2. Centers for Disease Control and Prevention. Hygiene-related diseases. http://www.cdc.gov/healthywater/hygiene/disease/dental_caries.html. Updated December 16, 2014. Accessed August 22, 2016.
3. Dye BA, Thornton-Evan G, Xianfen L, Iafolla TJ. Dental caries and sealant prevalence in children and adolescents in the United States, 2011-2012. http://www.cdc.gov/nchs/data/databriefs/db191.pdf. Published March 2015. NCHS Data Brief. Accessed August 22, 2016.
4. Dye BA, Thornton-Evan G, Xianfen L, Iafolla TJ. Dental caries and tooth loss in adults in the United States, 2011-2012. http://www.cdc.gov/nchs/data/databriefs/db197.pdf. NCHS Data Brief. Published May 2015. Accessed August 22, 2016.
5. Kassebaum NJ, Bernabé E, Dahiya M, Bhandari B, Murray CJ, Marcenes W. Global burden of untreated caries: a systematic review and metaregression. J Dent Res. 2015;94(5):650-658.
6. Smith RE, Badner VM, Morse DE, Freeman K. Maternal risk indicators for childhood caries in an inner city population. Community Dent Oral Epidemiol. 2002;30(3):176-181.
7. Boggess KA, Urlaub DM, Moos MK, Polinkovsky M, El-Khorazaty J, Lorenz C. Knowledge and beliefs regarding oral health among pregnant women. J Am Dent Assoc. 2011;142(11):1275-1282.
8. Roberts-Thomson KF, Spencer AJ. Public knowledge of the prevention of dental decay and gum diseases. Aust Dent J. 1999;44(4):253-258.
9. Cochrane NJ, Cai F, Hug NL, Burrow MF, Reynolds EC. New approaches to enhanced remineralization of tooth enamel. J Dent Res. 2010;89(11):1187-1197.
10. Prabhakar AR, Dodawad R, Os R. Evaluation of flow Rate, pH, buffering capacity, calcium, total protein and total antioxidant levels of saliva in caries free and caries active children—an in vivo study. Int J Clin Pediatr Dent. 2009;2(1):9-12.
11. Hicks J, Garcia-Godoy F, Flaitz C. Biological factors in dental caries: role of remineralization and fluoride in the dynamic process of demineralization and remuneration (part 3). J Clin Pediatr Dent. 2004;28(3):203-214.
12. Azarpazhooh A, Main PA. Pit and fissure sealants in the prevention of dental caries in children and adolescents: a systematic review. J Can Dent Assoc. 2008;74(2):171-177.
Longer hospitalization, greater care needed for depressed ischemic stroke patients
BALTIMORE – Patients admitted with acute ischemic stroke (AIS) with preexisting major depressive disorder (MDD) are less likely to die while in the hospital but are often hospitalized longer and are more likely to need specialty care when they are discharged, in comparison to similar patients without depression in the National Inpatient Sample.
“Our study displayed an increasing proportion of patients with MDD admitted due to AIS in the last decade with lower mortality but higher morbidity post stroke. In addition, there was less utilization of thrombolysis in this population,” study presenter Arpita Hazra, MD, Northwell Health, Jersey City, N.J., said at the annual meeting of the American Neurological Association.
Thrombolysis was carried out in fewer depressed patients than in those without depression (3.8% vs. 4.8%; P less than .001). The odds of death during hospitalization were 36% less for patients with MDD. However, patients with MDD tended to be hospitalized longer than nondepressed patients (median 3.6 vs. 3.4 days; P less than .001) and were nearly 40% more likely to require specialty care following discharge.
“There is a need to explore the reasons behind this disparity in outcomes and thrombolysis utilization in order to improve poststroke outcome in this vulnerable population,” Dr. Hazra said.
At face value, the observation of decreased mortality in AIS patients with preexisting MDD was surprising, according to Dr. Hazra. She suggested that this may reflect prior hospital treatment for these patients, because of other comorbidities associated with depression.
Dr. Hazra reported having no financial disclosures.
BALTIMORE – Patients admitted with acute ischemic stroke (AIS) with preexisting major depressive disorder (MDD) are less likely to die while in the hospital but are often hospitalized longer and are more likely to need specialty care when they are discharged, in comparison to similar patients without depression in the National Inpatient Sample.
“Our study displayed an increasing proportion of patients with MDD admitted due to AIS in the last decade with lower mortality but higher morbidity post stroke. In addition, there was less utilization of thrombolysis in this population,” study presenter Arpita Hazra, MD, Northwell Health, Jersey City, N.J., said at the annual meeting of the American Neurological Association.
Thrombolysis was carried out in fewer depressed patients than in those without depression (3.8% vs. 4.8%; P less than .001). The odds of death during hospitalization were 36% less for patients with MDD. However, patients with MDD tended to be hospitalized longer than nondepressed patients (median 3.6 vs. 3.4 days; P less than .001) and were nearly 40% more likely to require specialty care following discharge.
“There is a need to explore the reasons behind this disparity in outcomes and thrombolysis utilization in order to improve poststroke outcome in this vulnerable population,” Dr. Hazra said.
At face value, the observation of decreased mortality in AIS patients with preexisting MDD was surprising, according to Dr. Hazra. She suggested that this may reflect prior hospital treatment for these patients, because of other comorbidities associated with depression.
Dr. Hazra reported having no financial disclosures.
BALTIMORE – Patients admitted with acute ischemic stroke (AIS) with preexisting major depressive disorder (MDD) are less likely to die while in the hospital but are often hospitalized longer and are more likely to need specialty care when they are discharged, in comparison to similar patients without depression in the National Inpatient Sample.
“Our study displayed an increasing proportion of patients with MDD admitted due to AIS in the last decade with lower mortality but higher morbidity post stroke. In addition, there was less utilization of thrombolysis in this population,” study presenter Arpita Hazra, MD, Northwell Health, Jersey City, N.J., said at the annual meeting of the American Neurological Association.
Thrombolysis was carried out in fewer depressed patients than in those without depression (3.8% vs. 4.8%; P less than .001). The odds of death during hospitalization were 36% less for patients with MDD. However, patients with MDD tended to be hospitalized longer than nondepressed patients (median 3.6 vs. 3.4 days; P less than .001) and were nearly 40% more likely to require specialty care following discharge.
“There is a need to explore the reasons behind this disparity in outcomes and thrombolysis utilization in order to improve poststroke outcome in this vulnerable population,” Dr. Hazra said.
At face value, the observation of decreased mortality in AIS patients with preexisting MDD was surprising, according to Dr. Hazra. She suggested that this may reflect prior hospital treatment for these patients, because of other comorbidities associated with depression.
Dr. Hazra reported having no financial disclosures.
AT ANA 2016
Key clinical point:
Major finding: In-hospital mortality was significantly lower for depressed patients with acute ischemic stroke, compared with nondepressed patients, but depressed patients had a significantly longer length of hospitalization and higher rate of discharge to specialty care.
Data source: Study of 4.3 million hospital AIS-related admissions identified in the United States during 2002-2012 in the National Inpatient Sample.
Disclosures: Dr. Hazra reported having no financial disclosures.
OAK: Atezolizumab grows OS in advanced NSCLC
COPENHAGEN – The checkpoint inhibitor atezolizumab improved overall survival of advanced non–small-cell lung cancer, compared with docetaxel, primary analysis from the OAK trial shows.
In the first phase III trial of a monoclonal antibody directed against the programmed death 1 ligand (PD-L1) in non–small-lung cell lung cancer (NSCLC), median overall survival (OS) for patients assigned to atezolizumab (Tecentriq) was 13.8 months, compared with 9.6 months for patients assigned to docetaxel, reported Fabrice Barlesi, MD, head of the multidisciplinary oncology and therapeutic innovations department at Aix-Marseille University and the Assistance Publique Hôpitaux de Marseille, France.
Atezolizumab was previously shown in the phase II POPLAR trial to significantly increase overall survival compared with docetaxel in second- or third-line therapy in patients with locally advanced or metastatic NSCLC who had disease progression after platinum-based chemotherapy.
The OAK trial investigators enrolled 1,225 patients with locally advanced or metastatic NSCLC following one or two prior lines of therapy that contained at least one platinum-based regimen. The patients could have any degree of PD-L1 expression.
Dr. Barlesi presented results of a prespecified intention-to-treat analysis of the first 850 patients enrolled.
Following stratification for PD-L1, histology, and prior chemotherapy regimens, they were randomly assigned to either atezolizumab 1,200 mg IV every 3 weeks or docetaxel 75 mg/m2 every 3 weeks. In the atezolizumab arm, therapy could be continued until disease progression or clinical benefit. In the docetaxel arm, therapy was continued until progression.
As noted, atezolizumab was associated with significantly better OS, the primary endpoint (13.8 vs. 9.6 months) with a hazard ratio (HR) of 0.73 (P = .0003). OS rates at 12 months were 55% in the atezolizumab arm vs. 41% in the docetaxel arm, and at 18 months the rates were 40% and 27%, respectively.
The investigators found that atezolizumab provided a benefit regardless of PD-L1 expression, with a hazard ratio of 0.74 (P = .0102) for the 55% of patients with PD-L1 expression on at least 1% of their tumor cells, and 0.75 (P = .0205) for patients with PD-L1 on less than 1% of tumor cells.
Median overall survival was greater with both drugs for patients with higher levels of PD-L1 expression, with a median of 15.7 months for those treated with atezolizumab and 10.3 months for those treated with docetaxel. In contrast, the respective median overall survival durations in the patients with less than 1% PD-L1 expression were 12.6 and 8.9 months.
The greatest benefit for atezolizumab was seen in patients with PD-L1 expression of 50% or more of tumor cells or 10% or more of tumor-infiltrating immune cells, with a median OS at a minimum follow-up of 19 months of 20.5 months vs. 8.9 months, translating into a hazard ratio for atezolizumab of 0.41 (P less than .0001).
An analysis of OS by histology showed HRs of 0.73 for atezolizumab for patients with either non-squamous tumors (P = .0015) or squamous tumors (P = .0383). In addition, an analysis of OS in selected subgroups showed a trend favoring atezolizumab in patients who had never smoked, who tend to have a worse prognosis than would current or former smokers.
In an analysis of progression-free survival, there was no significant difference between the groups (median 4.0 vs. 2.8 months).
Adverse events of grade 3 or greater of any cause were lower with atezolizumab, at 37% vs. 54%. There was one treatment-related death from respiratory infection in a patient who received docetaxel.
Invited discussant Naiyer Rizvi, MD, an oncologist at Columbia University Medical Center in New York, said that the OAK trial confirms that atezolizumab is an appropriate second-line therapy for unselected patients with advanced NSCLC, and should be explored for its potential survival benefits in never smokers.
COPENHAGEN – The checkpoint inhibitor atezolizumab improved overall survival of advanced non–small-cell lung cancer, compared with docetaxel, primary analysis from the OAK trial shows.
In the first phase III trial of a monoclonal antibody directed against the programmed death 1 ligand (PD-L1) in non–small-lung cell lung cancer (NSCLC), median overall survival (OS) for patients assigned to atezolizumab (Tecentriq) was 13.8 months, compared with 9.6 months for patients assigned to docetaxel, reported Fabrice Barlesi, MD, head of the multidisciplinary oncology and therapeutic innovations department at Aix-Marseille University and the Assistance Publique Hôpitaux de Marseille, France.
Atezolizumab was previously shown in the phase II POPLAR trial to significantly increase overall survival compared with docetaxel in second- or third-line therapy in patients with locally advanced or metastatic NSCLC who had disease progression after platinum-based chemotherapy.
The OAK trial investigators enrolled 1,225 patients with locally advanced or metastatic NSCLC following one or two prior lines of therapy that contained at least one platinum-based regimen. The patients could have any degree of PD-L1 expression.
Dr. Barlesi presented results of a prespecified intention-to-treat analysis of the first 850 patients enrolled.
Following stratification for PD-L1, histology, and prior chemotherapy regimens, they were randomly assigned to either atezolizumab 1,200 mg IV every 3 weeks or docetaxel 75 mg/m2 every 3 weeks. In the atezolizumab arm, therapy could be continued until disease progression or clinical benefit. In the docetaxel arm, therapy was continued until progression.
As noted, atezolizumab was associated with significantly better OS, the primary endpoint (13.8 vs. 9.6 months) with a hazard ratio (HR) of 0.73 (P = .0003). OS rates at 12 months were 55% in the atezolizumab arm vs. 41% in the docetaxel arm, and at 18 months the rates were 40% and 27%, respectively.
The investigators found that atezolizumab provided a benefit regardless of PD-L1 expression, with a hazard ratio of 0.74 (P = .0102) for the 55% of patients with PD-L1 expression on at least 1% of their tumor cells, and 0.75 (P = .0205) for patients with PD-L1 on less than 1% of tumor cells.
Median overall survival was greater with both drugs for patients with higher levels of PD-L1 expression, with a median of 15.7 months for those treated with atezolizumab and 10.3 months for those treated with docetaxel. In contrast, the respective median overall survival durations in the patients with less than 1% PD-L1 expression were 12.6 and 8.9 months.
The greatest benefit for atezolizumab was seen in patients with PD-L1 expression of 50% or more of tumor cells or 10% or more of tumor-infiltrating immune cells, with a median OS at a minimum follow-up of 19 months of 20.5 months vs. 8.9 months, translating into a hazard ratio for atezolizumab of 0.41 (P less than .0001).
An analysis of OS by histology showed HRs of 0.73 for atezolizumab for patients with either non-squamous tumors (P = .0015) or squamous tumors (P = .0383). In addition, an analysis of OS in selected subgroups showed a trend favoring atezolizumab in patients who had never smoked, who tend to have a worse prognosis than would current or former smokers.
In an analysis of progression-free survival, there was no significant difference between the groups (median 4.0 vs. 2.8 months).
Adverse events of grade 3 or greater of any cause were lower with atezolizumab, at 37% vs. 54%. There was one treatment-related death from respiratory infection in a patient who received docetaxel.
Invited discussant Naiyer Rizvi, MD, an oncologist at Columbia University Medical Center in New York, said that the OAK trial confirms that atezolizumab is an appropriate second-line therapy for unselected patients with advanced NSCLC, and should be explored for its potential survival benefits in never smokers.
COPENHAGEN – The checkpoint inhibitor atezolizumab improved overall survival of advanced non–small-cell lung cancer, compared with docetaxel, primary analysis from the OAK trial shows.
In the first phase III trial of a monoclonal antibody directed against the programmed death 1 ligand (PD-L1) in non–small-lung cell lung cancer (NSCLC), median overall survival (OS) for patients assigned to atezolizumab (Tecentriq) was 13.8 months, compared with 9.6 months for patients assigned to docetaxel, reported Fabrice Barlesi, MD, head of the multidisciplinary oncology and therapeutic innovations department at Aix-Marseille University and the Assistance Publique Hôpitaux de Marseille, France.
Atezolizumab was previously shown in the phase II POPLAR trial to significantly increase overall survival compared with docetaxel in second- or third-line therapy in patients with locally advanced or metastatic NSCLC who had disease progression after platinum-based chemotherapy.
The OAK trial investigators enrolled 1,225 patients with locally advanced or metastatic NSCLC following one or two prior lines of therapy that contained at least one platinum-based regimen. The patients could have any degree of PD-L1 expression.
Dr. Barlesi presented results of a prespecified intention-to-treat analysis of the first 850 patients enrolled.
Following stratification for PD-L1, histology, and prior chemotherapy regimens, they were randomly assigned to either atezolizumab 1,200 mg IV every 3 weeks or docetaxel 75 mg/m2 every 3 weeks. In the atezolizumab arm, therapy could be continued until disease progression or clinical benefit. In the docetaxel arm, therapy was continued until progression.
As noted, atezolizumab was associated with significantly better OS, the primary endpoint (13.8 vs. 9.6 months) with a hazard ratio (HR) of 0.73 (P = .0003). OS rates at 12 months were 55% in the atezolizumab arm vs. 41% in the docetaxel arm, and at 18 months the rates were 40% and 27%, respectively.
The investigators found that atezolizumab provided a benefit regardless of PD-L1 expression, with a hazard ratio of 0.74 (P = .0102) for the 55% of patients with PD-L1 expression on at least 1% of their tumor cells, and 0.75 (P = .0205) for patients with PD-L1 on less than 1% of tumor cells.
Median overall survival was greater with both drugs for patients with higher levels of PD-L1 expression, with a median of 15.7 months for those treated with atezolizumab and 10.3 months for those treated with docetaxel. In contrast, the respective median overall survival durations in the patients with less than 1% PD-L1 expression were 12.6 and 8.9 months.
The greatest benefit for atezolizumab was seen in patients with PD-L1 expression of 50% or more of tumor cells or 10% or more of tumor-infiltrating immune cells, with a median OS at a minimum follow-up of 19 months of 20.5 months vs. 8.9 months, translating into a hazard ratio for atezolizumab of 0.41 (P less than .0001).
An analysis of OS by histology showed HRs of 0.73 for atezolizumab for patients with either non-squamous tumors (P = .0015) or squamous tumors (P = .0383). In addition, an analysis of OS in selected subgroups showed a trend favoring atezolizumab in patients who had never smoked, who tend to have a worse prognosis than would current or former smokers.
In an analysis of progression-free survival, there was no significant difference between the groups (median 4.0 vs. 2.8 months).
Adverse events of grade 3 or greater of any cause were lower with atezolizumab, at 37% vs. 54%. There was one treatment-related death from respiratory infection in a patient who received docetaxel.
Invited discussant Naiyer Rizvi, MD, an oncologist at Columbia University Medical Center in New York, said that the OAK trial confirms that atezolizumab is an appropriate second-line therapy for unselected patients with advanced NSCLC, and should be explored for its potential survival benefits in never smokers.
AT ESMO 2016
Key clinical point: Atezolizumab improved overall survival (OS), compared with docetaxel, in patients with advanced non–small-cell lung cancer.
Major finding: Median OS for patients assigned to atezolizumab was 13.8 months, compared with 9.6 months for patients assigned to docetaxel.
Data source: Prespecified analysis of a randomized phase III trial in 850 patients with metastatic or recurrent NSCLC after platinum-based chemotherapy.
Disclosures: The OAK trial was funded by F. Hoffman-La Roche. Dr. Barlesi disclosed consulting fees from that company and others. Dr, Rizvi disclosed consulting for Roche and other companies.
Ultrasound-Guided Percutaneous Reconstruction of the Anterolateral Ligament: Surgical Technique
Tryptase gene variant linked to GI, joint, and skin symptoms
Researchers have identified a genetic variant associated with inherited elevated basal serum tryptase levels and linked to a distinct group of comorbid multisystem complaints.
These features, including cutaneous flushing, certain chronic pain disorders, autonomic dysfunction, and gastrointestinal dysmotility, have been reported in association with genetic disorders or joint hypermobility syndromes such as Ehlers-Danlos syndrome type III (hypermobility type, EDS III) and often follow a dominant inheritance pattern in affected families, providing a reason to look into a genetic basis for these patient characteristics, according to Jonathan J. Lyons, MD, of the National Institute of Allergy and Infectious Diseases, and his coauthors. The researchers reported their findings Oct. 17 in Nature Genetics.
The researchers recruited 96 individuals from 35 families with a syndrome of elevated basal serum tryptase levels and multiple comorbid symptoms following an autosomal dominant pattern of inheritance.
These symptoms included gastrointestinal dysmotility such as irritable bowel syndrome or chronic gastroesophageal reflux, connective tissue abnormalities such as joint hypermobility, congenital skeletal abnormalities, retained primary dentition, symptoms suggestive of autonomic dysfunction such as postural orthostatic tachycardia syndrome, and elevated composite autonomic symptom scores. Other symptoms included recurrent cutaneous flushing and pruritus – often associated with urticaria and complaints of sleep disruption – and systemic reaction to stinging insects.
Using exome and genome sequencing followed by linkage analysis, researchers identified duplications and triplications within the TPSAB1 gene encoding alpha-tryptase (Nat Genet. 2016 Oct 17. doi: 10.1038/ng.3696). Further analysis found elevated alpha-tryptase/beta-tryptase ratios among affected family members and suggested that multiple copies of the alpha-tryptase sequence were inherited together.
To confirm the finding, researchers examined genetic data from a cohort of healthy unrelated volunteers in the National Human Genome Research Institute ClinSeq cohort, which identified 125 samples with partially enriched duplication of alpha tryptase–encoding sequence using a common haplotype.
Of these, three individuals had single-allele duplications of the alpha tryptase–encoding sequence and also presented with similar symptoms to the original cohort: cutaneous flushing, itching, or hives, systemic venom reactions, irritable bowel syndrome, retained primary dentition, and elevated autonomic symptom scores.
“We have found that this phenotype is most frequently inherited in an autosomal dominant manner and that, when this occurs, it is exclusively associated with increased copy number on a single allele of alpha tryptase–encoding sequence in the TPSAB1 gene, a genetic trait we have termed hereditary alpha-tryptasemia,” the researchers reported. “The families studied in our initial cohort likely represent the most severe phenotypes among individuals affected with hereditary alpha-tryptasemia, owing in part to the lack of detection of triplication of alpha tryptase–encoding sequence in unselected populations, which we have tentatively designated as hereditary alpha-tryptasemia syndrome.”
The authors suggested that part of the clinical presentation of this syndrome included symptoms that may be associated clinically with mast cell mediator release. In the context of elevated basal serum tryptase levels, this might prompt a doctor to investigate for clonal mast cell disease, which would include bone-marrow biopsy.
However, given that such an investigation would be challenging, and given that elevated tryptase levels are not uncommon in the generally population, they suggested tryptase genotyping may be warranted.
The study was supported by the National Institute of Allergy and Infectious Diseases, the ARTrust/the Mastocytosis Society, and the National Human Genome Research Institute. One author declared royalties associated with the tryptase UniCAP assay, and consulting fees from Genentech. Another author declared an advisory position and royalties from private industry.
Researchers have identified a genetic variant associated with inherited elevated basal serum tryptase levels and linked to a distinct group of comorbid multisystem complaints.
These features, including cutaneous flushing, certain chronic pain disorders, autonomic dysfunction, and gastrointestinal dysmotility, have been reported in association with genetic disorders or joint hypermobility syndromes such as Ehlers-Danlos syndrome type III (hypermobility type, EDS III) and often follow a dominant inheritance pattern in affected families, providing a reason to look into a genetic basis for these patient characteristics, according to Jonathan J. Lyons, MD, of the National Institute of Allergy and Infectious Diseases, and his coauthors. The researchers reported their findings Oct. 17 in Nature Genetics.
The researchers recruited 96 individuals from 35 families with a syndrome of elevated basal serum tryptase levels and multiple comorbid symptoms following an autosomal dominant pattern of inheritance.
These symptoms included gastrointestinal dysmotility such as irritable bowel syndrome or chronic gastroesophageal reflux, connective tissue abnormalities such as joint hypermobility, congenital skeletal abnormalities, retained primary dentition, symptoms suggestive of autonomic dysfunction such as postural orthostatic tachycardia syndrome, and elevated composite autonomic symptom scores. Other symptoms included recurrent cutaneous flushing and pruritus – often associated with urticaria and complaints of sleep disruption – and systemic reaction to stinging insects.
Using exome and genome sequencing followed by linkage analysis, researchers identified duplications and triplications within the TPSAB1 gene encoding alpha-tryptase (Nat Genet. 2016 Oct 17. doi: 10.1038/ng.3696). Further analysis found elevated alpha-tryptase/beta-tryptase ratios among affected family members and suggested that multiple copies of the alpha-tryptase sequence were inherited together.
To confirm the finding, researchers examined genetic data from a cohort of healthy unrelated volunteers in the National Human Genome Research Institute ClinSeq cohort, which identified 125 samples with partially enriched duplication of alpha tryptase–encoding sequence using a common haplotype.
Of these, three individuals had single-allele duplications of the alpha tryptase–encoding sequence and also presented with similar symptoms to the original cohort: cutaneous flushing, itching, or hives, systemic venom reactions, irritable bowel syndrome, retained primary dentition, and elevated autonomic symptom scores.
“We have found that this phenotype is most frequently inherited in an autosomal dominant manner and that, when this occurs, it is exclusively associated with increased copy number on a single allele of alpha tryptase–encoding sequence in the TPSAB1 gene, a genetic trait we have termed hereditary alpha-tryptasemia,” the researchers reported. “The families studied in our initial cohort likely represent the most severe phenotypes among individuals affected with hereditary alpha-tryptasemia, owing in part to the lack of detection of triplication of alpha tryptase–encoding sequence in unselected populations, which we have tentatively designated as hereditary alpha-tryptasemia syndrome.”
The authors suggested that part of the clinical presentation of this syndrome included symptoms that may be associated clinically with mast cell mediator release. In the context of elevated basal serum tryptase levels, this might prompt a doctor to investigate for clonal mast cell disease, which would include bone-marrow biopsy.
However, given that such an investigation would be challenging, and given that elevated tryptase levels are not uncommon in the generally population, they suggested tryptase genotyping may be warranted.
The study was supported by the National Institute of Allergy and Infectious Diseases, the ARTrust/the Mastocytosis Society, and the National Human Genome Research Institute. One author declared royalties associated with the tryptase UniCAP assay, and consulting fees from Genentech. Another author declared an advisory position and royalties from private industry.
Researchers have identified a genetic variant associated with inherited elevated basal serum tryptase levels and linked to a distinct group of comorbid multisystem complaints.
These features, including cutaneous flushing, certain chronic pain disorders, autonomic dysfunction, and gastrointestinal dysmotility, have been reported in association with genetic disorders or joint hypermobility syndromes such as Ehlers-Danlos syndrome type III (hypermobility type, EDS III) and often follow a dominant inheritance pattern in affected families, providing a reason to look into a genetic basis for these patient characteristics, according to Jonathan J. Lyons, MD, of the National Institute of Allergy and Infectious Diseases, and his coauthors. The researchers reported their findings Oct. 17 in Nature Genetics.
The researchers recruited 96 individuals from 35 families with a syndrome of elevated basal serum tryptase levels and multiple comorbid symptoms following an autosomal dominant pattern of inheritance.
These symptoms included gastrointestinal dysmotility such as irritable bowel syndrome or chronic gastroesophageal reflux, connective tissue abnormalities such as joint hypermobility, congenital skeletal abnormalities, retained primary dentition, symptoms suggestive of autonomic dysfunction such as postural orthostatic tachycardia syndrome, and elevated composite autonomic symptom scores. Other symptoms included recurrent cutaneous flushing and pruritus – often associated with urticaria and complaints of sleep disruption – and systemic reaction to stinging insects.
Using exome and genome sequencing followed by linkage analysis, researchers identified duplications and triplications within the TPSAB1 gene encoding alpha-tryptase (Nat Genet. 2016 Oct 17. doi: 10.1038/ng.3696). Further analysis found elevated alpha-tryptase/beta-tryptase ratios among affected family members and suggested that multiple copies of the alpha-tryptase sequence were inherited together.
To confirm the finding, researchers examined genetic data from a cohort of healthy unrelated volunteers in the National Human Genome Research Institute ClinSeq cohort, which identified 125 samples with partially enriched duplication of alpha tryptase–encoding sequence using a common haplotype.
Of these, three individuals had single-allele duplications of the alpha tryptase–encoding sequence and also presented with similar symptoms to the original cohort: cutaneous flushing, itching, or hives, systemic venom reactions, irritable bowel syndrome, retained primary dentition, and elevated autonomic symptom scores.
“We have found that this phenotype is most frequently inherited in an autosomal dominant manner and that, when this occurs, it is exclusively associated with increased copy number on a single allele of alpha tryptase–encoding sequence in the TPSAB1 gene, a genetic trait we have termed hereditary alpha-tryptasemia,” the researchers reported. “The families studied in our initial cohort likely represent the most severe phenotypes among individuals affected with hereditary alpha-tryptasemia, owing in part to the lack of detection of triplication of alpha tryptase–encoding sequence in unselected populations, which we have tentatively designated as hereditary alpha-tryptasemia syndrome.”
The authors suggested that part of the clinical presentation of this syndrome included symptoms that may be associated clinically with mast cell mediator release. In the context of elevated basal serum tryptase levels, this might prompt a doctor to investigate for clonal mast cell disease, which would include bone-marrow biopsy.
However, given that such an investigation would be challenging, and given that elevated tryptase levels are not uncommon in the generally population, they suggested tryptase genotyping may be warranted.
The study was supported by the National Institute of Allergy and Infectious Diseases, the ARTrust/the Mastocytosis Society, and the National Human Genome Research Institute. One author declared royalties associated with the tryptase UniCAP assay, and consulting fees from Genentech. Another author declared an advisory position and royalties from private industry.
FROM NATURE GENETICS
Key clinical point:
Major finding: Increased copy number on a single allele of alpha tryptase–encoding sequence in the TPSAB1 gene is associated with elevated basal serum tryptase and a collection of symptoms including irritable bowel syndrome, joint hypermobility, and autonomic dysfunction.
Data source: Study of 96 individuals from 35 families with a syndrome of elevated basal serum tryptase levels and multiple comorbid symptoms.
Disclosures: The study was supported by the National Institute of Allergy and Infectious Diseases, the ARTrust/the Mastocytosis Society, and the National Human Genome Research Institute. One author declared royalties associated with the tryptase UniCAP assay, and consulting fees from Genentech. Another author declared an advisory position and royalties from private industry.