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Surgical left atrial appendage closure slashes stroke risk
BARCELONA – Routine surgical closure of the left atrial appendage during open heart surgery provides long-term protection against cerebral ischemic events, according to the findings of the first-ever randomized controlled trial to address the issue.
“I think we can say, based on our study, that it would be advisable to routinely add surgical closure of the left atrial appendage to planned open heart surgery,” Jesper Park-Hansen, MD, said at the annual congress of the European Society of Cardiology.
In light of the demonstrated success of percutaneous closure of the LAA using the Watchman and other devices for stroke prevention in patients with atrial fibrillation, Dr. Park-Hansen and his coinvestigators at the University of Copenhagen organized LAACS (the Left Atrial Appendage Closure Study). The goal was to generate solid, randomized trial evidence as to whether preemptive routine surgical closure of the LAA at the time of cardiac surgery is of benefit. Some cardiac surgeons already do this routinely; many others don’t because of the lack of Level 1 supporting evidence.
LAACS included 141 patients randomized to surgical LAA closure or not at the point of first-time open heart surgery. The study population included patients with and without a history of atrial fibrillation. LAA closure was accomplished via a purse string closure with a silk string around the neck of the appendage backed up by an additional single running suture. Transesophageal echocardiography performed in 10 patients a mean of 520 days post closure showed no signs of leakage or incomplete closure.
The primary composite outcome was comprised of clinical stroke or transient ischemic attack diagnosed by a neurologist, or a silent cerebral infarct detected on MRI performed 2-4 weeks post discharge and again at least 6 months later. At a mean follow-up of 3.7 years and a maximum of 6 years, this outcome had occurred in 6.3% of the LAAC group, significantly lower than the 18.3% rate in controls. All but one patient with a cerebral ischemic event in the control group had atrial fibrillation. The risk of an event was unrelated to whether or not a patient had a history of atrial fibrillation prior to surgery or to CHA2DS2-VASc score.
Dr. Park-Hansen emphasized that he and his coinvestigators don’t consider LAACS to be the final word on routine prophylactic appendage closure.
“This is the first randomized study. We are eager to move on to another randomized study on a larger scale. That is the next step for us,” he said.
“The challenge now – and what we will be discussing with our surgeons – is to agree on a feasible safe and effective means of left atrial appendage closure. My personal opinion is the Lariat suture delivery device or some other easily reproducible method of closure could be a good way to go,” Dr. Park-Hansen added.
The research group’s cardiac surgeons already have ruled out excision and stapling because of concerns about bleeding risk and the additional cost imposed by stapling.
Discussant Volkmar Falk, MD, commented that LAACS was too small, probably severely underpowered, should have included a preoperative MRI so investigators could reliably capture perioperative silent cerebral infarcts, and the double suture purse string is “probably not the best method” to occlude the LAA.
“LAACS addresses an important question, but alas, it does not provide the answer,” declared Dr. Falk, professor and director of the department of cardiothoracic and vascular surgery at Charité Medical University in Berlin.
Dr. Park-Hansen and Dr. Falk reported having no financial conflicts of interest.
BARCELONA – Routine surgical closure of the left atrial appendage during open heart surgery provides long-term protection against cerebral ischemic events, according to the findings of the first-ever randomized controlled trial to address the issue.
“I think we can say, based on our study, that it would be advisable to routinely add surgical closure of the left atrial appendage to planned open heart surgery,” Jesper Park-Hansen, MD, said at the annual congress of the European Society of Cardiology.
In light of the demonstrated success of percutaneous closure of the LAA using the Watchman and other devices for stroke prevention in patients with atrial fibrillation, Dr. Park-Hansen and his coinvestigators at the University of Copenhagen organized LAACS (the Left Atrial Appendage Closure Study). The goal was to generate solid, randomized trial evidence as to whether preemptive routine surgical closure of the LAA at the time of cardiac surgery is of benefit. Some cardiac surgeons already do this routinely; many others don’t because of the lack of Level 1 supporting evidence.
LAACS included 141 patients randomized to surgical LAA closure or not at the point of first-time open heart surgery. The study population included patients with and without a history of atrial fibrillation. LAA closure was accomplished via a purse string closure with a silk string around the neck of the appendage backed up by an additional single running suture. Transesophageal echocardiography performed in 10 patients a mean of 520 days post closure showed no signs of leakage or incomplete closure.
The primary composite outcome was comprised of clinical stroke or transient ischemic attack diagnosed by a neurologist, or a silent cerebral infarct detected on MRI performed 2-4 weeks post discharge and again at least 6 months later. At a mean follow-up of 3.7 years and a maximum of 6 years, this outcome had occurred in 6.3% of the LAAC group, significantly lower than the 18.3% rate in controls. All but one patient with a cerebral ischemic event in the control group had atrial fibrillation. The risk of an event was unrelated to whether or not a patient had a history of atrial fibrillation prior to surgery or to CHA2DS2-VASc score.
Dr. Park-Hansen emphasized that he and his coinvestigators don’t consider LAACS to be the final word on routine prophylactic appendage closure.
“This is the first randomized study. We are eager to move on to another randomized study on a larger scale. That is the next step for us,” he said.
“The challenge now – and what we will be discussing with our surgeons – is to agree on a feasible safe and effective means of left atrial appendage closure. My personal opinion is the Lariat suture delivery device or some other easily reproducible method of closure could be a good way to go,” Dr. Park-Hansen added.
The research group’s cardiac surgeons already have ruled out excision and stapling because of concerns about bleeding risk and the additional cost imposed by stapling.
Discussant Volkmar Falk, MD, commented that LAACS was too small, probably severely underpowered, should have included a preoperative MRI so investigators could reliably capture perioperative silent cerebral infarcts, and the double suture purse string is “probably not the best method” to occlude the LAA.
“LAACS addresses an important question, but alas, it does not provide the answer,” declared Dr. Falk, professor and director of the department of cardiothoracic and vascular surgery at Charité Medical University in Berlin.
Dr. Park-Hansen and Dr. Falk reported having no financial conflicts of interest.
BARCELONA – Routine surgical closure of the left atrial appendage during open heart surgery provides long-term protection against cerebral ischemic events, according to the findings of the first-ever randomized controlled trial to address the issue.
“I think we can say, based on our study, that it would be advisable to routinely add surgical closure of the left atrial appendage to planned open heart surgery,” Jesper Park-Hansen, MD, said at the annual congress of the European Society of Cardiology.
In light of the demonstrated success of percutaneous closure of the LAA using the Watchman and other devices for stroke prevention in patients with atrial fibrillation, Dr. Park-Hansen and his coinvestigators at the University of Copenhagen organized LAACS (the Left Atrial Appendage Closure Study). The goal was to generate solid, randomized trial evidence as to whether preemptive routine surgical closure of the LAA at the time of cardiac surgery is of benefit. Some cardiac surgeons already do this routinely; many others don’t because of the lack of Level 1 supporting evidence.
LAACS included 141 patients randomized to surgical LAA closure or not at the point of first-time open heart surgery. The study population included patients with and without a history of atrial fibrillation. LAA closure was accomplished via a purse string closure with a silk string around the neck of the appendage backed up by an additional single running suture. Transesophageal echocardiography performed in 10 patients a mean of 520 days post closure showed no signs of leakage or incomplete closure.
The primary composite outcome was comprised of clinical stroke or transient ischemic attack diagnosed by a neurologist, or a silent cerebral infarct detected on MRI performed 2-4 weeks post discharge and again at least 6 months later. At a mean follow-up of 3.7 years and a maximum of 6 years, this outcome had occurred in 6.3% of the LAAC group, significantly lower than the 18.3% rate in controls. All but one patient with a cerebral ischemic event in the control group had atrial fibrillation. The risk of an event was unrelated to whether or not a patient had a history of atrial fibrillation prior to surgery or to CHA2DS2-VASc score.
Dr. Park-Hansen emphasized that he and his coinvestigators don’t consider LAACS to be the final word on routine prophylactic appendage closure.
“This is the first randomized study. We are eager to move on to another randomized study on a larger scale. That is the next step for us,” he said.
“The challenge now – and what we will be discussing with our surgeons – is to agree on a feasible safe and effective means of left atrial appendage closure. My personal opinion is the Lariat suture delivery device or some other easily reproducible method of closure could be a good way to go,” Dr. Park-Hansen added.
The research group’s cardiac surgeons already have ruled out excision and stapling because of concerns about bleeding risk and the additional cost imposed by stapling.
Discussant Volkmar Falk, MD, commented that LAACS was too small, probably severely underpowered, should have included a preoperative MRI so investigators could reliably capture perioperative silent cerebral infarcts, and the double suture purse string is “probably not the best method” to occlude the LAA.
“LAACS addresses an important question, but alas, it does not provide the answer,” declared Dr. Falk, professor and director of the department of cardiothoracic and vascular surgery at Charité Medical University in Berlin.
Dr. Park-Hansen and Dr. Falk reported having no financial conflicts of interest.
AT THE ESC CONGRESS 2017
Key clinical point:
Major finding: The composite rate of clinical stroke, TIA, or silent cerebral infarct in the years following open heart surgery was threefold higher in patients randomized to no prophylactic surgical closure of the left atrial appendage, compared with patients who got appendage closure during their surgery.
Data source: A randomized trial in which 141 patients undergoing first-time open heart surgery were assigned to prophylactic surgical closure of the left atrial appendage or not.
Disclosures: The study was conducted free of commercial support. The presenter reported having no financial conflicts of interest.
Obinutuzumab edges out rituximab for PFS in follicular lymphoma
In a head-to-head trial of anti-CD20 monoclonal antibodies in first-line therapy for follicular lymphoma, obinutuzumab-based chemotherapy was associated with slightly but significantly better progression-free survival than rituximab-based therapy, but at the cost of higher toxicities, including severe adverse events.
Among 1,202 patients with follicular lymphoma followed for a median of 34.5 months, the estimated 3-year rate of progression-free survival (PFS) for patients randomized to obinutuzumab-based chemotherapy and maintenance was 80%, compared with 73.3% for patients randomized to rituximab chemotherapy and maintenance. Response rates and overall survival were similar between the treatment groups, Robert Marcus, MB, BS, of King’s College Hospital, London, and his coinvestigators reported in the GALLIUM trial.
They acknowledged, however, that there were substantial differences between the treatment groups in the cumulative doses of obinutuzumab (Gazyva) and rituximab (Rituxan and others), which could have affected the relative efficacy of each regimen.
In addition, while patients were randomly assigned to one monoclonal antibody or the other, the choice of chemotherapy regimens, while standardized, was left to the discretion of investigators at each treatment site, another factor that might have influenced outcomes.
The investigators reported the results of a preplanned interim efficacy analysis. They compared obinutuzumab or rituximab plus chemotherapy in patients with indolent non-Hodgkin lymphoma, but the trial was powered to detect a PFS difference only in patients with follicular lymphoma. Patients who had a clinical response to induction therapy went on to maintenance therapy with the same monoclonal antibody.
In all, 1,202 patients with follicular lymphoma were enrolled and randomized, 601 in each arm, to receive induction with either intravenous obinutuzumab 1,000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of subsequent cycles, or rituximab 375 mg/m2 on day 1 of each cycle for six or eight cycles, depending on the accompanying chemotherapy regimen. The regimens used were either CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), or bendamustine.
Patients with partial or complete responses were then maintained on the same monoclonal antibody they had received during induction, either obinutuzumab 1,000 mg or rituximab 375 mg/m2 every 2 months for 2 years, or until disease progression. Patients were not allowed to be crossed over to the other maintenance therapy.
Patients with stable disease after induction continued to be followed, but did not receive maintenance therapy.
The interim analysis was performed after 245 of 370 anticipated events (disease progression, relapse, or death) had occurred. At that time, the independent data and safety monitoring committee recommended full analysis of the trial data, and the sponsor agreed.
After a median follow-up of 34.5 months, an intention-to-treat analysis showed that the investigator-assessed, estimated 3-year rate of PFS was 80.0% in the obinutuzumab arm, compared with 73.3%; in the rituximab arm. This translated into a hazard ratio (HR) for progression, relapse, or death of 0.66 (P = .001). An independent review committee calculated a HR favoring obinutuzumab of 0.71 (P = .01).
Estimated 3-year overall survival rates were not significantly different at 94% and 92.1%, respectively.
Overall response rates were similar between the groups, at 88.5% with obinutuzumab group and 86.9% with rituximab, a difference that was not significant.
Obinutuzumab was associated with a higher rate of prespecified events of special interest, including infections, cardiac events, second neoplasms, infusion-related events, neutropenia, and thrombocytopenia.
Adverse events deemed to be related to the antibodies occurred in 59.3% of patients on obinutuzumab, and 48.9% of patients on rituximab.
There were more frequent grade 3 or 4 adverse events and deaths with obinutuzumab, occurring in 74.6% of patients vs. 67.8% on rituximab. Fatal adverse events occurred in 4% and 3.4% of patients, respectively.
A total of 81 patients died during the trial, including 35 in the obinutuzumab group and 46 in the rituximab group.
F. Hoffmann–La Roche supported the trial. Dr. Marcus disclosed consulting fees and lecture fees from Takeda Pharmaceuticals and travel support, consulting fees, and lecture fees from Roche. The majority of coauthors disclosed similar relationships.
Should obinutuzumab replace rituximab as the standard antibody in the treatment of patients receiving chemoimmunotherapy regimens for follicular lymphoma? Results from this trial would suggest that there might be no advantage for an obinutuzumab-containing chemoimmunotherapy regimen if maintenance treatment was not planned. Even with maintenance therapy, there is no evidence from this trial of an overall survival benefit with obinutuzumab. These findings, combined with the higher rate of toxic effects and, presumably, the higher cost of obinutuzumab, raise important questions regarding the advantage of its use. This issue is complicated further because it is possible that giving rituximab at a dose of 1,000 mg might reduce or eliminate any difference in progression-free survival – that is, if the difference is primarily a dose effect.
When the data on minimal residual disease are made available, the case in favor of obinutuzumab may appear to be more compelling if indeed a higher proportion of patients who received obinutuzumab have minimal residual disease status at some point in treatment and remain in remission longer than those who received rituximab. At the moment, the competition between these agents looks too close to call.
These comments are excerpted from an editorial (N Engl J Med. 2017 Oct 5;377;14:1389-90) by James O. Armitage, MD, University of Nebraska, Omaha, and Dan L. Longo, MD, Dana-Farber Cancer Institute, Boston. Dr. Armitage reported personal fees from Conatus, Samus Therapeutics, and Tesaro. Dr. Longo reported no relevant disclosures. He is deputy editor of The New England Journal of Medicine.
Should obinutuzumab replace rituximab as the standard antibody in the treatment of patients receiving chemoimmunotherapy regimens for follicular lymphoma? Results from this trial would suggest that there might be no advantage for an obinutuzumab-containing chemoimmunotherapy regimen if maintenance treatment was not planned. Even with maintenance therapy, there is no evidence from this trial of an overall survival benefit with obinutuzumab. These findings, combined with the higher rate of toxic effects and, presumably, the higher cost of obinutuzumab, raise important questions regarding the advantage of its use. This issue is complicated further because it is possible that giving rituximab at a dose of 1,000 mg might reduce or eliminate any difference in progression-free survival – that is, if the difference is primarily a dose effect.
When the data on minimal residual disease are made available, the case in favor of obinutuzumab may appear to be more compelling if indeed a higher proportion of patients who received obinutuzumab have minimal residual disease status at some point in treatment and remain in remission longer than those who received rituximab. At the moment, the competition between these agents looks too close to call.
These comments are excerpted from an editorial (N Engl J Med. 2017 Oct 5;377;14:1389-90) by James O. Armitage, MD, University of Nebraska, Omaha, and Dan L. Longo, MD, Dana-Farber Cancer Institute, Boston. Dr. Armitage reported personal fees from Conatus, Samus Therapeutics, and Tesaro. Dr. Longo reported no relevant disclosures. He is deputy editor of The New England Journal of Medicine.
Should obinutuzumab replace rituximab as the standard antibody in the treatment of patients receiving chemoimmunotherapy regimens for follicular lymphoma? Results from this trial would suggest that there might be no advantage for an obinutuzumab-containing chemoimmunotherapy regimen if maintenance treatment was not planned. Even with maintenance therapy, there is no evidence from this trial of an overall survival benefit with obinutuzumab. These findings, combined with the higher rate of toxic effects and, presumably, the higher cost of obinutuzumab, raise important questions regarding the advantage of its use. This issue is complicated further because it is possible that giving rituximab at a dose of 1,000 mg might reduce or eliminate any difference in progression-free survival – that is, if the difference is primarily a dose effect.
When the data on minimal residual disease are made available, the case in favor of obinutuzumab may appear to be more compelling if indeed a higher proportion of patients who received obinutuzumab have minimal residual disease status at some point in treatment and remain in remission longer than those who received rituximab. At the moment, the competition between these agents looks too close to call.
These comments are excerpted from an editorial (N Engl J Med. 2017 Oct 5;377;14:1389-90) by James O. Armitage, MD, University of Nebraska, Omaha, and Dan L. Longo, MD, Dana-Farber Cancer Institute, Boston. Dr. Armitage reported personal fees from Conatus, Samus Therapeutics, and Tesaro. Dr. Longo reported no relevant disclosures. He is deputy editor of The New England Journal of Medicine.
In a head-to-head trial of anti-CD20 monoclonal antibodies in first-line therapy for follicular lymphoma, obinutuzumab-based chemotherapy was associated with slightly but significantly better progression-free survival than rituximab-based therapy, but at the cost of higher toxicities, including severe adverse events.
Among 1,202 patients with follicular lymphoma followed for a median of 34.5 months, the estimated 3-year rate of progression-free survival (PFS) for patients randomized to obinutuzumab-based chemotherapy and maintenance was 80%, compared with 73.3% for patients randomized to rituximab chemotherapy and maintenance. Response rates and overall survival were similar between the treatment groups, Robert Marcus, MB, BS, of King’s College Hospital, London, and his coinvestigators reported in the GALLIUM trial.
They acknowledged, however, that there were substantial differences between the treatment groups in the cumulative doses of obinutuzumab (Gazyva) and rituximab (Rituxan and others), which could have affected the relative efficacy of each regimen.
In addition, while patients were randomly assigned to one monoclonal antibody or the other, the choice of chemotherapy regimens, while standardized, was left to the discretion of investigators at each treatment site, another factor that might have influenced outcomes.
The investigators reported the results of a preplanned interim efficacy analysis. They compared obinutuzumab or rituximab plus chemotherapy in patients with indolent non-Hodgkin lymphoma, but the trial was powered to detect a PFS difference only in patients with follicular lymphoma. Patients who had a clinical response to induction therapy went on to maintenance therapy with the same monoclonal antibody.
In all, 1,202 patients with follicular lymphoma were enrolled and randomized, 601 in each arm, to receive induction with either intravenous obinutuzumab 1,000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of subsequent cycles, or rituximab 375 mg/m2 on day 1 of each cycle for six or eight cycles, depending on the accompanying chemotherapy regimen. The regimens used were either CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), or bendamustine.
Patients with partial or complete responses were then maintained on the same monoclonal antibody they had received during induction, either obinutuzumab 1,000 mg or rituximab 375 mg/m2 every 2 months for 2 years, or until disease progression. Patients were not allowed to be crossed over to the other maintenance therapy.
Patients with stable disease after induction continued to be followed, but did not receive maintenance therapy.
The interim analysis was performed after 245 of 370 anticipated events (disease progression, relapse, or death) had occurred. At that time, the independent data and safety monitoring committee recommended full analysis of the trial data, and the sponsor agreed.
After a median follow-up of 34.5 months, an intention-to-treat analysis showed that the investigator-assessed, estimated 3-year rate of PFS was 80.0% in the obinutuzumab arm, compared with 73.3%; in the rituximab arm. This translated into a hazard ratio (HR) for progression, relapse, or death of 0.66 (P = .001). An independent review committee calculated a HR favoring obinutuzumab of 0.71 (P = .01).
Estimated 3-year overall survival rates were not significantly different at 94% and 92.1%, respectively.
Overall response rates were similar between the groups, at 88.5% with obinutuzumab group and 86.9% with rituximab, a difference that was not significant.
Obinutuzumab was associated with a higher rate of prespecified events of special interest, including infections, cardiac events, second neoplasms, infusion-related events, neutropenia, and thrombocytopenia.
Adverse events deemed to be related to the antibodies occurred in 59.3% of patients on obinutuzumab, and 48.9% of patients on rituximab.
There were more frequent grade 3 or 4 adverse events and deaths with obinutuzumab, occurring in 74.6% of patients vs. 67.8% on rituximab. Fatal adverse events occurred in 4% and 3.4% of patients, respectively.
A total of 81 patients died during the trial, including 35 in the obinutuzumab group and 46 in the rituximab group.
F. Hoffmann–La Roche supported the trial. Dr. Marcus disclosed consulting fees and lecture fees from Takeda Pharmaceuticals and travel support, consulting fees, and lecture fees from Roche. The majority of coauthors disclosed similar relationships.
In a head-to-head trial of anti-CD20 monoclonal antibodies in first-line therapy for follicular lymphoma, obinutuzumab-based chemotherapy was associated with slightly but significantly better progression-free survival than rituximab-based therapy, but at the cost of higher toxicities, including severe adverse events.
Among 1,202 patients with follicular lymphoma followed for a median of 34.5 months, the estimated 3-year rate of progression-free survival (PFS) for patients randomized to obinutuzumab-based chemotherapy and maintenance was 80%, compared with 73.3% for patients randomized to rituximab chemotherapy and maintenance. Response rates and overall survival were similar between the treatment groups, Robert Marcus, MB, BS, of King’s College Hospital, London, and his coinvestigators reported in the GALLIUM trial.
They acknowledged, however, that there were substantial differences between the treatment groups in the cumulative doses of obinutuzumab (Gazyva) and rituximab (Rituxan and others), which could have affected the relative efficacy of each regimen.
In addition, while patients were randomly assigned to one monoclonal antibody or the other, the choice of chemotherapy regimens, while standardized, was left to the discretion of investigators at each treatment site, another factor that might have influenced outcomes.
The investigators reported the results of a preplanned interim efficacy analysis. They compared obinutuzumab or rituximab plus chemotherapy in patients with indolent non-Hodgkin lymphoma, but the trial was powered to detect a PFS difference only in patients with follicular lymphoma. Patients who had a clinical response to induction therapy went on to maintenance therapy with the same monoclonal antibody.
In all, 1,202 patients with follicular lymphoma were enrolled and randomized, 601 in each arm, to receive induction with either intravenous obinutuzumab 1,000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of subsequent cycles, or rituximab 375 mg/m2 on day 1 of each cycle for six or eight cycles, depending on the accompanying chemotherapy regimen. The regimens used were either CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), or bendamustine.
Patients with partial or complete responses were then maintained on the same monoclonal antibody they had received during induction, either obinutuzumab 1,000 mg or rituximab 375 mg/m2 every 2 months for 2 years, or until disease progression. Patients were not allowed to be crossed over to the other maintenance therapy.
Patients with stable disease after induction continued to be followed, but did not receive maintenance therapy.
The interim analysis was performed after 245 of 370 anticipated events (disease progression, relapse, or death) had occurred. At that time, the independent data and safety monitoring committee recommended full analysis of the trial data, and the sponsor agreed.
After a median follow-up of 34.5 months, an intention-to-treat analysis showed that the investigator-assessed, estimated 3-year rate of PFS was 80.0% in the obinutuzumab arm, compared with 73.3%; in the rituximab arm. This translated into a hazard ratio (HR) for progression, relapse, or death of 0.66 (P = .001). An independent review committee calculated a HR favoring obinutuzumab of 0.71 (P = .01).
Estimated 3-year overall survival rates were not significantly different at 94% and 92.1%, respectively.
Overall response rates were similar between the groups, at 88.5% with obinutuzumab group and 86.9% with rituximab, a difference that was not significant.
Obinutuzumab was associated with a higher rate of prespecified events of special interest, including infections, cardiac events, second neoplasms, infusion-related events, neutropenia, and thrombocytopenia.
Adverse events deemed to be related to the antibodies occurred in 59.3% of patients on obinutuzumab, and 48.9% of patients on rituximab.
There were more frequent grade 3 or 4 adverse events and deaths with obinutuzumab, occurring in 74.6% of patients vs. 67.8% on rituximab. Fatal adverse events occurred in 4% and 3.4% of patients, respectively.
A total of 81 patients died during the trial, including 35 in the obinutuzumab group and 46 in the rituximab group.
F. Hoffmann–La Roche supported the trial. Dr. Marcus disclosed consulting fees and lecture fees from Takeda Pharmaceuticals and travel support, consulting fees, and lecture fees from Roche. The majority of coauthors disclosed similar relationships.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Obinutuzumab-based chemotherapy and maintenance was associated with better progression-free survival, but not overall survival, compared with rituximab-based chemotherapy and maintenance.
Major finding: Three-year progression-free survival was 80% with obinutuzumab, vs. 73.3% with rituximab.
Data source: Interim analysis of a randomized phase 3, open-label trial of 1,202 patients with follicular lymphoma.
Disclosures: F. Hoffmann–La Roche supported the trial. Dr. Marcus disclosed consulting fees and lecture fees from Takeda Pharmaceuticals and travel support, consulting fees, and lecture fees from Roche. The majority of coauthors disclosed similar relationships.
Working up patients with allergic contact dermatitis
When working up patients with allergic contact dermatitis (ACD), the patch test used may depend on how frequently testing is performed in the practice, and the type of allergies that are being evaluated, according to Joseph Fowler Jr., MD, of the department of dermatology at the University of Louisville (Ky).
T.R.U.E. TEST is more convenient than standard patch testing is but misses allergic contact dermatitis up to 40% of the time, he pointed out. The benefit of the T.R.U.E. TEST is that it’s easy to use, allergens come preapplied to a gel-based tape so there’s very little prep time, and they are well standardized with the same quantity on each patch every time.
T.R.U.E. TEST seems to work well for when testing for metal allergies, as well as allergies to topical antibiotics, steroids, and rubber, but not as well for dental implants, fragrances, newer preservatives, surfactants, acrylates, and some industrial and cosmetic allergens. It’s not so effective in many occupational settings, but even so, T.R.U.E. TEST is a good option when testing is performed infrequently, and “is much better than no patch testing at all,” according to Dr. Fowler, who spoke at the Annual Coastal Dermatology Symposium, jointly presented by the University of Louisville and Global Academy for Medical Education.
In a presentation on contact dermatitis and itch, he pointed out that what appears to be atopic dermatitis (AD) in a patient might actually be ACD and that ACD is common in patients with AD and complicates its treatment. Metals, fragrances, and topical components – namely lanolin and neomycin – are the most likely allergens to cause trouble in AD. Nickel allergy can be particularly problematic, causing severe lesions beyond the point of contact (Dermatitis. 2012 Nov-Dec;23[6]:275-80).
“Strongly consider patch testing any chronic, difficult to control atopic patient,” especially when AD is not affecting the typical areas – or spreads beyond them – and when it doesn’t respond to the usual treatments. The onset of AD beyond age 5 years is another clue that contact dermatitis might be at work. Patch testing atopic patients is “more likely to be helpful in disease management than scratch or RAST [radioallergosorbent] testing,” Dr. Fowler said.
It’s best if patch testing is done while patients are off immunosuppressants, but current immunosuppressive therapy should not be an absolute contraindication to testing, he said. Not all of them throw off the results. “You do not need to worry about patch testing a patient who is on antihistamines, tumor necrosis factor–alpha inhibitors, NSAIDs, or methotrexate.” However, when it comes to patch testing a patient on cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil, he said, “probably not” (Dermatitis. 2012 Nov-Dec;23[6]:301-3).
Pruritus might or might not be related to the skin issues. For itch caused by skin diseases such as scabies, dermatitis, or psoriasis, “treat the dermatosis to treat the itch,” Dr. Fowler said.
Several topicals can help while the skin problems are being tamed, including hypochlorous acid to stabilize mast cells; strontium 4% hydrogel; and compounded topical ketamine, amitriptyline, and lidocaine, which seems to be particularly helpful (J Am Acad Dermatol. 2017 Apr;76[4]:760-1). Other than for urticaria, antihistamines are of little use, except to provide sedation.
Renal disease, liver disease, lymphoma, and neurologic abnormalities are among the systemic problems that can cause itch; the giveaway is that there’s no primary skin disease, Dr. Fowler said. While systemic problems are being addressed, gabapentin, tricyclic antidepressants, and anxiolytics can help. For generalized pruritus, with no primary skin disease, a referral to a neurologist is essential, he said.
This publication and the Global Academy for Medical Education are owned by Frontline Medical News. Dr. Fowler is a consultant, speaker, and/or researcher for a number of companies, including AbbVie, Regeneron/Sanofi, Allergan, Galderma, and Merck.
When working up patients with allergic contact dermatitis (ACD), the patch test used may depend on how frequently testing is performed in the practice, and the type of allergies that are being evaluated, according to Joseph Fowler Jr., MD, of the department of dermatology at the University of Louisville (Ky).
T.R.U.E. TEST is more convenient than standard patch testing is but misses allergic contact dermatitis up to 40% of the time, he pointed out. The benefit of the T.R.U.E. TEST is that it’s easy to use, allergens come preapplied to a gel-based tape so there’s very little prep time, and they are well standardized with the same quantity on each patch every time.
T.R.U.E. TEST seems to work well for when testing for metal allergies, as well as allergies to topical antibiotics, steroids, and rubber, but not as well for dental implants, fragrances, newer preservatives, surfactants, acrylates, and some industrial and cosmetic allergens. It’s not so effective in many occupational settings, but even so, T.R.U.E. TEST is a good option when testing is performed infrequently, and “is much better than no patch testing at all,” according to Dr. Fowler, who spoke at the Annual Coastal Dermatology Symposium, jointly presented by the University of Louisville and Global Academy for Medical Education.
In a presentation on contact dermatitis and itch, he pointed out that what appears to be atopic dermatitis (AD) in a patient might actually be ACD and that ACD is common in patients with AD and complicates its treatment. Metals, fragrances, and topical components – namely lanolin and neomycin – are the most likely allergens to cause trouble in AD. Nickel allergy can be particularly problematic, causing severe lesions beyond the point of contact (Dermatitis. 2012 Nov-Dec;23[6]:275-80).
“Strongly consider patch testing any chronic, difficult to control atopic patient,” especially when AD is not affecting the typical areas – or spreads beyond them – and when it doesn’t respond to the usual treatments. The onset of AD beyond age 5 years is another clue that contact dermatitis might be at work. Patch testing atopic patients is “more likely to be helpful in disease management than scratch or RAST [radioallergosorbent] testing,” Dr. Fowler said.
It’s best if patch testing is done while patients are off immunosuppressants, but current immunosuppressive therapy should not be an absolute contraindication to testing, he said. Not all of them throw off the results. “You do not need to worry about patch testing a patient who is on antihistamines, tumor necrosis factor–alpha inhibitors, NSAIDs, or methotrexate.” However, when it comes to patch testing a patient on cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil, he said, “probably not” (Dermatitis. 2012 Nov-Dec;23[6]:301-3).
Pruritus might or might not be related to the skin issues. For itch caused by skin diseases such as scabies, dermatitis, or psoriasis, “treat the dermatosis to treat the itch,” Dr. Fowler said.
Several topicals can help while the skin problems are being tamed, including hypochlorous acid to stabilize mast cells; strontium 4% hydrogel; and compounded topical ketamine, amitriptyline, and lidocaine, which seems to be particularly helpful (J Am Acad Dermatol. 2017 Apr;76[4]:760-1). Other than for urticaria, antihistamines are of little use, except to provide sedation.
Renal disease, liver disease, lymphoma, and neurologic abnormalities are among the systemic problems that can cause itch; the giveaway is that there’s no primary skin disease, Dr. Fowler said. While systemic problems are being addressed, gabapentin, tricyclic antidepressants, and anxiolytics can help. For generalized pruritus, with no primary skin disease, a referral to a neurologist is essential, he said.
This publication and the Global Academy for Medical Education are owned by Frontline Medical News. Dr. Fowler is a consultant, speaker, and/or researcher for a number of companies, including AbbVie, Regeneron/Sanofi, Allergan, Galderma, and Merck.
When working up patients with allergic contact dermatitis (ACD), the patch test used may depend on how frequently testing is performed in the practice, and the type of allergies that are being evaluated, according to Joseph Fowler Jr., MD, of the department of dermatology at the University of Louisville (Ky).
T.R.U.E. TEST is more convenient than standard patch testing is but misses allergic contact dermatitis up to 40% of the time, he pointed out. The benefit of the T.R.U.E. TEST is that it’s easy to use, allergens come preapplied to a gel-based tape so there’s very little prep time, and they are well standardized with the same quantity on each patch every time.
T.R.U.E. TEST seems to work well for when testing for metal allergies, as well as allergies to topical antibiotics, steroids, and rubber, but not as well for dental implants, fragrances, newer preservatives, surfactants, acrylates, and some industrial and cosmetic allergens. It’s not so effective in many occupational settings, but even so, T.R.U.E. TEST is a good option when testing is performed infrequently, and “is much better than no patch testing at all,” according to Dr. Fowler, who spoke at the Annual Coastal Dermatology Symposium, jointly presented by the University of Louisville and Global Academy for Medical Education.
In a presentation on contact dermatitis and itch, he pointed out that what appears to be atopic dermatitis (AD) in a patient might actually be ACD and that ACD is common in patients with AD and complicates its treatment. Metals, fragrances, and topical components – namely lanolin and neomycin – are the most likely allergens to cause trouble in AD. Nickel allergy can be particularly problematic, causing severe lesions beyond the point of contact (Dermatitis. 2012 Nov-Dec;23[6]:275-80).
“Strongly consider patch testing any chronic, difficult to control atopic patient,” especially when AD is not affecting the typical areas – or spreads beyond them – and when it doesn’t respond to the usual treatments. The onset of AD beyond age 5 years is another clue that contact dermatitis might be at work. Patch testing atopic patients is “more likely to be helpful in disease management than scratch or RAST [radioallergosorbent] testing,” Dr. Fowler said.
It’s best if patch testing is done while patients are off immunosuppressants, but current immunosuppressive therapy should not be an absolute contraindication to testing, he said. Not all of them throw off the results. “You do not need to worry about patch testing a patient who is on antihistamines, tumor necrosis factor–alpha inhibitors, NSAIDs, or methotrexate.” However, when it comes to patch testing a patient on cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil, he said, “probably not” (Dermatitis. 2012 Nov-Dec;23[6]:301-3).
Pruritus might or might not be related to the skin issues. For itch caused by skin diseases such as scabies, dermatitis, or psoriasis, “treat the dermatosis to treat the itch,” Dr. Fowler said.
Several topicals can help while the skin problems are being tamed, including hypochlorous acid to stabilize mast cells; strontium 4% hydrogel; and compounded topical ketamine, amitriptyline, and lidocaine, which seems to be particularly helpful (J Am Acad Dermatol. 2017 Apr;76[4]:760-1). Other than for urticaria, antihistamines are of little use, except to provide sedation.
Renal disease, liver disease, lymphoma, and neurologic abnormalities are among the systemic problems that can cause itch; the giveaway is that there’s no primary skin disease, Dr. Fowler said. While systemic problems are being addressed, gabapentin, tricyclic antidepressants, and anxiolytics can help. For generalized pruritus, with no primary skin disease, a referral to a neurologist is essential, he said.
This publication and the Global Academy for Medical Education are owned by Frontline Medical News. Dr. Fowler is a consultant, speaker, and/or researcher for a number of companies, including AbbVie, Regeneron/Sanofi, Allergan, Galderma, and Merck.
FROM THE COASTAL DERMATOLOGY SYMPOSIUM
Whose nurse is she/he?
I suspect that there is at least one person in your office or on your team whose name is followed by the initials “RN.” How do you refer to that individual? Do you introduce her as “My nurse Louise”? Or do you say “I would like you to meet Lance, who is one of our nurses”? How often do you say “Rachel will be your nurse today”?
Is there really much difference between “my,” “our,” and “your” in this context? I suspect that most of us unconsciously avoid “my.” But, back in the era when solo practitioner owner/operators walked the earth, “my nurse” was a more frequent descriptor. The system was male dominated and hierarchical. And, of course, the doctor was paying the nurse’s salary.
However, a recent Ethics Rounds in the September 2017 Pediatrics titled “Physician-Nurse Interactions in Critical Care” has gotten me thinking more about what may seem to be semantic hairsplitting between “our nurse” and “your nurse” (doi: 10.1542/peds.2017-0352). The scenario revolves around a young neonatal ICU nurse in her first clinical position who is criticized by her supervisor for advocating for a young mother by questioning the doctor. A good part of the discussion focuses on the ethical dilemma faced by someone whose training has emphasized her obligation to advocate for her patients suddenly finding herself in a situation in which she sees the doctor’s care plan as flawed or at best inadequate. In this particular case, a more experienced nurse would probably already have acquired strategies and a vocabulary that could minimize or avert the conflict. However,
I hope that you have fostered a professional atmosphere that leaves room in which – as well as a process by which – a nurse can question your management of a patient without fear of retribution. Although it is never easy to have your actions questioned, it is certainly easier when the process takes place in a retrospective review rather than when the issue presents itself in the glare of real time and the nurse feels he must speak up now to advocate for the patient adequately.
When the call comes in from a panicked parent at 4 p.m., pleading to have her sick child seen, how does the nurse balance his commitment to the health of the patients against his concern for the doctor’s well being. Occasionally, I hear a nurse erring on the side of being zealous guardians of the doctor’s free time. However, I sense that, day in and day out, it is the nurse’s obligation to the patient that prevails most of the time. I hope I am correct.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”
Email him at [email protected].
I suspect that there is at least one person in your office or on your team whose name is followed by the initials “RN.” How do you refer to that individual? Do you introduce her as “My nurse Louise”? Or do you say “I would like you to meet Lance, who is one of our nurses”? How often do you say “Rachel will be your nurse today”?
Is there really much difference between “my,” “our,” and “your” in this context? I suspect that most of us unconsciously avoid “my.” But, back in the era when solo practitioner owner/operators walked the earth, “my nurse” was a more frequent descriptor. The system was male dominated and hierarchical. And, of course, the doctor was paying the nurse’s salary.
However, a recent Ethics Rounds in the September 2017 Pediatrics titled “Physician-Nurse Interactions in Critical Care” has gotten me thinking more about what may seem to be semantic hairsplitting between “our nurse” and “your nurse” (doi: 10.1542/peds.2017-0352). The scenario revolves around a young neonatal ICU nurse in her first clinical position who is criticized by her supervisor for advocating for a young mother by questioning the doctor. A good part of the discussion focuses on the ethical dilemma faced by someone whose training has emphasized her obligation to advocate for her patients suddenly finding herself in a situation in which she sees the doctor’s care plan as flawed or at best inadequate. In this particular case, a more experienced nurse would probably already have acquired strategies and a vocabulary that could minimize or avert the conflict. However,
I hope that you have fostered a professional atmosphere that leaves room in which – as well as a process by which – a nurse can question your management of a patient without fear of retribution. Although it is never easy to have your actions questioned, it is certainly easier when the process takes place in a retrospective review rather than when the issue presents itself in the glare of real time and the nurse feels he must speak up now to advocate for the patient adequately.
When the call comes in from a panicked parent at 4 p.m., pleading to have her sick child seen, how does the nurse balance his commitment to the health of the patients against his concern for the doctor’s well being. Occasionally, I hear a nurse erring on the side of being zealous guardians of the doctor’s free time. However, I sense that, day in and day out, it is the nurse’s obligation to the patient that prevails most of the time. I hope I am correct.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”
Email him at [email protected].
I suspect that there is at least one person in your office or on your team whose name is followed by the initials “RN.” How do you refer to that individual? Do you introduce her as “My nurse Louise”? Or do you say “I would like you to meet Lance, who is one of our nurses”? How often do you say “Rachel will be your nurse today”?
Is there really much difference between “my,” “our,” and “your” in this context? I suspect that most of us unconsciously avoid “my.” But, back in the era when solo practitioner owner/operators walked the earth, “my nurse” was a more frequent descriptor. The system was male dominated and hierarchical. And, of course, the doctor was paying the nurse’s salary.
However, a recent Ethics Rounds in the September 2017 Pediatrics titled “Physician-Nurse Interactions in Critical Care” has gotten me thinking more about what may seem to be semantic hairsplitting between “our nurse” and “your nurse” (doi: 10.1542/peds.2017-0352). The scenario revolves around a young neonatal ICU nurse in her first clinical position who is criticized by her supervisor for advocating for a young mother by questioning the doctor. A good part of the discussion focuses on the ethical dilemma faced by someone whose training has emphasized her obligation to advocate for her patients suddenly finding herself in a situation in which she sees the doctor’s care plan as flawed or at best inadequate. In this particular case, a more experienced nurse would probably already have acquired strategies and a vocabulary that could minimize or avert the conflict. However,
I hope that you have fostered a professional atmosphere that leaves room in which – as well as a process by which – a nurse can question your management of a patient without fear of retribution. Although it is never easy to have your actions questioned, it is certainly easier when the process takes place in a retrospective review rather than when the issue presents itself in the glare of real time and the nurse feels he must speak up now to advocate for the patient adequately.
When the call comes in from a panicked parent at 4 p.m., pleading to have her sick child seen, how does the nurse balance his commitment to the health of the patients against his concern for the doctor’s well being. Occasionally, I hear a nurse erring on the side of being zealous guardians of the doctor’s free time. However, I sense that, day in and day out, it is the nurse’s obligation to the patient that prevails most of the time. I hope I am correct.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”
Email him at [email protected].
In the reemergence of typhus, the challenge is early diagnosis
SAN DIEGO – Typhus in many forms, particularly scrub typhus, has reemerged worldwide, but none of these rickettsial infections poses a significant public health threat if promptly diagnosed, according to an update presented at an annual scientific meeting on infectious diseases.
Scrub typhus, which is spread by several species of trombiculid mites or chiggers, poses a large threat in regard to typhus epidemics, particularly in Asia, but sporadic cases of different types of typhus are being seen everywhere, including in the United States, according to George M. Varghese, MD, department of infectious diseases, Christian Medical College, Vellore, India.
“The typhus diseases are clinically similar but epidemiologically and etiologically distinct,” reported Dr. Varghese, “but doxycycline is the drug of choice for almost all of the rickettsial infections.”
The bacteria responsible for scrub typhus is Orientia tsutsugamushi, which is no longer included in the genus Rickettsia, but Dr. Varghese, who has published frequently on the epidemiology of scrub typhus, said that it is still appropriately grouped among rickettsial infections. It shares many features with the other rickettsioses, which were considered to be fading but are now resurging after the large epidemics that occurred prior to the introduction of antibiotics.
In the World Wars, Rickettsia prowazekii – which is carried and spread by body lice – was the most well known typhus threat. According to Dr. Varghese, this bacterium may have killed more soldiers in these conflicts than did firearms. Although R. prowazekii has not disappeared as a source of typhus outbreaks, particularly in South America and Africa, there are current epidemics produced from rickettsial infections carried by fleas, such as R. typhi, or ticks, like R. rickettsii, or mice, like R. felis.
For clinical detection of these forms of typhus, there are differences. Although all are associated with a rapid onset of fever, headache, and myalgia, subtle signs can be helpful in making a diagnosis while waiting for laboratory confirmation. For example, scrub typhus, unlike Rocky Mountain Fever, which is caused by tick bites, does not generally include a rash. Rather, eschars, which are small patches of necrotic skin, are far more characteristic.
“Serological tests are the most common diagnostic tool for typhus, but serology may not allow early diagnosis. You can obtain a false positive in the early stages of disease,” Dr. Varghese warned. To speed the diagnosis, he said that looking for the clinical clues characteristic of the suspected form of typhus, such as the scrub typhus-associated eschar, “is valuable.” However, he also emphasized that even with positive serology results, “good epidemiology and history is helpful for laboratory interpretation.”
A variety of serological tests can identify typhus pathogens, but ELISA is now the most widely used, according to Dr. Varghese, noting that this test offers a sensitivity of 93% and a specificity of 91%. Both are higher than those provided by alternatives. As a result of improved sensitivity of diagnostic tests, prevalence rates of some forms of typhus have proved to be unexpectedly high. For example, in a study undertaken in his region of India, the seroprevalence of scrub typhus was 31.8% (Trop Med Int Health. 2017;22:576-82. doi: 10.1111/tmi.12853).
Of unmet needs in the clinical management of typhus, Dr. Varghese listed better strategies for point-of-care diagnosis and treatment and better data on how to manage patients who are severely ill. Advanced disease, which is common to rural areas with limited access to health care, is the source of almost all typhus mortality, according to Dr. Varghese. He described a trial now being initiated in severe disease that will compare intravenous doxycycline to IV azithromycin and to a combination of both IV doxycycline and azithromycin.
Although Dr. Varghese cautioned that reports of resistant typhus infections, particularly in Thailand, might prove to be the next big clinical challenge in typhus, he said that progress is being made toward reducing the burden of this disease in his area of the world. In a disease associated with a mortality of 50% if left untreated, he attributes gains to earlier diagnosis and prompt treatment.
At his medical center, “we have been working with this disease for a decade and a half,” he said, referring to scrub typhus. “When we started off, the mortality was around 15% after diagnosis. Today, the mortality is about 5%-7%.”
Dr. Varghese reported that he has no financial relationships relevant to this topic. The event was the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.
SAN DIEGO – Typhus in many forms, particularly scrub typhus, has reemerged worldwide, but none of these rickettsial infections poses a significant public health threat if promptly diagnosed, according to an update presented at an annual scientific meeting on infectious diseases.
Scrub typhus, which is spread by several species of trombiculid mites or chiggers, poses a large threat in regard to typhus epidemics, particularly in Asia, but sporadic cases of different types of typhus are being seen everywhere, including in the United States, according to George M. Varghese, MD, department of infectious diseases, Christian Medical College, Vellore, India.
“The typhus diseases are clinically similar but epidemiologically and etiologically distinct,” reported Dr. Varghese, “but doxycycline is the drug of choice for almost all of the rickettsial infections.”
The bacteria responsible for scrub typhus is Orientia tsutsugamushi, which is no longer included in the genus Rickettsia, but Dr. Varghese, who has published frequently on the epidemiology of scrub typhus, said that it is still appropriately grouped among rickettsial infections. It shares many features with the other rickettsioses, which were considered to be fading but are now resurging after the large epidemics that occurred prior to the introduction of antibiotics.
In the World Wars, Rickettsia prowazekii – which is carried and spread by body lice – was the most well known typhus threat. According to Dr. Varghese, this bacterium may have killed more soldiers in these conflicts than did firearms. Although R. prowazekii has not disappeared as a source of typhus outbreaks, particularly in South America and Africa, there are current epidemics produced from rickettsial infections carried by fleas, such as R. typhi, or ticks, like R. rickettsii, or mice, like R. felis.
For clinical detection of these forms of typhus, there are differences. Although all are associated with a rapid onset of fever, headache, and myalgia, subtle signs can be helpful in making a diagnosis while waiting for laboratory confirmation. For example, scrub typhus, unlike Rocky Mountain Fever, which is caused by tick bites, does not generally include a rash. Rather, eschars, which are small patches of necrotic skin, are far more characteristic.
“Serological tests are the most common diagnostic tool for typhus, but serology may not allow early diagnosis. You can obtain a false positive in the early stages of disease,” Dr. Varghese warned. To speed the diagnosis, he said that looking for the clinical clues characteristic of the suspected form of typhus, such as the scrub typhus-associated eschar, “is valuable.” However, he also emphasized that even with positive serology results, “good epidemiology and history is helpful for laboratory interpretation.”
A variety of serological tests can identify typhus pathogens, but ELISA is now the most widely used, according to Dr. Varghese, noting that this test offers a sensitivity of 93% and a specificity of 91%. Both are higher than those provided by alternatives. As a result of improved sensitivity of diagnostic tests, prevalence rates of some forms of typhus have proved to be unexpectedly high. For example, in a study undertaken in his region of India, the seroprevalence of scrub typhus was 31.8% (Trop Med Int Health. 2017;22:576-82. doi: 10.1111/tmi.12853).
Of unmet needs in the clinical management of typhus, Dr. Varghese listed better strategies for point-of-care diagnosis and treatment and better data on how to manage patients who are severely ill. Advanced disease, which is common to rural areas with limited access to health care, is the source of almost all typhus mortality, according to Dr. Varghese. He described a trial now being initiated in severe disease that will compare intravenous doxycycline to IV azithromycin and to a combination of both IV doxycycline and azithromycin.
Although Dr. Varghese cautioned that reports of resistant typhus infections, particularly in Thailand, might prove to be the next big clinical challenge in typhus, he said that progress is being made toward reducing the burden of this disease in his area of the world. In a disease associated with a mortality of 50% if left untreated, he attributes gains to earlier diagnosis and prompt treatment.
At his medical center, “we have been working with this disease for a decade and a half,” he said, referring to scrub typhus. “When we started off, the mortality was around 15% after diagnosis. Today, the mortality is about 5%-7%.”
Dr. Varghese reported that he has no financial relationships relevant to this topic. The event was the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.
SAN DIEGO – Typhus in many forms, particularly scrub typhus, has reemerged worldwide, but none of these rickettsial infections poses a significant public health threat if promptly diagnosed, according to an update presented at an annual scientific meeting on infectious diseases.
Scrub typhus, which is spread by several species of trombiculid mites or chiggers, poses a large threat in regard to typhus epidemics, particularly in Asia, but sporadic cases of different types of typhus are being seen everywhere, including in the United States, according to George M. Varghese, MD, department of infectious diseases, Christian Medical College, Vellore, India.
“The typhus diseases are clinically similar but epidemiologically and etiologically distinct,” reported Dr. Varghese, “but doxycycline is the drug of choice for almost all of the rickettsial infections.”
The bacteria responsible for scrub typhus is Orientia tsutsugamushi, which is no longer included in the genus Rickettsia, but Dr. Varghese, who has published frequently on the epidemiology of scrub typhus, said that it is still appropriately grouped among rickettsial infections. It shares many features with the other rickettsioses, which were considered to be fading but are now resurging after the large epidemics that occurred prior to the introduction of antibiotics.
In the World Wars, Rickettsia prowazekii – which is carried and spread by body lice – was the most well known typhus threat. According to Dr. Varghese, this bacterium may have killed more soldiers in these conflicts than did firearms. Although R. prowazekii has not disappeared as a source of typhus outbreaks, particularly in South America and Africa, there are current epidemics produced from rickettsial infections carried by fleas, such as R. typhi, or ticks, like R. rickettsii, or mice, like R. felis.
For clinical detection of these forms of typhus, there are differences. Although all are associated with a rapid onset of fever, headache, and myalgia, subtle signs can be helpful in making a diagnosis while waiting for laboratory confirmation. For example, scrub typhus, unlike Rocky Mountain Fever, which is caused by tick bites, does not generally include a rash. Rather, eschars, which are small patches of necrotic skin, are far more characteristic.
“Serological tests are the most common diagnostic tool for typhus, but serology may not allow early diagnosis. You can obtain a false positive in the early stages of disease,” Dr. Varghese warned. To speed the diagnosis, he said that looking for the clinical clues characteristic of the suspected form of typhus, such as the scrub typhus-associated eschar, “is valuable.” However, he also emphasized that even with positive serology results, “good epidemiology and history is helpful for laboratory interpretation.”
A variety of serological tests can identify typhus pathogens, but ELISA is now the most widely used, according to Dr. Varghese, noting that this test offers a sensitivity of 93% and a specificity of 91%. Both are higher than those provided by alternatives. As a result of improved sensitivity of diagnostic tests, prevalence rates of some forms of typhus have proved to be unexpectedly high. For example, in a study undertaken in his region of India, the seroprevalence of scrub typhus was 31.8% (Trop Med Int Health. 2017;22:576-82. doi: 10.1111/tmi.12853).
Of unmet needs in the clinical management of typhus, Dr. Varghese listed better strategies for point-of-care diagnosis and treatment and better data on how to manage patients who are severely ill. Advanced disease, which is common to rural areas with limited access to health care, is the source of almost all typhus mortality, according to Dr. Varghese. He described a trial now being initiated in severe disease that will compare intravenous doxycycline to IV azithromycin and to a combination of both IV doxycycline and azithromycin.
Although Dr. Varghese cautioned that reports of resistant typhus infections, particularly in Thailand, might prove to be the next big clinical challenge in typhus, he said that progress is being made toward reducing the burden of this disease in his area of the world. In a disease associated with a mortality of 50% if left untreated, he attributes gains to earlier diagnosis and prompt treatment.
At his medical center, “we have been working with this disease for a decade and a half,” he said, referring to scrub typhus. “When we started off, the mortality was around 15% after diagnosis. Today, the mortality is about 5%-7%.”
Dr. Varghese reported that he has no financial relationships relevant to this topic. The event was the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.
AT IDWEEK 2017
Key clinical point:
Major finding: Almost all of the estimated 15,000 annual global deaths attributed to rickettsial infections could be eliminated with prompt doxycycline therapy.
Data source: Topic review.
Disclosures: Dr. Varghese reported that he has no relevant conflicts to disclose.
Study: Macrolide treatment lowers risk of failure in pediatric CAP patients
SAN DIEGO – Macrolide use showed lower treatment failure rates than did amoxicillin or beta-lactam treatment for pediatric community acquired pneumonia (CAP) patients, according to a study presented at an annual scientific meeting on infectious diseases.
While guidelines recommend amoxicillin as the first-line therapy against CAP, investigators have noticed an increase in macrolide prescriptions to pediatric outpatients, despite reported shortcomings in its use against atypical pneumonia.
“Macrolides are probably prescribed out of proportion to the presence of atypical pneumonia in that practice setting,” said Lori Handy, MD, of Children’s Hospital of Philadelphia. This could be an issue, according to Dr. Handy: “We also know that depending on the study, up to 40% of Streptococcus pneumoniae is resistant to macrolides, meaning there are children out there who may have S. pneumoniae who are receiving therapy not targeted at their disease pathogen.”
To examine the possible impact of an increase in macrolide prescriptions, the investigators conducted a retrospective cohort study of 10,470 CAP pediatric patients across 31 primary care practices in the Children’s Hospital of Philadelphia network who were diagnosed between January 2009 and December 2013.
The studied cohort was split into three groups based on treatment options: amoxicillin monotherapy (4,252, 40.6%), macrolide monotherapy (4,459, 42.6%), and broad-spectrum beta-lactams (1,759, 16.8%).
Patient age ranged from 3 months to 18 years, the majority were white, with a roughly equal number of each sex. Of the children studied, 634 (6.1%) experienced treatment failure, defined as a change in antibiotics, an emergency department visit for related symptoms, or hospitalization for pneumonia, all of which had to occur more than 24 hours after a pediatric visit, according to Dr. Handy.
Of the children who failed treatment, 341 (54%) were in the amoxicillin group, 145 (23%) were in the macrolide group, and 147 (23%) were in the broad-spectrum group.
Patients younger than 5 years old who received macrolide therapy were half as likely to experience treatment failure compared with those given amoxicillin (odds ratio [OR] .52 [95% confidence interval (CI), 0.34-0.78]).
“What this translates to in practice is that about 32 children would need to treated with macrolides to prevent one failure in the amoxicillin group,” said Dr. Handy.
Patients 5 years and older showed even lower odds of treatment failure, at approximately one-third the rate of amoxicillin treated patients (OR .31 [95% CI, 0.23-0.92]).
Dr. Handy stated that the retrospective nature of the study and the possibility of changes in the epidemiology of CAP occurring since 2013 should be considered when evaluating the findings.
In addition, she pointed out, CAP is a clinical diagnosis, and there is generally no microbiological data associated with it in order to determine the etiology of the infection.
Overall, in healthy children with CAP, it would be better to use macrolide antibiotics compared with amoxicillin, Dr. Handy concluded. However, without the microbiological data, a more randomized, controlled trial would be needed to determine how to best treat these patients, she added.
During discussion, members of the audience asked about the appropriateness of measuring a change in antibiotics as an endpoint, especially in children with viral pneumonia, who may have had parents request stronger medication when their children did not improve quickly enough.
The 47 patients who were hospitalized would not have provided enough control to properly test the results, Dr. Handy replied, although she did acknowledge the potential issue of viral infections.
She stated the need for further study to assess its possible impact, saying she didn’t know whether viral infections may have skewed their results. “Either they’ve done nothing because they’re equally distributed among the groups or they’ve pushed them one way or the other way,” she said.
Dr. Handy and her colleagues reported having no relevant financial disclosures. The event was the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.
[email protected]
On Twitter @eaztweets
SAN DIEGO – Macrolide use showed lower treatment failure rates than did amoxicillin or beta-lactam treatment for pediatric community acquired pneumonia (CAP) patients, according to a study presented at an annual scientific meeting on infectious diseases.
While guidelines recommend amoxicillin as the first-line therapy against CAP, investigators have noticed an increase in macrolide prescriptions to pediatric outpatients, despite reported shortcomings in its use against atypical pneumonia.
“Macrolides are probably prescribed out of proportion to the presence of atypical pneumonia in that practice setting,” said Lori Handy, MD, of Children’s Hospital of Philadelphia. This could be an issue, according to Dr. Handy: “We also know that depending on the study, up to 40% of Streptococcus pneumoniae is resistant to macrolides, meaning there are children out there who may have S. pneumoniae who are receiving therapy not targeted at their disease pathogen.”
To examine the possible impact of an increase in macrolide prescriptions, the investigators conducted a retrospective cohort study of 10,470 CAP pediatric patients across 31 primary care practices in the Children’s Hospital of Philadelphia network who were diagnosed between January 2009 and December 2013.
The studied cohort was split into three groups based on treatment options: amoxicillin monotherapy (4,252, 40.6%), macrolide monotherapy (4,459, 42.6%), and broad-spectrum beta-lactams (1,759, 16.8%).
Patient age ranged from 3 months to 18 years, the majority were white, with a roughly equal number of each sex. Of the children studied, 634 (6.1%) experienced treatment failure, defined as a change in antibiotics, an emergency department visit for related symptoms, or hospitalization for pneumonia, all of which had to occur more than 24 hours after a pediatric visit, according to Dr. Handy.
Of the children who failed treatment, 341 (54%) were in the amoxicillin group, 145 (23%) were in the macrolide group, and 147 (23%) were in the broad-spectrum group.
Patients younger than 5 years old who received macrolide therapy were half as likely to experience treatment failure compared with those given amoxicillin (odds ratio [OR] .52 [95% confidence interval (CI), 0.34-0.78]).
“What this translates to in practice is that about 32 children would need to treated with macrolides to prevent one failure in the amoxicillin group,” said Dr. Handy.
Patients 5 years and older showed even lower odds of treatment failure, at approximately one-third the rate of amoxicillin treated patients (OR .31 [95% CI, 0.23-0.92]).
Dr. Handy stated that the retrospective nature of the study and the possibility of changes in the epidemiology of CAP occurring since 2013 should be considered when evaluating the findings.
In addition, she pointed out, CAP is a clinical diagnosis, and there is generally no microbiological data associated with it in order to determine the etiology of the infection.
Overall, in healthy children with CAP, it would be better to use macrolide antibiotics compared with amoxicillin, Dr. Handy concluded. However, without the microbiological data, a more randomized, controlled trial would be needed to determine how to best treat these patients, she added.
During discussion, members of the audience asked about the appropriateness of measuring a change in antibiotics as an endpoint, especially in children with viral pneumonia, who may have had parents request stronger medication when their children did not improve quickly enough.
The 47 patients who were hospitalized would not have provided enough control to properly test the results, Dr. Handy replied, although she did acknowledge the potential issue of viral infections.
She stated the need for further study to assess its possible impact, saying she didn’t know whether viral infections may have skewed their results. “Either they’ve done nothing because they’re equally distributed among the groups or they’ve pushed them one way or the other way,” she said.
Dr. Handy and her colleagues reported having no relevant financial disclosures. The event was the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.
[email protected]
On Twitter @eaztweets
SAN DIEGO – Macrolide use showed lower treatment failure rates than did amoxicillin or beta-lactam treatment for pediatric community acquired pneumonia (CAP) patients, according to a study presented at an annual scientific meeting on infectious diseases.
While guidelines recommend amoxicillin as the first-line therapy against CAP, investigators have noticed an increase in macrolide prescriptions to pediatric outpatients, despite reported shortcomings in its use against atypical pneumonia.
“Macrolides are probably prescribed out of proportion to the presence of atypical pneumonia in that practice setting,” said Lori Handy, MD, of Children’s Hospital of Philadelphia. This could be an issue, according to Dr. Handy: “We also know that depending on the study, up to 40% of Streptococcus pneumoniae is resistant to macrolides, meaning there are children out there who may have S. pneumoniae who are receiving therapy not targeted at their disease pathogen.”
To examine the possible impact of an increase in macrolide prescriptions, the investigators conducted a retrospective cohort study of 10,470 CAP pediatric patients across 31 primary care practices in the Children’s Hospital of Philadelphia network who were diagnosed between January 2009 and December 2013.
The studied cohort was split into three groups based on treatment options: amoxicillin monotherapy (4,252, 40.6%), macrolide monotherapy (4,459, 42.6%), and broad-spectrum beta-lactams (1,759, 16.8%).
Patient age ranged from 3 months to 18 years, the majority were white, with a roughly equal number of each sex. Of the children studied, 634 (6.1%) experienced treatment failure, defined as a change in antibiotics, an emergency department visit for related symptoms, or hospitalization for pneumonia, all of which had to occur more than 24 hours after a pediatric visit, according to Dr. Handy.
Of the children who failed treatment, 341 (54%) were in the amoxicillin group, 145 (23%) were in the macrolide group, and 147 (23%) were in the broad-spectrum group.
Patients younger than 5 years old who received macrolide therapy were half as likely to experience treatment failure compared with those given amoxicillin (odds ratio [OR] .52 [95% confidence interval (CI), 0.34-0.78]).
“What this translates to in practice is that about 32 children would need to treated with macrolides to prevent one failure in the amoxicillin group,” said Dr. Handy.
Patients 5 years and older showed even lower odds of treatment failure, at approximately one-third the rate of amoxicillin treated patients (OR .31 [95% CI, 0.23-0.92]).
Dr. Handy stated that the retrospective nature of the study and the possibility of changes in the epidemiology of CAP occurring since 2013 should be considered when evaluating the findings.
In addition, she pointed out, CAP is a clinical diagnosis, and there is generally no microbiological data associated with it in order to determine the etiology of the infection.
Overall, in healthy children with CAP, it would be better to use macrolide antibiotics compared with amoxicillin, Dr. Handy concluded. However, without the microbiological data, a more randomized, controlled trial would be needed to determine how to best treat these patients, she added.
During discussion, members of the audience asked about the appropriateness of measuring a change in antibiotics as an endpoint, especially in children with viral pneumonia, who may have had parents request stronger medication when their children did not improve quickly enough.
The 47 patients who were hospitalized would not have provided enough control to properly test the results, Dr. Handy replied, although she did acknowledge the potential issue of viral infections.
She stated the need for further study to assess its possible impact, saying she didn’t know whether viral infections may have skewed their results. “Either they’ve done nothing because they’re equally distributed among the groups or they’ve pushed them one way or the other way,” she said.
Dr. Handy and her colleagues reported having no relevant financial disclosures. The event was the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.
[email protected]
On Twitter @eaztweets
AT ID WEEK 2017
Key clinical point:
Major finding: Macrolide treatment was associated with treatment failure OR of .52 in patients younger than 5 years and .31 among patients older than 5 years.
Data source: Retrospective study of 10,460 pediatric patients receiving antibiotics for community acquired pneumonia during 2009-2013.
Disclosures: Dr. Handy and her colleagues reported having no relevant financial disclosures.
Rare type of MCL mimics Castleman disease
A rare type of mantle cell lymphoma (MCL) has features that are similar to those of Castleman disease, according to a recent report based on three patient cases.
Lymph node biopsies for these patients initially indicated histologic features consistent with those of plasma cell (PC)-type Castleman disease, reported Takuro Igawa, MD, PhD, of Okayama (Japan) University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, and his coauthors. Further work-up, including flow cytometric analysis and cyclin D1 immunostaining, showed features consistent with those of MCL.
“This rare type of MCL can mimic Castleman disease in the clinical setting and upon histological examination,” Dr. Igawa and his colleagues wrote (Pathol Res Pract. 2017 Sep 18. pii: S0344-0338[17]30684-2. doi: 10.1016/j.prp.2017.09.015). “These confusing characteristics can make the diagnosis challenging, and careful flow cytometric analysis is recommended when a histopathological diagnosis is made.”
The patients in the study, all male, were 51, 74, and 81 years of age. Each presented with systemic lymphadenopathy, along with abnormal laboratory findings that according to the investigators are not usually associated with B-cell lymphomas such as MCL, including anemia, polyclonal IgG hypergammaglobulinemia, and elevated levels of C-reactive protein.
In lymph node biopsy specimens, the MCL component was “masked by histological features of PC-type Castleman disease” such as interfollicular plasmacytosis and atrophic germinal centers, the researchers wrote.
However, further pathologic investigations revealed features that were “essential to distinguish these 3 cases of MCL from PC-type Castleman disease,” they added.
In particular, an abnormal B-cell population was found using flow cytometric analysis, while subsequent cyclin D1 immunostaining in all three cases showed abnormal B-cells primarily in the mantle zone that were positive for CD20 and CD5, both typically expressed by MCL, along with SOX11, which is an “excellent diagnostic marker for MCL, including atypical MCL,” the investigators wrote.
These case reports also provide some evidence that interleukin-6 (IL-6), which is thought to be a driver of Castleman disease, might also be implicated in the pathogenesis of this rare MCL variant. the researchers found that all three cases had positive IL-6 staining in the interfollicular areas.
If further studies confirm the role of IL-6 in this rare setting, “specific treatments other than chemotherapy could potentially be used for patients with MCL with features of Castleman disease, such as an anti-IL-6 receptor antibody (tocilizumab), which is already used for patients with Castleman disease,” they said.
A rare type of mantle cell lymphoma (MCL) has features that are similar to those of Castleman disease, according to a recent report based on three patient cases.
Lymph node biopsies for these patients initially indicated histologic features consistent with those of plasma cell (PC)-type Castleman disease, reported Takuro Igawa, MD, PhD, of Okayama (Japan) University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, and his coauthors. Further work-up, including flow cytometric analysis and cyclin D1 immunostaining, showed features consistent with those of MCL.
“This rare type of MCL can mimic Castleman disease in the clinical setting and upon histological examination,” Dr. Igawa and his colleagues wrote (Pathol Res Pract. 2017 Sep 18. pii: S0344-0338[17]30684-2. doi: 10.1016/j.prp.2017.09.015). “These confusing characteristics can make the diagnosis challenging, and careful flow cytometric analysis is recommended when a histopathological diagnosis is made.”
The patients in the study, all male, were 51, 74, and 81 years of age. Each presented with systemic lymphadenopathy, along with abnormal laboratory findings that according to the investigators are not usually associated with B-cell lymphomas such as MCL, including anemia, polyclonal IgG hypergammaglobulinemia, and elevated levels of C-reactive protein.
In lymph node biopsy specimens, the MCL component was “masked by histological features of PC-type Castleman disease” such as interfollicular plasmacytosis and atrophic germinal centers, the researchers wrote.
However, further pathologic investigations revealed features that were “essential to distinguish these 3 cases of MCL from PC-type Castleman disease,” they added.
In particular, an abnormal B-cell population was found using flow cytometric analysis, while subsequent cyclin D1 immunostaining in all three cases showed abnormal B-cells primarily in the mantle zone that were positive for CD20 and CD5, both typically expressed by MCL, along with SOX11, which is an “excellent diagnostic marker for MCL, including atypical MCL,” the investigators wrote.
These case reports also provide some evidence that interleukin-6 (IL-6), which is thought to be a driver of Castleman disease, might also be implicated in the pathogenesis of this rare MCL variant. the researchers found that all three cases had positive IL-6 staining in the interfollicular areas.
If further studies confirm the role of IL-6 in this rare setting, “specific treatments other than chemotherapy could potentially be used for patients with MCL with features of Castleman disease, such as an anti-IL-6 receptor antibody (tocilizumab), which is already used for patients with Castleman disease,” they said.
A rare type of mantle cell lymphoma (MCL) has features that are similar to those of Castleman disease, according to a recent report based on three patient cases.
Lymph node biopsies for these patients initially indicated histologic features consistent with those of plasma cell (PC)-type Castleman disease, reported Takuro Igawa, MD, PhD, of Okayama (Japan) University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, and his coauthors. Further work-up, including flow cytometric analysis and cyclin D1 immunostaining, showed features consistent with those of MCL.
“This rare type of MCL can mimic Castleman disease in the clinical setting and upon histological examination,” Dr. Igawa and his colleagues wrote (Pathol Res Pract. 2017 Sep 18. pii: S0344-0338[17]30684-2. doi: 10.1016/j.prp.2017.09.015). “These confusing characteristics can make the diagnosis challenging, and careful flow cytometric analysis is recommended when a histopathological diagnosis is made.”
The patients in the study, all male, were 51, 74, and 81 years of age. Each presented with systemic lymphadenopathy, along with abnormal laboratory findings that according to the investigators are not usually associated with B-cell lymphomas such as MCL, including anemia, polyclonal IgG hypergammaglobulinemia, and elevated levels of C-reactive protein.
In lymph node biopsy specimens, the MCL component was “masked by histological features of PC-type Castleman disease” such as interfollicular plasmacytosis and atrophic germinal centers, the researchers wrote.
However, further pathologic investigations revealed features that were “essential to distinguish these 3 cases of MCL from PC-type Castleman disease,” they added.
In particular, an abnormal B-cell population was found using flow cytometric analysis, while subsequent cyclin D1 immunostaining in all three cases showed abnormal B-cells primarily in the mantle zone that were positive for CD20 and CD5, both typically expressed by MCL, along with SOX11, which is an “excellent diagnostic marker for MCL, including atypical MCL,” the investigators wrote.
These case reports also provide some evidence that interleukin-6 (IL-6), which is thought to be a driver of Castleman disease, might also be implicated in the pathogenesis of this rare MCL variant. the researchers found that all three cases had positive IL-6 staining in the interfollicular areas.
If further studies confirm the role of IL-6 in this rare setting, “specific treatments other than chemotherapy could potentially be used for patients with MCL with features of Castleman disease, such as an anti-IL-6 receptor antibody (tocilizumab), which is already used for patients with Castleman disease,” they said.
FROM PATHOLOGY – RESEARCH AND PRACTICE
Key clinical point:
Major finding: Lymph node biopsy revealed histologic features consistent with plasma cell (PC)-type Castleman disease, but cyclin D1 immunostaining and flow cytometric analysis showed features consistent with a diagnosis of MCL.
Data source: A report on three patient cases of MCL with features of PC-type Castleman disease retrieved from surgical pathology consultation files.
Disclosures: The authors reported no conflicts of interest.
Plenary sessions at ANA 2017 cover wide spectrum of neurologic topics
The six plenary sessions of the annual meeting of the American Neurological Association, taking place Oct. 15-17 in San Diego, promise to cover a broad range of research areas, including neuronal circuits and behavior, global neurology, precision medicine, antisense oligonucleotide therapies, and molecular imaging.
The morning of Oct. 15 starts off with the plenary session, “Linking Circuits to Behavior: Promise & Peril,” which seeks to impart how technologies such as optogenetics enable manipulation of discrete neural populations but require careful consideration of the methods for interpreting the resulting data in order to translate it to human functional neuroimaging for potential therapeutic use.
Later, in the afternoon of Oct. 15, the traditional Derek Denny-Brown Young Neurological Scholar Symposium will showcase the presentations from the two clinical science winners and one basic science winner of the Derek Denny-Brown Young Neurological Scholar Awards, as well as the 2017 Distinguished Neurology Teacher Award, the 2017 Grass Foundation ANA Award in Neuroscience, and the 2017 Wolfe Neuropathy Research Prize. The Derek Denny-Brown Young Neurological Scholar Award recognizes neurologists and neuroscientists in the first 10 years of their career at the assistant/associate faculty (equivalent) level who have made outstanding basic and clinical scientific advances toward the prevention, diagnosis, treatment, and cure of neurologic diseases. This year, award winner Keven N. Sheth, MD, of Yale University, New Haven, Conn., will present on “Instructive, Pragmatic, and Successful Trials in Acute Brain Injury: Making Intracerebral Hemorrhage the LEAST Devastating Form of Stroke”; Leslie E. Skolarus, MD, of the University of Michigan, Ann Arbor, will present on “Reducing the Burden of Stroke in a Disadvantaged Community”; and Conrad Chris Weihl, MD, PhD, of Washington University in St. Louis will present on “Connecting Protein Quality Control Pathways in Skeletal Muscle and Muscle Disease.” The 2017 Distinguished Neurology Teacher Award goes to Zachary Nathaniel London, MD, of the University of Michigan, Ann Arbor. The winner of this year’s Grass Foundation ANA Award in Neuroscience, which goes to an outstanding young physician-scientist conducting research in basic or clinical neuroscience, is Clotilde Lagier-Tourenne, MD, PhD, of Massachusetts General Hospital, Boston, who will discuss “Modeling C9ORF72 Disease: A Crucial Step for Therapeutic Development in ALS and Frontotemporal Dementia.” The symposium’s final presentation will have Stefanie Geisler, MD, of Washington University in St. Louis, talk about “Targeting a Core Axonal Degeneration Program to Treat Vincristine and Bortezomib-Induced Axonal Degeneration.” Dr. Geisler won the Wolfe Neuropathy Research Prize, which honors outstanding investigators who identify a new cause or treatment of axonal peripheral neuropathy.
The morning plenary session on Oct. 16 will focus on translational neuroscience efforts that are paying off with discoveries and insights into neurologic disorders that have higher prevalence or greater relevance to low- and middle-income countries. Presentations on these efforts will include discussion of the causation and prevention of Konzo, a distinct upper–motor neuron disease associated with cassava cyanogenic poisoning in sub-Saharan Africa; a case-control study on the impact of multiple mycotoxins on the development of Nodding syndrome in northern Uganda; efforts to address neurologic manifestations of sexually transmitted virus infections in Peru; a longitudinal cohort study of neurologic sequelae in Ebola virus disease survivors in Liberia; efforts to protect against cerebral malaria; the epidemiology of peripheral neuropathy in urban and rural Bangladeshi type 2 diabetes patients; and the use of smartphones and teleconsultations to improve care for people with epilepsy in low- and middle-income countries.
“Precision Medicine in Neurologic Disease” is the theme of four presentations in the afternoon plenary session on Oct. 16. Huda Y. Zoghbi, MD, of Baylor University, and Texas Children’s Hospital in Houston will talk about how her work in animal models of disease has enabled new insights into the effect that certain regulator proteins have on levels of disease-driving proteins such as tau and alpha-synuclein in neurodegenerative diseases. Amy Wagers, PhD, of Harvard Medical School, Boston, will describe her lab’s use of the gene-editing potential of the CRISPR-Cas9 system to fix frame-disrupting mutations in the Duchenne muscular dystrophy gene, DMD, which encodes dystrophin, and produce functional dystrophin expression in muscle stem cells in a mouse model of the disease, which partially recovered functional deficiencies of dystrophic muscle. Donald Berry, PhD, of the University of Texas, M.D. Anderson Cancer Center in Houston plans to discuss the importance of adaptive platform trials – which match therapies to patients – from oncology to neurologic therapy trials and the lessons learned from two major ongoing oncology treatment trials. Cristina Sampaio, MD, PhD, of the CHDI Foundation, aims to inform attendees of the power of prognostic and predictive biomarker-guided trials in neurology to improve the likelihood of success of drug development. Three high-scoring abstracts in the field of precision medicine also will be presented.
The final day of the meeting brings a morning plenary session on “Antisense Oligonucleotide Treatment of Genetic Neurological Diseases” that will focus on the use of antisense oligonucleotides (ASOs) to silence specific genes or alter their pre-mRNA splicing in Duchenne muscular dystrophy, spinal muscular atrophy, Huntington’s disease, amyotrophic lateral sclerosis, and tauopathies. Additional presentations will focus on abstracts about blood and salivary biomarkers in Huntington’s disease and the early efficacy and safety results of an ASO in patients with hereditary transthyretin amyloidosis with polyneuropathy.
The expanding use and development of methods to assess brain pathology in vivo sets the scene for the meeting’s final plenary session, “Molecular Imaging in Neurologic Disease” in the afternoon of Oct. 17. The use of positron emission tomography and single-photon emission computed tomography (SPECT) tracers for glucose metabolism, the dopamine system, amyloid-beta, tau, synaptic markers, and activated microglia has grown substantially to investigate disease mechanisms, develop new therapeutics, and provide diagnostic and prognostic clinical care. Reisa Sperling, MD, of Harvard Medical School, Boston, will provide an overview of the direction of PET ligand use and development in diagnosing early Alzheimer’s disease. Nicolaas I. Bohnen, MD, PhD, of the University of Michigan, Ann Arbor, will describe a hypothesis for how hypercholinergic activity in the brain of Parkinson’s disease patients may for a time compensate for the loss of striatal dopamine and influence the appearance of a tremor-predominant motor phenotype in patients. Richard E. Carson, PhD, of Yale University will focus on the development of PET ligands to monitor synaptic density loss in neuropsychiatric disorders. Noninvasive imaging has also begun to influence research in the detection of neuroinflammation in a wide variety of conditions, with most research focusing on tracers for activated microglia and astrocytes, according to speaker Martin Pomper, MD, PhD, of Johns Hopkins University, Baltimore. The session will conclude with three molecular imaging abstract presentations.
The six plenary sessions of the annual meeting of the American Neurological Association, taking place Oct. 15-17 in San Diego, promise to cover a broad range of research areas, including neuronal circuits and behavior, global neurology, precision medicine, antisense oligonucleotide therapies, and molecular imaging.
The morning of Oct. 15 starts off with the plenary session, “Linking Circuits to Behavior: Promise & Peril,” which seeks to impart how technologies such as optogenetics enable manipulation of discrete neural populations but require careful consideration of the methods for interpreting the resulting data in order to translate it to human functional neuroimaging for potential therapeutic use.
Later, in the afternoon of Oct. 15, the traditional Derek Denny-Brown Young Neurological Scholar Symposium will showcase the presentations from the two clinical science winners and one basic science winner of the Derek Denny-Brown Young Neurological Scholar Awards, as well as the 2017 Distinguished Neurology Teacher Award, the 2017 Grass Foundation ANA Award in Neuroscience, and the 2017 Wolfe Neuropathy Research Prize. The Derek Denny-Brown Young Neurological Scholar Award recognizes neurologists and neuroscientists in the first 10 years of their career at the assistant/associate faculty (equivalent) level who have made outstanding basic and clinical scientific advances toward the prevention, diagnosis, treatment, and cure of neurologic diseases. This year, award winner Keven N. Sheth, MD, of Yale University, New Haven, Conn., will present on “Instructive, Pragmatic, and Successful Trials in Acute Brain Injury: Making Intracerebral Hemorrhage the LEAST Devastating Form of Stroke”; Leslie E. Skolarus, MD, of the University of Michigan, Ann Arbor, will present on “Reducing the Burden of Stroke in a Disadvantaged Community”; and Conrad Chris Weihl, MD, PhD, of Washington University in St. Louis will present on “Connecting Protein Quality Control Pathways in Skeletal Muscle and Muscle Disease.” The 2017 Distinguished Neurology Teacher Award goes to Zachary Nathaniel London, MD, of the University of Michigan, Ann Arbor. The winner of this year’s Grass Foundation ANA Award in Neuroscience, which goes to an outstanding young physician-scientist conducting research in basic or clinical neuroscience, is Clotilde Lagier-Tourenne, MD, PhD, of Massachusetts General Hospital, Boston, who will discuss “Modeling C9ORF72 Disease: A Crucial Step for Therapeutic Development in ALS and Frontotemporal Dementia.” The symposium’s final presentation will have Stefanie Geisler, MD, of Washington University in St. Louis, talk about “Targeting a Core Axonal Degeneration Program to Treat Vincristine and Bortezomib-Induced Axonal Degeneration.” Dr. Geisler won the Wolfe Neuropathy Research Prize, which honors outstanding investigators who identify a new cause or treatment of axonal peripheral neuropathy.
The morning plenary session on Oct. 16 will focus on translational neuroscience efforts that are paying off with discoveries and insights into neurologic disorders that have higher prevalence or greater relevance to low- and middle-income countries. Presentations on these efforts will include discussion of the causation and prevention of Konzo, a distinct upper–motor neuron disease associated with cassava cyanogenic poisoning in sub-Saharan Africa; a case-control study on the impact of multiple mycotoxins on the development of Nodding syndrome in northern Uganda; efforts to address neurologic manifestations of sexually transmitted virus infections in Peru; a longitudinal cohort study of neurologic sequelae in Ebola virus disease survivors in Liberia; efforts to protect against cerebral malaria; the epidemiology of peripheral neuropathy in urban and rural Bangladeshi type 2 diabetes patients; and the use of smartphones and teleconsultations to improve care for people with epilepsy in low- and middle-income countries.
“Precision Medicine in Neurologic Disease” is the theme of four presentations in the afternoon plenary session on Oct. 16. Huda Y. Zoghbi, MD, of Baylor University, and Texas Children’s Hospital in Houston will talk about how her work in animal models of disease has enabled new insights into the effect that certain regulator proteins have on levels of disease-driving proteins such as tau and alpha-synuclein in neurodegenerative diseases. Amy Wagers, PhD, of Harvard Medical School, Boston, will describe her lab’s use of the gene-editing potential of the CRISPR-Cas9 system to fix frame-disrupting mutations in the Duchenne muscular dystrophy gene, DMD, which encodes dystrophin, and produce functional dystrophin expression in muscle stem cells in a mouse model of the disease, which partially recovered functional deficiencies of dystrophic muscle. Donald Berry, PhD, of the University of Texas, M.D. Anderson Cancer Center in Houston plans to discuss the importance of adaptive platform trials – which match therapies to patients – from oncology to neurologic therapy trials and the lessons learned from two major ongoing oncology treatment trials. Cristina Sampaio, MD, PhD, of the CHDI Foundation, aims to inform attendees of the power of prognostic and predictive biomarker-guided trials in neurology to improve the likelihood of success of drug development. Three high-scoring abstracts in the field of precision medicine also will be presented.
The final day of the meeting brings a morning plenary session on “Antisense Oligonucleotide Treatment of Genetic Neurological Diseases” that will focus on the use of antisense oligonucleotides (ASOs) to silence specific genes or alter their pre-mRNA splicing in Duchenne muscular dystrophy, spinal muscular atrophy, Huntington’s disease, amyotrophic lateral sclerosis, and tauopathies. Additional presentations will focus on abstracts about blood and salivary biomarkers in Huntington’s disease and the early efficacy and safety results of an ASO in patients with hereditary transthyretin amyloidosis with polyneuropathy.
The expanding use and development of methods to assess brain pathology in vivo sets the scene for the meeting’s final plenary session, “Molecular Imaging in Neurologic Disease” in the afternoon of Oct. 17. The use of positron emission tomography and single-photon emission computed tomography (SPECT) tracers for glucose metabolism, the dopamine system, amyloid-beta, tau, synaptic markers, and activated microglia has grown substantially to investigate disease mechanisms, develop new therapeutics, and provide diagnostic and prognostic clinical care. Reisa Sperling, MD, of Harvard Medical School, Boston, will provide an overview of the direction of PET ligand use and development in diagnosing early Alzheimer’s disease. Nicolaas I. Bohnen, MD, PhD, of the University of Michigan, Ann Arbor, will describe a hypothesis for how hypercholinergic activity in the brain of Parkinson’s disease patients may for a time compensate for the loss of striatal dopamine and influence the appearance of a tremor-predominant motor phenotype in patients. Richard E. Carson, PhD, of Yale University will focus on the development of PET ligands to monitor synaptic density loss in neuropsychiatric disorders. Noninvasive imaging has also begun to influence research in the detection of neuroinflammation in a wide variety of conditions, with most research focusing on tracers for activated microglia and astrocytes, according to speaker Martin Pomper, MD, PhD, of Johns Hopkins University, Baltimore. The session will conclude with three molecular imaging abstract presentations.
The six plenary sessions of the annual meeting of the American Neurological Association, taking place Oct. 15-17 in San Diego, promise to cover a broad range of research areas, including neuronal circuits and behavior, global neurology, precision medicine, antisense oligonucleotide therapies, and molecular imaging.
The morning of Oct. 15 starts off with the plenary session, “Linking Circuits to Behavior: Promise & Peril,” which seeks to impart how technologies such as optogenetics enable manipulation of discrete neural populations but require careful consideration of the methods for interpreting the resulting data in order to translate it to human functional neuroimaging for potential therapeutic use.
Later, in the afternoon of Oct. 15, the traditional Derek Denny-Brown Young Neurological Scholar Symposium will showcase the presentations from the two clinical science winners and one basic science winner of the Derek Denny-Brown Young Neurological Scholar Awards, as well as the 2017 Distinguished Neurology Teacher Award, the 2017 Grass Foundation ANA Award in Neuroscience, and the 2017 Wolfe Neuropathy Research Prize. The Derek Denny-Brown Young Neurological Scholar Award recognizes neurologists and neuroscientists in the first 10 years of their career at the assistant/associate faculty (equivalent) level who have made outstanding basic and clinical scientific advances toward the prevention, diagnosis, treatment, and cure of neurologic diseases. This year, award winner Keven N. Sheth, MD, of Yale University, New Haven, Conn., will present on “Instructive, Pragmatic, and Successful Trials in Acute Brain Injury: Making Intracerebral Hemorrhage the LEAST Devastating Form of Stroke”; Leslie E. Skolarus, MD, of the University of Michigan, Ann Arbor, will present on “Reducing the Burden of Stroke in a Disadvantaged Community”; and Conrad Chris Weihl, MD, PhD, of Washington University in St. Louis will present on “Connecting Protein Quality Control Pathways in Skeletal Muscle and Muscle Disease.” The 2017 Distinguished Neurology Teacher Award goes to Zachary Nathaniel London, MD, of the University of Michigan, Ann Arbor. The winner of this year’s Grass Foundation ANA Award in Neuroscience, which goes to an outstanding young physician-scientist conducting research in basic or clinical neuroscience, is Clotilde Lagier-Tourenne, MD, PhD, of Massachusetts General Hospital, Boston, who will discuss “Modeling C9ORF72 Disease: A Crucial Step for Therapeutic Development in ALS and Frontotemporal Dementia.” The symposium’s final presentation will have Stefanie Geisler, MD, of Washington University in St. Louis, talk about “Targeting a Core Axonal Degeneration Program to Treat Vincristine and Bortezomib-Induced Axonal Degeneration.” Dr. Geisler won the Wolfe Neuropathy Research Prize, which honors outstanding investigators who identify a new cause or treatment of axonal peripheral neuropathy.
The morning plenary session on Oct. 16 will focus on translational neuroscience efforts that are paying off with discoveries and insights into neurologic disorders that have higher prevalence or greater relevance to low- and middle-income countries. Presentations on these efforts will include discussion of the causation and prevention of Konzo, a distinct upper–motor neuron disease associated with cassava cyanogenic poisoning in sub-Saharan Africa; a case-control study on the impact of multiple mycotoxins on the development of Nodding syndrome in northern Uganda; efforts to address neurologic manifestations of sexually transmitted virus infections in Peru; a longitudinal cohort study of neurologic sequelae in Ebola virus disease survivors in Liberia; efforts to protect against cerebral malaria; the epidemiology of peripheral neuropathy in urban and rural Bangladeshi type 2 diabetes patients; and the use of smartphones and teleconsultations to improve care for people with epilepsy in low- and middle-income countries.
“Precision Medicine in Neurologic Disease” is the theme of four presentations in the afternoon plenary session on Oct. 16. Huda Y. Zoghbi, MD, of Baylor University, and Texas Children’s Hospital in Houston will talk about how her work in animal models of disease has enabled new insights into the effect that certain regulator proteins have on levels of disease-driving proteins such as tau and alpha-synuclein in neurodegenerative diseases. Amy Wagers, PhD, of Harvard Medical School, Boston, will describe her lab’s use of the gene-editing potential of the CRISPR-Cas9 system to fix frame-disrupting mutations in the Duchenne muscular dystrophy gene, DMD, which encodes dystrophin, and produce functional dystrophin expression in muscle stem cells in a mouse model of the disease, which partially recovered functional deficiencies of dystrophic muscle. Donald Berry, PhD, of the University of Texas, M.D. Anderson Cancer Center in Houston plans to discuss the importance of adaptive platform trials – which match therapies to patients – from oncology to neurologic therapy trials and the lessons learned from two major ongoing oncology treatment trials. Cristina Sampaio, MD, PhD, of the CHDI Foundation, aims to inform attendees of the power of prognostic and predictive biomarker-guided trials in neurology to improve the likelihood of success of drug development. Three high-scoring abstracts in the field of precision medicine also will be presented.
The final day of the meeting brings a morning plenary session on “Antisense Oligonucleotide Treatment of Genetic Neurological Diseases” that will focus on the use of antisense oligonucleotides (ASOs) to silence specific genes or alter their pre-mRNA splicing in Duchenne muscular dystrophy, spinal muscular atrophy, Huntington’s disease, amyotrophic lateral sclerosis, and tauopathies. Additional presentations will focus on abstracts about blood and salivary biomarkers in Huntington’s disease and the early efficacy and safety results of an ASO in patients with hereditary transthyretin amyloidosis with polyneuropathy.
The expanding use and development of methods to assess brain pathology in vivo sets the scene for the meeting’s final plenary session, “Molecular Imaging in Neurologic Disease” in the afternoon of Oct. 17. The use of positron emission tomography and single-photon emission computed tomography (SPECT) tracers for glucose metabolism, the dopamine system, amyloid-beta, tau, synaptic markers, and activated microglia has grown substantially to investigate disease mechanisms, develop new therapeutics, and provide diagnostic and prognostic clinical care. Reisa Sperling, MD, of Harvard Medical School, Boston, will provide an overview of the direction of PET ligand use and development in diagnosing early Alzheimer’s disease. Nicolaas I. Bohnen, MD, PhD, of the University of Michigan, Ann Arbor, will describe a hypothesis for how hypercholinergic activity in the brain of Parkinson’s disease patients may for a time compensate for the loss of striatal dopamine and influence the appearance of a tremor-predominant motor phenotype in patients. Richard E. Carson, PhD, of Yale University will focus on the development of PET ligands to monitor synaptic density loss in neuropsychiatric disorders. Noninvasive imaging has also begun to influence research in the detection of neuroinflammation in a wide variety of conditions, with most research focusing on tracers for activated microglia and astrocytes, according to speaker Martin Pomper, MD, PhD, of Johns Hopkins University, Baltimore. The session will conclude with three molecular imaging abstract presentations.
VCR regimen showed efficacy in mantle cell and indolent lymphomas
The combination of bortezomib, cladribine, and rituximab (VCR) was an effective treatment regimen for patients with CD20-positive mantle cell lymphoma (MCL) and indolent non-Hodgkin’s lymphoma (iNHL), based on results of a recent phase 2, open-label study.
The overall response rate was 92% in the single-center, 24-patient study. The 2-year progression-free survival (PFS) was 82% and 54%, respectively, for MCL and iNHL patients; PFS was 80% for treatment-naive patients and 57% for those with refractory/recalcitrant disease, according to Soham D. Puvvada, MD, of the University of Arizona Cancer Center in Tucson, and her associates.
Two-year overall survival was 91% for MCL and 69% for iNHL patients. Median time to progression was 34.5 months, and median PFS had not been reached at 2 years, according to the researchers.
While the study (NCT00980395) was small and limited by its single-center design, the VCR combination “has encouraging activity in both MCL and iNHL and could be compared to standard therapies in future studies,” the researchers wrote. “For MCL in particular, we believe a noninferiority comparison to standard therapies would be justified by our results.”
Adverse events were most commonly hematologic, and three patients experienced febrile neutropenia, data show.
“Although hematological toxicity can be an issue, the regimen provides an alternative option in transplant ineligible relapsed/refractory MCL and iNHL,” wrote Dr. Puvvada and her colleagues. The study was published in Clinical Lymphoma, Myeloma & Leukemia (doi: 10.1016/j.clml.2017.09.001).
The researchers studied the combination of bortezomib, the proteasome inhibitor initially approved for relapsed/refractory MCL, cladribine, which has shown activity and promising response rates in patients with indolent lymphomas, and rituximab in patients with CD20-positive mantle cell or indolent lymphoma.
Patients with follicular lymphomas were eligible to be included in the study if they had received at least one previous line of therapy. All other participants could be treatment naive or have relapsed after previous treatment.
Of the 24 patients enrolled, 11 had MCL, 5 had follicular lymphoma, 4 had marginal zone lymphoma, 3 had lymphoplasmacytic lymphoma, and 1 had small lymphocytic lymphoma.
The VCR regimen, given every 28 days for no more than six cycles, included rituximab at 375 mg/m2 given intravenously on day 1 of each cycle, cladribine 4 mg/m2 given intravenously over 2 hours on days 1 through 5, and bortezomib 1.3 mg/m2 given intravenously on days 1 and 4. Patients received a median of five cycles of therapy.
Adverse events of grade 3 or greater occurred in 14 patients (58%); 8 patients had leukopenia, 6 had thrombocytopenia, 5 had fatigue, and 5 had neutropenia, which included febrile neutropenia in 3 patients.
With a median follow-up of 38.5 months, overall response rate for VCR was 96%. Complete responses occurred in 8 of 23 evaluable patients (35%) and partial responses in 14 more patients (61%).
The combination of bortezomib, cladribine, and rituximab (VCR) was an effective treatment regimen for patients with CD20-positive mantle cell lymphoma (MCL) and indolent non-Hodgkin’s lymphoma (iNHL), based on results of a recent phase 2, open-label study.
The overall response rate was 92% in the single-center, 24-patient study. The 2-year progression-free survival (PFS) was 82% and 54%, respectively, for MCL and iNHL patients; PFS was 80% for treatment-naive patients and 57% for those with refractory/recalcitrant disease, according to Soham D. Puvvada, MD, of the University of Arizona Cancer Center in Tucson, and her associates.
Two-year overall survival was 91% for MCL and 69% for iNHL patients. Median time to progression was 34.5 months, and median PFS had not been reached at 2 years, according to the researchers.
While the study (NCT00980395) was small and limited by its single-center design, the VCR combination “has encouraging activity in both MCL and iNHL and could be compared to standard therapies in future studies,” the researchers wrote. “For MCL in particular, we believe a noninferiority comparison to standard therapies would be justified by our results.”
Adverse events were most commonly hematologic, and three patients experienced febrile neutropenia, data show.
“Although hematological toxicity can be an issue, the regimen provides an alternative option in transplant ineligible relapsed/refractory MCL and iNHL,” wrote Dr. Puvvada and her colleagues. The study was published in Clinical Lymphoma, Myeloma & Leukemia (doi: 10.1016/j.clml.2017.09.001).
The researchers studied the combination of bortezomib, the proteasome inhibitor initially approved for relapsed/refractory MCL, cladribine, which has shown activity and promising response rates in patients with indolent lymphomas, and rituximab in patients with CD20-positive mantle cell or indolent lymphoma.
Patients with follicular lymphomas were eligible to be included in the study if they had received at least one previous line of therapy. All other participants could be treatment naive or have relapsed after previous treatment.
Of the 24 patients enrolled, 11 had MCL, 5 had follicular lymphoma, 4 had marginal zone lymphoma, 3 had lymphoplasmacytic lymphoma, and 1 had small lymphocytic lymphoma.
The VCR regimen, given every 28 days for no more than six cycles, included rituximab at 375 mg/m2 given intravenously on day 1 of each cycle, cladribine 4 mg/m2 given intravenously over 2 hours on days 1 through 5, and bortezomib 1.3 mg/m2 given intravenously on days 1 and 4. Patients received a median of five cycles of therapy.
Adverse events of grade 3 or greater occurred in 14 patients (58%); 8 patients had leukopenia, 6 had thrombocytopenia, 5 had fatigue, and 5 had neutropenia, which included febrile neutropenia in 3 patients.
With a median follow-up of 38.5 months, overall response rate for VCR was 96%. Complete responses occurred in 8 of 23 evaluable patients (35%) and partial responses in 14 more patients (61%).
The combination of bortezomib, cladribine, and rituximab (VCR) was an effective treatment regimen for patients with CD20-positive mantle cell lymphoma (MCL) and indolent non-Hodgkin’s lymphoma (iNHL), based on results of a recent phase 2, open-label study.
The overall response rate was 92% in the single-center, 24-patient study. The 2-year progression-free survival (PFS) was 82% and 54%, respectively, for MCL and iNHL patients; PFS was 80% for treatment-naive patients and 57% for those with refractory/recalcitrant disease, according to Soham D. Puvvada, MD, of the University of Arizona Cancer Center in Tucson, and her associates.
Two-year overall survival was 91% for MCL and 69% for iNHL patients. Median time to progression was 34.5 months, and median PFS had not been reached at 2 years, according to the researchers.
While the study (NCT00980395) was small and limited by its single-center design, the VCR combination “has encouraging activity in both MCL and iNHL and could be compared to standard therapies in future studies,” the researchers wrote. “For MCL in particular, we believe a noninferiority comparison to standard therapies would be justified by our results.”
Adverse events were most commonly hematologic, and three patients experienced febrile neutropenia, data show.
“Although hematological toxicity can be an issue, the regimen provides an alternative option in transplant ineligible relapsed/refractory MCL and iNHL,” wrote Dr. Puvvada and her colleagues. The study was published in Clinical Lymphoma, Myeloma & Leukemia (doi: 10.1016/j.clml.2017.09.001).
The researchers studied the combination of bortezomib, the proteasome inhibitor initially approved for relapsed/refractory MCL, cladribine, which has shown activity and promising response rates in patients with indolent lymphomas, and rituximab in patients with CD20-positive mantle cell or indolent lymphoma.
Patients with follicular lymphomas were eligible to be included in the study if they had received at least one previous line of therapy. All other participants could be treatment naive or have relapsed after previous treatment.
Of the 24 patients enrolled, 11 had MCL, 5 had follicular lymphoma, 4 had marginal zone lymphoma, 3 had lymphoplasmacytic lymphoma, and 1 had small lymphocytic lymphoma.
The VCR regimen, given every 28 days for no more than six cycles, included rituximab at 375 mg/m2 given intravenously on day 1 of each cycle, cladribine 4 mg/m2 given intravenously over 2 hours on days 1 through 5, and bortezomib 1.3 mg/m2 given intravenously on days 1 and 4. Patients received a median of five cycles of therapy.
Adverse events of grade 3 or greater occurred in 14 patients (58%); 8 patients had leukopenia, 6 had thrombocytopenia, 5 had fatigue, and 5 had neutropenia, which included febrile neutropenia in 3 patients.
With a median follow-up of 38.5 months, overall response rate for VCR was 96%. Complete responses occurred in 8 of 23 evaluable patients (35%) and partial responses in 14 more patients (61%).
FROM LYMPHOMA, MYELOMA & LEUKEMIA
Key clinical point:
Major finding: The overall response rate was 92%, with a 2-year PFS of 82% and 54% for patients with mantle cell lymphoma (MCL) and indolent non-Hodgkin’s lymphoma (iNHL), respectively. Adverse events were most commonly hematologic, and three patients experienced febrile neutropenia.
Data source: A phase 2, open-label study including 24 patients with mantle cell or indolent lymphomas.
Disclosures: No disclosures were reported in the accepted manuscript.
FDA approves test to screen donated blood for Zika virus
The cobas Zika test has been approved for detecting the virus in whole blood, blood components, and donated organs, the U.S. Food and Drug Administration announced in a press release.
“Today’s action represents the first approval of a Zika virus detection test for use with screening the nation’s blood supply,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in a press release. “Screening blood donations for the Zika virus is critical to preventing infected donations from entering the U.S. blood supply.”
In August 2016, the FDA issued a final guidance document recommending that all individual units of whole blood and blood components be screened with an investigational blood screening test available under an investigational new drug application. Data obtained on the cobas Zika test under its investigational new drug application and from additional studies performed by the manufacturer demonstrated that the cobas Zika test is effective. Testing individual samples from blood donations at five external laboratory sites resulted in a clinical specificity exceeding 99%.
The cobas Zika test is intended for use on the fully automated cobas 6800 and cobas 8800 systems. The cobas Zika test, cobas 6800, and cobas 8800 systems are manufactured by Roche Molecular Systems.
The cobas Zika test has been approved for detecting the virus in whole blood, blood components, and donated organs, the U.S. Food and Drug Administration announced in a press release.
“Today’s action represents the first approval of a Zika virus detection test for use with screening the nation’s blood supply,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in a press release. “Screening blood donations for the Zika virus is critical to preventing infected donations from entering the U.S. blood supply.”
In August 2016, the FDA issued a final guidance document recommending that all individual units of whole blood and blood components be screened with an investigational blood screening test available under an investigational new drug application. Data obtained on the cobas Zika test under its investigational new drug application and from additional studies performed by the manufacturer demonstrated that the cobas Zika test is effective. Testing individual samples from blood donations at five external laboratory sites resulted in a clinical specificity exceeding 99%.
The cobas Zika test is intended for use on the fully automated cobas 6800 and cobas 8800 systems. The cobas Zika test, cobas 6800, and cobas 8800 systems are manufactured by Roche Molecular Systems.
The cobas Zika test has been approved for detecting the virus in whole blood, blood components, and donated organs, the U.S. Food and Drug Administration announced in a press release.
“Today’s action represents the first approval of a Zika virus detection test for use with screening the nation’s blood supply,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in a press release. “Screening blood donations for the Zika virus is critical to preventing infected donations from entering the U.S. blood supply.”
In August 2016, the FDA issued a final guidance document recommending that all individual units of whole blood and blood components be screened with an investigational blood screening test available under an investigational new drug application. Data obtained on the cobas Zika test under its investigational new drug application and from additional studies performed by the manufacturer demonstrated that the cobas Zika test is effective. Testing individual samples from blood donations at five external laboratory sites resulted in a clinical specificity exceeding 99%.
The cobas Zika test is intended for use on the fully automated cobas 6800 and cobas 8800 systems. The cobas Zika test, cobas 6800, and cobas 8800 systems are manufactured by Roche Molecular Systems.