Kerri Wachter

Catheter-associated urinary tract infection (CAUTI) is a large problem for most hospitals but one that can be prevented with the adoption of the right technical evidence and behavior-changing strategies, according to a patient safety expert.

"Preventing CAUTI is no different than preventing other patient safety problems, in that there are technical aspects ... and socioadaptive components – and these are critically important," Dr. Sanjay Saint said during a webinar sponsored by National Priorities Partnership and the Partnership for Patients.

It’s estimated that CAUTI costs approximately $400 million each year. More important, as many as 380,000 infections and 9,000 deaths related to CAUTI each year could be prevented, according to the Centers for Disease Control and Prevention.

In terms of the technical aspects, the No. 1 rule of UTI prevention is to make sure that the patient really needs the catheter. (See related video.) Appropriate indications include bladder outlet obstruction, incontinence/sacral wound, urine-output monitoring, patient’s request (end of life), and during or just after surgery, said Dr. Saint, who is a professor of medicine at the Veterans Affairs Medical Center and the University of Michigan, both in Ann Arbor.

One reason that catheters are used inappropriately is that physicians are unaware that a catheter is being used, he said. In one study, researchers found that 18%, 25%, and 38% of residents, house officers, and attending physicians, respectively, were unaware of the catheter (Am. J. Med. 2000;109:476-80).

There have been four recent guidelines on CAUTI prevention, said Dr. Saint. In general, these recommendations can be remembered by the mnemonic "ABCDE":

"Preventing CAUTI is absolutely a team sport."

• Adherence to infection control principles (aseptic insertion, proper maintenance, education) is vital.

• Bladder ultrasound may avoid catheterization.

• Condom or intermittent catheterization is appropriate in certain patients.

• Do not use the indwelling catheter unless you must.

• Early removal of the catheter using reminders or stop-orders appears warranted.

To understand the socioadaptive side of infection prevention, Dr. Saint and his colleagues conducted a national mixed-methods study – why some hospitals are better at preventing infection than are others. It included phone interviews and site visits to hospitals across the United States to identify barriers to and facilitators of the use of evidence-based practices to prevent infection (Infect. Control Hosp. Epidemiol. 2008;29:333-41).

They identified two key barriers: "active resisters" and "organization constipators."

Active resisters are people who prefer doing things the way they have always done them (Acad. Manag. Rev. 2008;33:362-77).

Organization constipators are passive-aggressives who undermine change without active resistance (Jt. Comm. J. Qual. Patient Saf. 2009;35:449-55).

The most important key facilitator is leadership at all levels – not just the director – but also infection-prevention personnel, patient-safety officers, hospitalists, ED physicians, chief medical officers, and nurse managers. "Engaging leadership is critically important, and we found that leadership at all levels is important," he said.

They also identified four key behaviors of effective infection prevention leaders (Infect. Control Hosp. Epidemiol. 2000;21:375-80):

• Cultivating a culture of clinical excellence with a clear vision that is successfully conveyed to the staff.

• Inspiring staff by motivating and energizing followers.

• Being solution oriented: focusing on overcoming barriers rather than complaining and dealing directly with resistant staff.

• Thinking strategically, while acting locally. Planning ahead and leaving little to chance; politicking before crucial issues come up for a vote in committees.

"Preventing CAUTI is absolutely a team sport," Dr. Saint concluded.

Dr. Saint has not reported any relevant financial relationships.

Catheter-associated urinary tract infection (CAUTI) is a large problem for most hospitals but one that can be prevented with the adoption of the right technical evidence and behavior-changing strategies, according to a patient safety expert.

"Preventing CAUTI is no different than preventing other patient safety problems, in that there are technical aspects ... and socioadaptive components – and these are critically important," Dr. Sanjay Saint said during a webinar sponsored by National Priorities Partnership and the Partnership for Patients.

It’s estimated that CAUTI costs approximately $400 million each year. More important, as many as 380,000 infections and 9,000 deaths related to CAUTI each year could be prevented, according to the Centers for Disease Control and Prevention.

In terms of the technical aspects, the No. 1 rule of UTI prevention is to make sure that the patient really needs the catheter. (See related video.) Appropriate indications include bladder outlet obstruction, incontinence/sacral wound, urine-output monitoring, patient’s request (end of life), and during or just after surgery, said Dr. Saint, who is a professor of medicine at the Veterans Affairs Medical Center and the University of Michigan, both in Ann Arbor.

One reason that catheters are used inappropriately is that physicians are unaware that a catheter is being used, he said. In one study, researchers found that 18%, 25%, and 38% of residents, house officers, and attending physicians, respectively, were unaware of the catheter (Am. J. Med. 2000;109:476-80).

There have been four recent guidelines on CAUTI prevention, said Dr. Saint. In general, these recommendations can be remembered by the mnemonic "ABCDE":

"Preventing CAUTI is absolutely a team sport."

• Adherence to infection control principles (aseptic insertion, proper maintenance, education) is vital.

• Bladder ultrasound may avoid catheterization.

• Condom or intermittent catheterization is appropriate in certain patients.

• Do not use the indwelling catheter unless you must.

• Early removal of the catheter using reminders or stop-orders appears warranted.

To understand the socioadaptive side of infection prevention, Dr. Saint and his colleagues conducted a national mixed-methods study – why some hospitals are better at preventing infection than are others. It included phone interviews and site visits to hospitals across the United States to identify barriers to and facilitators of the use of evidence-based practices to prevent infection (Infect. Control Hosp. Epidemiol. 2008;29:333-41).

They identified two key barriers: "active resisters" and "organization constipators."

Active resisters are people who prefer doing things the way they have always done them (Acad. Manag. Rev. 2008;33:362-77).

Organization constipators are passive-aggressives who undermine change without active resistance (Jt. Comm. J. Qual. Patient Saf. 2009;35:449-55).

The most important key facilitator is leadership at all levels – not just the director – but also infection-prevention personnel, patient-safety officers, hospitalists, ED physicians, chief medical officers, and nurse managers. "Engaging leadership is critically important, and we found that leadership at all levels is important," he said.

They also identified four key behaviors of effective infection prevention leaders (Infect. Control Hosp. Epidemiol. 2000;21:375-80):

• Cultivating a culture of clinical excellence with a clear vision that is successfully conveyed to the staff.

• Inspiring staff by motivating and energizing followers.

• Being solution oriented: focusing on overcoming barriers rather than complaining and dealing directly with resistant staff.

• Thinking strategically, while acting locally. Planning ahead and leaving little to chance; politicking before crucial issues come up for a vote in committees.

"Preventing CAUTI is absolutely a team sport," Dr. Saint concluded.

Dr. Saint has not reported any relevant financial relationships.

Catheter-associated urinary tract infection (CAUTI) is a large problem for most hospitals but one that can be prevented with the adoption of the right technical evidence and behavior-changing strategies, according to a patient safety expert.

"Preventing CAUTI is no different than preventing other patient safety problems, in that there are technical aspects ... and socioadaptive components – and these are critically important," Dr. Sanjay Saint said during a webinar sponsored by National Priorities Partnership and the Partnership for Patients.

It’s estimated that CAUTI costs approximately $400 million each year. More important, as many as 380,000 infections and 9,000 deaths related to CAUTI each year could be prevented, according to the Centers for Disease Control and Prevention.

In terms of the technical aspects, the No. 1 rule of UTI prevention is to make sure that the patient really needs the catheter. (See related video.) Appropriate indications include bladder outlet obstruction, incontinence/sacral wound, urine-output monitoring, patient’s request (end of life), and during or just after surgery, said Dr. Saint, who is a professor of medicine at the Veterans Affairs Medical Center and the University of Michigan, both in Ann Arbor.

One reason that catheters are used inappropriately is that physicians are unaware that a catheter is being used, he said. In one study, researchers found that 18%, 25%, and 38% of residents, house officers, and attending physicians, respectively, were unaware of the catheter (Am. J. Med. 2000;109:476-80).

There have been four recent guidelines on CAUTI prevention, said Dr. Saint. In general, these recommendations can be remembered by the mnemonic "ABCDE":

"Preventing CAUTI is absolutely a team sport."

• Adherence to infection control principles (aseptic insertion, proper maintenance, education) is vital.

• Bladder ultrasound may avoid catheterization.

• Condom or intermittent catheterization is appropriate in certain patients.

• Do not use the indwelling catheter unless you must.

• Early removal of the catheter using reminders or stop-orders appears warranted.

To understand the socioadaptive side of infection prevention, Dr. Saint and his colleagues conducted a national mixed-methods study – why some hospitals are better at preventing infection than are others. It included phone interviews and site visits to hospitals across the United States to identify barriers to and facilitators of the use of evidence-based practices to prevent infection (Infect. Control Hosp. Epidemiol. 2008;29:333-41).

They identified two key barriers: "active resisters" and "organization constipators."

Active resisters are people who prefer doing things the way they have always done them (Acad. Manag. Rev. 2008;33:362-77).

Organization constipators are passive-aggressives who undermine change without active resistance (Jt. Comm. J. Qual. Patient Saf. 2009;35:449-55).

The most important key facilitator is leadership at all levels – not just the director – but also infection-prevention personnel, patient-safety officers, hospitalists, ED physicians, chief medical officers, and nurse managers. "Engaging leadership is critically important, and we found that leadership at all levels is important," he said.

They also identified four key behaviors of effective infection prevention leaders (Infect. Control Hosp. Epidemiol. 2000;21:375-80):

• Cultivating a culture of clinical excellence with a clear vision that is successfully conveyed to the staff.

• Inspiring staff by motivating and energizing followers.

• Being solution oriented: focusing on overcoming barriers rather than complaining and dealing directly with resistant staff.

• Thinking strategically, while acting locally. Planning ahead and leaving little to chance; politicking before crucial issues come up for a vote in committees.

"Preventing CAUTI is absolutely a team sport," Dr. Saint concluded.

Dr. Saint has not reported any relevant financial relationships.

STOCKHOLM – Adding the investigational drug iniparib to a gemcitabine and cisplatin doublet failed to improve outcomes significantly in a phase II study of 119 patients with advanced non–small-cell lung cancer.

The disappointing result follows a phase III trial in which iniparib failed to confirm survival gains when added to gemcitabine (Gemzar) and carboplatin chemotherapy in patients with metastatic triple-negative breast cancer.

Iniparib (BSI-201) had been the leading agent in a new class of therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, but the phase III flop in breast cancer left researchers questioning whether it has a different mechanism of action.

In the current lung cancer trial, median progression-free survival was slightly longer at 5.7 months in those who received iniparib in addition to gemcitabine/cisplatinchemotherapy, compared with 4.3 months for those on gemcitabine/cisplatin alone. The difference was not statistically significant, however (hazard ratio, 0.89; P = .48).

Based on preliminary data at a median follow-up of 8.4 months, median overall survival was 8.5 months for the doublet-only arm and 11.2 months for the iniparib arm, Dr. Silvia Novello reported at the European Multidisciplinary Cancer Congress. Both survival measures were secondary end points.

"Be cautious when interpreting the 1.4-month increase in median progression-free survival and when interpreting the preliminary 2.7 months in median OS [overall survival] seen in the investigational arm vs. the chemotherapy arm because this could be due to differences in baseline patient characteristics," Dr. Novello told attendees at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

In particular, ECOG (Eastern Cooperative Oncology Group) performance status and sex were not balanced, with more patients having a performance status of 0 (61% vs. 49%) and more men (80% vs. 67%) in the investigational arm than in the control group, explained Dr. Novello, a thoracic oncologist at the University of Torino (Italy).

The study’s primary end point was overall response rate as determined by investigators using RECIST 1.1. The investigators previously reported this measure of complete and partial responses was higher in the control group – 26% for those on gemcitabine/cisplatin alone and 20% for those in the doublet plus iniparib group. The only complete response was in a patient given iniparib.

The study included patients who had measurable, untreated stage IV non–small-cell lung cancer (NSCLC) and an ECOG performance status of 0-1. They were randomized 2:1 to receive gemcitabine/cisplatin plus iniparib (80 patients) or gemcitabine/cisplatin alone (39 patients).

Roughly half of patients in each group completed five to six cycles – 44% vs. 50% for the chemotherapy and investigational arms.

Gemcitabine 1,250 mg/m² was given intravenously on days 1 and 8, and cisplatin was given 75 mg/m² intravenously on day 1 in 21-day cycles. Iniparib 5.6 mg/kg also was given intravenously on days 1, 4, 8, and 11 in the experimental arm. Patients underwent a maximum of six cycles, with no maintenance phase.

Safety data showed 82% of the chemotherapy arm and 85% of the iniparib arm had any grade 3/4 treatment-emergent adverse events.

Anemia and nausea were more common in the iniparib arm, but other common adverse events were essentially the same.

Biomarker studies are ongoing potentially to define a subgroup of patients who may benefit from iniparib treatment, according to Dr. Novello.

Invited discussant Dr. Luis Paz-Ares, medial oncology chief of service at Hospital Universitario Virgen del Rocio in Seville, Spain, emphasized the importance of this substudy. "I think it would be very relevant to know if there are some subsets of patients that may benefit," he said. "I think the main part of this trial is the markers, and I will be very interested to see the results of this."

The study is sponsored by Sanofi-Aventis in collaboration with BiPar Sciences. Dr. Novello has previously reported that she has no relevant financial disclosures.

STOCKHOLM – Adding the investigational drug iniparib to a gemcitabine and cisplatin doublet failed to improve outcomes significantly in a phase II study of 119 patients with advanced non–small-cell lung cancer.

The disappointing result follows a phase III trial in which iniparib failed to confirm survival gains when added to gemcitabine (Gemzar) and carboplatin chemotherapy in patients with metastatic triple-negative breast cancer.

Iniparib (BSI-201) had been the leading agent in a new class of therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, but the phase III flop in breast cancer left researchers questioning whether it has a different mechanism of action.

In the current lung cancer trial, median progression-free survival was slightly longer at 5.7 months in those who received iniparib in addition to gemcitabine/cisplatinchemotherapy, compared with 4.3 months for those on gemcitabine/cisplatin alone. The difference was not statistically significant, however (hazard ratio, 0.89; P = .48).

Based on preliminary data at a median follow-up of 8.4 months, median overall survival was 8.5 months for the doublet-only arm and 11.2 months for the iniparib arm, Dr. Silvia Novello reported at the European Multidisciplinary Cancer Congress. Both survival measures were secondary end points.

"Be cautious when interpreting the 1.4-month increase in median progression-free survival and when interpreting the preliminary 2.7 months in median OS [overall survival] seen in the investigational arm vs. the chemotherapy arm because this could be due to differences in baseline patient characteristics," Dr. Novello told attendees at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

In particular, ECOG (Eastern Cooperative Oncology Group) performance status and sex were not balanced, with more patients having a performance status of 0 (61% vs. 49%) and more men (80% vs. 67%) in the investigational arm than in the control group, explained Dr. Novello, a thoracic oncologist at the University of Torino (Italy).

The study’s primary end point was overall response rate as determined by investigators using RECIST 1.1. The investigators previously reported this measure of complete and partial responses was higher in the control group – 26% for those on gemcitabine/cisplatin alone and 20% for those in the doublet plus iniparib group. The only complete response was in a patient given iniparib.

The study included patients who had measurable, untreated stage IV non–small-cell lung cancer (NSCLC) and an ECOG performance status of 0-1. They were randomized 2:1 to receive gemcitabine/cisplatin plus iniparib (80 patients) or gemcitabine/cisplatin alone (39 patients).

Roughly half of patients in each group completed five to six cycles – 44% vs. 50% for the chemotherapy and investigational arms.

Gemcitabine 1,250 mg/m² was given intravenously on days 1 and 8, and cisplatin was given 75 mg/m² intravenously on day 1 in 21-day cycles. Iniparib 5.6 mg/kg also was given intravenously on days 1, 4, 8, and 11 in the experimental arm. Patients underwent a maximum of six cycles, with no maintenance phase.

Safety data showed 82% of the chemotherapy arm and 85% of the iniparib arm had any grade 3/4 treatment-emergent adverse events.

Anemia and nausea were more common in the iniparib arm, but other common adverse events were essentially the same.

Biomarker studies are ongoing potentially to define a subgroup of patients who may benefit from iniparib treatment, according to Dr. Novello.

Invited discussant Dr. Luis Paz-Ares, medial oncology chief of service at Hospital Universitario Virgen del Rocio in Seville, Spain, emphasized the importance of this substudy. "I think it would be very relevant to know if there are some subsets of patients that may benefit," he said. "I think the main part of this trial is the markers, and I will be very interested to see the results of this."

The study is sponsored by Sanofi-Aventis in collaboration with BiPar Sciences. Dr. Novello has previously reported that she has no relevant financial disclosures.

STOCKHOLM – Adding the investigational drug iniparib to a gemcitabine and cisplatin doublet failed to improve outcomes significantly in a phase II study of 119 patients with advanced non–small-cell lung cancer.

The disappointing result follows a phase III trial in which iniparib failed to confirm survival gains when added to gemcitabine (Gemzar) and carboplatin chemotherapy in patients with metastatic triple-negative breast cancer.

Iniparib (BSI-201) had been the leading agent in a new class of therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, but the phase III flop in breast cancer left researchers questioning whether it has a different mechanism of action.

In the current lung cancer trial, median progression-free survival was slightly longer at 5.7 months in those who received iniparib in addition to gemcitabine/cisplatinchemotherapy, compared with 4.3 months for those on gemcitabine/cisplatin alone. The difference was not statistically significant, however (hazard ratio, 0.89; P = .48).

Based on preliminary data at a median follow-up of 8.4 months, median overall survival was 8.5 months for the doublet-only arm and 11.2 months for the iniparib arm, Dr. Silvia Novello reported at the European Multidisciplinary Cancer Congress. Both survival measures were secondary end points.

"Be cautious when interpreting the 1.4-month increase in median progression-free survival and when interpreting the preliminary 2.7 months in median OS [overall survival] seen in the investigational arm vs. the chemotherapy arm because this could be due to differences in baseline patient characteristics," Dr. Novello told attendees at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

In particular, ECOG (Eastern Cooperative Oncology Group) performance status and sex were not balanced, with more patients having a performance status of 0 (61% vs. 49%) and more men (80% vs. 67%) in the investigational arm than in the control group, explained Dr. Novello, a thoracic oncologist at the University of Torino (Italy).

The study’s primary end point was overall response rate as determined by investigators using RECIST 1.1. The investigators previously reported this measure of complete and partial responses was higher in the control group – 26% for those on gemcitabine/cisplatin alone and 20% for those in the doublet plus iniparib group. The only complete response was in a patient given iniparib.

The study included patients who had measurable, untreated stage IV non–small-cell lung cancer (NSCLC) and an ECOG performance status of 0-1. They were randomized 2:1 to receive gemcitabine/cisplatin plus iniparib (80 patients) or gemcitabine/cisplatin alone (39 patients).

Roughly half of patients in each group completed five to six cycles – 44% vs. 50% for the chemotherapy and investigational arms.

Gemcitabine 1,250 mg/m² was given intravenously on days 1 and 8, and cisplatin was given 75 mg/m² intravenously on day 1 in 21-day cycles. Iniparib 5.6 mg/kg also was given intravenously on days 1, 4, 8, and 11 in the experimental arm. Patients underwent a maximum of six cycles, with no maintenance phase.

Safety data showed 82% of the chemotherapy arm and 85% of the iniparib arm had any grade 3/4 treatment-emergent adverse events.

Anemia and nausea were more common in the iniparib arm, but other common adverse events were essentially the same.

Biomarker studies are ongoing potentially to define a subgroup of patients who may benefit from iniparib treatment, according to Dr. Novello.

Invited discussant Dr. Luis Paz-Ares, medial oncology chief of service at Hospital Universitario Virgen del Rocio in Seville, Spain, emphasized the importance of this substudy. "I think it would be very relevant to know if there are some subsets of patients that may benefit," he said. "I think the main part of this trial is the markers, and I will be very interested to see the results of this."

The study is sponsored by Sanofi-Aventis in collaboration with BiPar Sciences. Dr. Novello has previously reported that she has no relevant financial disclosures.

The prevention of venous thromboembolism in hospitals remains a high patient-safety priority, and there are several concrete policy and practice steps that can help, according VTE expert William H. Geerts.

A coordinated nationwide strategy using a single set of guidelines and standardized resources – policies, local guidelines, order sets, measurement tools – is needed, he said during a webinar sponsored by the Partnership for Patients and the National Priorities Partnership.

There should also be consequences for adhering to VTE prophylaxis guidelines, such as accreditation, transfer payments, or public reporting, Dr. Geerts said.

For the local level, he delineated eight key strategies to successfully implementing quality DVT prophylaxis:

• Adequate local commitment and resources.

• Organization-wide standardized simple policy.

• Minimization of variation in practice.

• Inclusion of VTE prophylaxis in order sets with an opt-out approach.

• Responsibility for VTE falls on everyone hospital wide.

• Implementation of mandatory audits and feedback.

• Measurement of success of interventions in reducing VTE.

• Implementation of consequences of adherence.

Dr. Geerts, who is professor of medicine at the University of Toronto and director of the thromboembolism program at Sunnybrook Health Sciences Centre, also in Toronto, pointed out that 60% of all VTEs are hospital acquired, making VTE a major public health priority. It’s estimated that 187,000 hospital-acquired VTEs occur each year in the United States. "Most of these are preventable," he said.

The Partnership for Patients aims to halve preventable VTEs by 2013. The rationale for including thromboprophylaxis as a key national patient safety goal involves four points, according to Dr. Geerts. VTE is common in hospital patients. The acute and long-term outcomes for patients with VTE are bad. VTE is preventable and can be accomplished safely and inexpensively. Preventing VTE is the standard of care for almost all hospital patients.

Importantly, more than 400 randomized studies prove that VTE can be prevented safely and inexpensively, he said. Data also suggest that "it’s not just enough to give prophylaxis but the quality of the prophylaxis is also very important. We can expect that if we provide quality prophylaxis for there to be – not only fewer [DVTs] – but also [lower] costs associated with doing that." He included a list of generally accepted thromboprophylaxis options.

He pointed out that patients who are fully mobile and are expected to have a hospital stay of less than 2 days don’t need thromboprophylaxis. However, this is a very small proportion of hospital patients.

Resources: Society of Hospital Medicine’s Venous Thromboembolism Resource Room and the National Quality Forum Patient Safety Page.

Dr. Geerts’ conflicts of interest were not provided by webinar sponsors. He has previously disclosed consulting or receiving speaking fees from Bayer Healthcare, Boehringer-Ingelheim, Covidien, Pfizer,and Sanofi Aventis.

The prevention of venous thromboembolism in hospitals remains a high patient-safety priority, and there are several concrete policy and practice steps that can help, according VTE expert William H. Geerts.

A coordinated nationwide strategy using a single set of guidelines and standardized resources – policies, local guidelines, order sets, measurement tools – is needed, he said during a webinar sponsored by the Partnership for Patients and the National Priorities Partnership.

There should also be consequences for adhering to VTE prophylaxis guidelines, such as accreditation, transfer payments, or public reporting, Dr. Geerts said.

For the local level, he delineated eight key strategies to successfully implementing quality DVT prophylaxis:

• Adequate local commitment and resources.

• Organization-wide standardized simple policy.

• Minimization of variation in practice.

• Inclusion of VTE prophylaxis in order sets with an opt-out approach.

• Responsibility for VTE falls on everyone hospital wide.

• Implementation of mandatory audits and feedback.

• Measurement of success of interventions in reducing VTE.

• Implementation of consequences of adherence.

Dr. Geerts, who is professor of medicine at the University of Toronto and director of the thromboembolism program at Sunnybrook Health Sciences Centre, also in Toronto, pointed out that 60% of all VTEs are hospital acquired, making VTE a major public health priority. It’s estimated that 187,000 hospital-acquired VTEs occur each year in the United States. "Most of these are preventable," he said.

The Partnership for Patients aims to halve preventable VTEs by 2013. The rationale for including thromboprophylaxis as a key national patient safety goal involves four points, according to Dr. Geerts. VTE is common in hospital patients. The acute and long-term outcomes for patients with VTE are bad. VTE is preventable and can be accomplished safely and inexpensively. Preventing VTE is the standard of care for almost all hospital patients.

Importantly, more than 400 randomized studies prove that VTE can be prevented safely and inexpensively, he said. Data also suggest that "it’s not just enough to give prophylaxis but the quality of the prophylaxis is also very important. We can expect that if we provide quality prophylaxis for there to be – not only fewer [DVTs] – but also [lower] costs associated with doing that." He included a list of generally accepted thromboprophylaxis options.

He pointed out that patients who are fully mobile and are expected to have a hospital stay of less than 2 days don’t need thromboprophylaxis. However, this is a very small proportion of hospital patients.

Resources: Society of Hospital Medicine’s Venous Thromboembolism Resource Room and the National Quality Forum Patient Safety Page.

Dr. Geerts’ conflicts of interest were not provided by webinar sponsors. He has previously disclosed consulting or receiving speaking fees from Bayer Healthcare, Boehringer-Ingelheim, Covidien, Pfizer,and Sanofi Aventis.

The prevention of venous thromboembolism in hospitals remains a high patient-safety priority, and there are several concrete policy and practice steps that can help, according VTE expert William H. Geerts.

A coordinated nationwide strategy using a single set of guidelines and standardized resources – policies, local guidelines, order sets, measurement tools – is needed, he said during a webinar sponsored by the Partnership for Patients and the National Priorities Partnership.

There should also be consequences for adhering to VTE prophylaxis guidelines, such as accreditation, transfer payments, or public reporting, Dr. Geerts said.

For the local level, he delineated eight key strategies to successfully implementing quality DVT prophylaxis:

• Adequate local commitment and resources.

• Organization-wide standardized simple policy.

• Minimization of variation in practice.

• Inclusion of VTE prophylaxis in order sets with an opt-out approach.

• Responsibility for VTE falls on everyone hospital wide.

• Implementation of mandatory audits and feedback.

• Measurement of success of interventions in reducing VTE.

• Implementation of consequences of adherence.

Dr. Geerts, who is professor of medicine at the University of Toronto and director of the thromboembolism program at Sunnybrook Health Sciences Centre, also in Toronto, pointed out that 60% of all VTEs are hospital acquired, making VTE a major public health priority. It’s estimated that 187,000 hospital-acquired VTEs occur each year in the United States. "Most of these are preventable," he said.

The Partnership for Patients aims to halve preventable VTEs by 2013. The rationale for including thromboprophylaxis as a key national patient safety goal involves four points, according to Dr. Geerts. VTE is common in hospital patients. The acute and long-term outcomes for patients with VTE are bad. VTE is preventable and can be accomplished safely and inexpensively. Preventing VTE is the standard of care for almost all hospital patients.

Importantly, more than 400 randomized studies prove that VTE can be prevented safely and inexpensively, he said. Data also suggest that "it’s not just enough to give prophylaxis but the quality of the prophylaxis is also very important. We can expect that if we provide quality prophylaxis for there to be – not only fewer [DVTs] – but also [lower] costs associated with doing that." He included a list of generally accepted thromboprophylaxis options.

He pointed out that patients who are fully mobile and are expected to have a hospital stay of less than 2 days don’t need thromboprophylaxis. However, this is a very small proportion of hospital patients.

Resources: Society of Hospital Medicine’s Venous Thromboembolism Resource Room and the National Quality Forum Patient Safety Page.

Dr. Geerts’ conflicts of interest were not provided by webinar sponsors. He has previously disclosed consulting or receiving speaking fees from Bayer Healthcare, Boehringer-Ingelheim, Covidien, Pfizer,and Sanofi Aventis.

Major Finding: TNF

Data Source: A study of 2,224 individuals.

Disclosures: The study was supported by a research grant from the Italian Association for the Defense of Psoriatic Patients, the Interdisciplinary Centre for Clinical Research at the University of Erlangen-Nuremberg (Germany), and the Bath (England) Institute for Rheumatic Diseases. Two researchers were received grants from Wyeth-Pharm GmbH (Germany).

European researchers have confirmed a new independent susceptibility allele for psoriatic arthritis that could possibly represent a new candidate pharmacogenetic marker for the disease.

“In this collaborative work, we replicated the association of TNF*-857T as a susceptibility allele for [psoriatic arthritis (PsA)] independent of the main PSORS1 risk allele,” wrote Emiliano Giardina, Ph.D., of the University of Rome, and his colleagues in an article published online in the journal (doi:10.1002/art.30591).

It's long been known that the strongest and most replicated susceptibility region for psoriatic vulgaris – and by extension PsA – is within the major histocompatibility complex (MHC) region (PSORS1-psoriasis susceptibility region). “This locus maps to chromosome 6p21.3, comprising many different class I antigens associated with disease expression. Human leukocyte antigen (HLA)-C was repetitively reported as the PSORS1 gene and HLA-Cw*06:02 as the susceptibility allele,” they noted.

In this study, the researchers attempted to confirm this finding by assessing allele and genotype frequencies of TNF*-857 in three independent cohorts. They included a German cohort (374 cases and 561 controls), an Italian cohort (400 cases and 400 controls), and a British cohort (135 cases and 354 controls.

The overall cohort of 2,224 individuals of European ancestry was assessed for distribution of HLA-Cw*06:02/PSORS1 risk allele and also was typed for TNF*-857T. The overall allele frequency of TNF*-857T was significantly higher in individuals with PsA (27%) than in control individuals (20%).

The researchers calculated the genotype frequencies of TNF*-857T in samples that were positive and negative for the PSORS1 risk allele, in order to verify the existence of an association independent of the PSORS1 risk allele.

“Overall, the frequency of heterozygous or homozygous carriers of TNF*-857T (TT/CT) in individuals negative for the PSORS1/HLA-C risk allele was significantly higher in PsA patients (30%) than in control subjects (21%),” they reported. This yielded an odds ratio of 1.35

“As expected, the haplotype analysis confirmed TNF*-857T as a susceptibility factor independent of the PSORS1/HLA-C risk allele,” they wrote. Association of PsA to TNF*-857T was significant in individuals not carrying the PSORS1/HLA-C risk allele, with an odds ratio of 1.27.

“Although the functional role of TNF*-857T remains to be determined, previous data could show that the allele T increases the transcription of TNF-alpha.”

In addition, tumor necrosis factor–alpha is known to play a pivotal role in both the activation and extravasation of T cells in the highly vascularized synovium, as well as in subchondral osteoclastogenesis promoting bone erosions. Genes encoding for TNF-alpha, along with other cytokines, could be candidate pharmacogenetic markers.

View on the News

Findings Confrims Earlier Research

A most intriguing aspect of psoriasis epidemiology is that about a quarter of these patients will develop psoriatic arthritis, and this disease clusters in families with remarkably high heritability. Despite evidence for genetic factors in this disease, the search for genes associated with arthritis and not psoriasis has been challenging because almost all PsA patients also have psoriasis. PSORS-1, the MHC region that contains Cw6, the allele with the strongest association with psoriasis, is characterized by long linkage disequilibrium. One report noted an association of PsA with the TNF*-857T allele that was independent of PSORS1. In this multinational study of 909 patients and 1,315 healthy controls, the TNF*-857T allele was found at significantly higher frequency in PsA patients negative for the PSORS1 allele (30%), compared with controls (21%). This study replicates findings in the previous study and is also of note because the TNF*-867T allele increases the transcription of TNF, a pivotal cytokine in the pathogenesis of PsA. Also of possible relevance is that this allele is associated with response to etanercept in RA. The replication of this important association should catalyze additional genetic and pharmacogenetic studies to better understand the diagnostic and functional significance of this allele in psoriatic disease.

CHRISTOPHER T. RITCHLIN, M.D., is professor of medicine, allergy/immunology, and rheumatology at the University of Rochester (N.Y.) He reported having no conflicts of interest that are relevant to this piece.

Vitals

Major Finding: TNF

Data Source: A study of 2,224 individuals.

Disclosures: The study was supported by a research grant from the Italian Association for the Defense of Psoriatic Patients, the Interdisciplinary Centre for Clinical Research at the University of Erlangen-Nuremberg (Germany), and the Bath (England) Institute for Rheumatic Diseases. Two researchers were received grants from Wyeth-Pharm GmbH (Germany).

European researchers have confirmed a new independent susceptibility allele for psoriatic arthritis that could possibly represent a new candidate pharmacogenetic marker for the disease.

“In this collaborative work, we replicated the association of TNF*-857T as a susceptibility allele for [psoriatic arthritis (PsA)] independent of the main PSORS1 risk allele,” wrote Emiliano Giardina, Ph.D., of the University of Rome, and his colleagues in an article published online in the journal (doi:10.1002/art.30591).

It's long been known that the strongest and most replicated susceptibility region for psoriatic vulgaris – and by extension PsA – is within the major histocompatibility complex (MHC) region (PSORS1-psoriasis susceptibility region). “This locus maps to chromosome 6p21.3, comprising many different class I antigens associated with disease expression. Human leukocyte antigen (HLA)-C was repetitively reported as the PSORS1 gene and HLA-Cw*06:02 as the susceptibility allele,” they noted.

In this study, the researchers attempted to confirm this finding by assessing allele and genotype frequencies of TNF*-857 in three independent cohorts. They included a German cohort (374 cases and 561 controls), an Italian cohort (400 cases and 400 controls), and a British cohort (135 cases and 354 controls.

The overall cohort of 2,224 individuals of European ancestry was assessed for distribution of HLA-Cw*06:02/PSORS1 risk allele and also was typed for TNF*-857T. The overall allele frequency of TNF*-857T was significantly higher in individuals with PsA (27%) than in control individuals (20%).

The researchers calculated the genotype frequencies of TNF*-857T in samples that were positive and negative for the PSORS1 risk allele, in order to verify the existence of an association independent of the PSORS1 risk allele.

“Overall, the frequency of heterozygous or homozygous carriers of TNF*-857T (TT/CT) in individuals negative for the PSORS1/HLA-C risk allele was significantly higher in PsA patients (30%) than in control subjects (21%),” they reported. This yielded an odds ratio of 1.35

“As expected, the haplotype analysis confirmed TNF*-857T as a susceptibility factor independent of the PSORS1/HLA-C risk allele,” they wrote. Association of PsA to TNF*-857T was significant in individuals not carrying the PSORS1/HLA-C risk allele, with an odds ratio of 1.27.

“Although the functional role of TNF*-857T remains to be determined, previous data could show that the allele T increases the transcription of TNF-alpha.”

In addition, tumor necrosis factor–alpha is known to play a pivotal role in both the activation and extravasation of T cells in the highly vascularized synovium, as well as in subchondral osteoclastogenesis promoting bone erosions. Genes encoding for TNF-alpha, along with other cytokines, could be candidate pharmacogenetic markers.

View on the News

Findings Confrims Earlier Research

A most intriguing aspect of psoriasis epidemiology is that about a quarter of these patients will develop psoriatic arthritis, and this disease clusters in families with remarkably high heritability. Despite evidence for genetic factors in this disease, the search for genes associated with arthritis and not psoriasis has been challenging because almost all PsA patients also have psoriasis. PSORS-1, the MHC region that contains Cw6, the allele with the strongest association with psoriasis, is characterized by long linkage disequilibrium. One report noted an association of PsA with the TNF*-857T allele that was independent of PSORS1. In this multinational study of 909 patients and 1,315 healthy controls, the TNF*-857T allele was found at significantly higher frequency in PsA patients negative for the PSORS1 allele (30%), compared with controls (21%). This study replicates findings in the previous study and is also of note because the TNF*-867T allele increases the transcription of TNF, a pivotal cytokine in the pathogenesis of PsA. Also of possible relevance is that this allele is associated with response to etanercept in RA. The replication of this important association should catalyze additional genetic and pharmacogenetic studies to better understand the diagnostic and functional significance of this allele in psoriatic disease.

CHRISTOPHER T. RITCHLIN, M.D., is professor of medicine, allergy/immunology, and rheumatology at the University of Rochester (N.Y.) He reported having no conflicts of interest that are relevant to this piece.

Vitals

Major Finding: TNF

Data Source: A study of 2,224 individuals.

Disclosures: The study was supported by a research grant from the Italian Association for the Defense of Psoriatic Patients, the Interdisciplinary Centre for Clinical Research at the University of Erlangen-Nuremberg (Germany), and the Bath (England) Institute for Rheumatic Diseases. Two researchers were received grants from Wyeth-Pharm GmbH (Germany).

European researchers have confirmed a new independent susceptibility allele for psoriatic arthritis that could possibly represent a new candidate pharmacogenetic marker for the disease.

“In this collaborative work, we replicated the association of TNF*-857T as a susceptibility allele for [psoriatic arthritis (PsA)] independent of the main PSORS1 risk allele,” wrote Emiliano Giardina, Ph.D., of the University of Rome, and his colleagues in an article published online in the journal (doi:10.1002/art.30591).

It's long been known that the strongest and most replicated susceptibility region for psoriatic vulgaris – and by extension PsA – is within the major histocompatibility complex (MHC) region (PSORS1-psoriasis susceptibility region). “This locus maps to chromosome 6p21.3, comprising many different class I antigens associated with disease expression. Human leukocyte antigen (HLA)-C was repetitively reported as the PSORS1 gene and HLA-Cw*06:02 as the susceptibility allele,” they noted.

In this study, the researchers attempted to confirm this finding by assessing allele and genotype frequencies of TNF*-857 in three independent cohorts. They included a German cohort (374 cases and 561 controls), an Italian cohort (400 cases and 400 controls), and a British cohort (135 cases and 354 controls.

The overall cohort of 2,224 individuals of European ancestry was assessed for distribution of HLA-Cw*06:02/PSORS1 risk allele and also was typed for TNF*-857T. The overall allele frequency of TNF*-857T was significantly higher in individuals with PsA (27%) than in control individuals (20%).

The researchers calculated the genotype frequencies of TNF*-857T in samples that were positive and negative for the PSORS1 risk allele, in order to verify the existence of an association independent of the PSORS1 risk allele.

“Overall, the frequency of heterozygous or homozygous carriers of TNF*-857T (TT/CT) in individuals negative for the PSORS1/HLA-C risk allele was significantly higher in PsA patients (30%) than in control subjects (21%),” they reported. This yielded an odds ratio of 1.35

“As expected, the haplotype analysis confirmed TNF*-857T as a susceptibility factor independent of the PSORS1/HLA-C risk allele,” they wrote. Association of PsA to TNF*-857T was significant in individuals not carrying the PSORS1/HLA-C risk allele, with an odds ratio of 1.27.

“Although the functional role of TNF*-857T remains to be determined, previous data could show that the allele T increases the transcription of TNF-alpha.”

In addition, tumor necrosis factor–alpha is known to play a pivotal role in both the activation and extravasation of T cells in the highly vascularized synovium, as well as in subchondral osteoclastogenesis promoting bone erosions. Genes encoding for TNF-alpha, along with other cytokines, could be candidate pharmacogenetic markers.

View on the News

Findings Confrims Earlier Research

A most intriguing aspect of psoriasis epidemiology is that about a quarter of these patients will develop psoriatic arthritis, and this disease clusters in families with remarkably high heritability. Despite evidence for genetic factors in this disease, the search for genes associated with arthritis and not psoriasis has been challenging because almost all PsA patients also have psoriasis. PSORS-1, the MHC region that contains Cw6, the allele with the strongest association with psoriasis, is characterized by long linkage disequilibrium. One report noted an association of PsA with the TNF*-857T allele that was independent of PSORS1. In this multinational study of 909 patients and 1,315 healthy controls, the TNF*-857T allele was found at significantly higher frequency in PsA patients negative for the PSORS1 allele (30%), compared with controls (21%). This study replicates findings in the previous study and is also of note because the TNF*-867T allele increases the transcription of TNF, a pivotal cytokine in the pathogenesis of PsA. Also of possible relevance is that this allele is associated with response to etanercept in RA. The replication of this important association should catalyze additional genetic and pharmacogenetic studies to better understand the diagnostic and functional significance of this allele in psoriatic disease.

CHRISTOPHER T. RITCHLIN, M.D., is professor of medicine, allergy/immunology, and rheumatology at the University of Rochester (N.Y.) He reported having no conflicts of interest that are relevant to this piece.

Vitals

Unilateral hip arthritis may cause alterations in the joint loading of the contralateral knee before the onset of symptomatic osteoarthritis in that knee, a small study has shown.

This finding could open up the possibility of interventions that could prevent or slow the progression of knee osteoarthritis (OA) in those with unilateral hip arthritis.

The results come from a study of 55 participants, who underwent gait analysis of dynamic joint loading and dual-energy x-ray absorptiometry (DXA) to determine bone mineral density (BMD) of the tibial plateau (Arthritis Rheum. 2011 30 Aug. [doi:10.1002/art.30626]).

“This study demonstrates that in unilateral hip OA, the contralateral knee is subjected to significantly higher dynamic joint loading, as assessed by PAddM [peak external knee adduction moment] and by total medial compartment loads, relative to the ipsilateral knee. Importantly, this asymmetry of knee loading is observed even though the knees are asymptomatic and do not have clinical evidence of OA,” wrote Dr. Najia Shakoor and her coinvestigators at Rush Medical College, Chicago.

Asked to comment on the findings, Dr. Nancy E. Lane noted that “it is not a surprise that changes in gait are present before the disease becomes clinically symptomatic.

“The more we can study gait to provide early detection of OA, we might be able to provide an intervention that might slow the progression of the disease,” noted Dr. Lane, professor of medicine and rheumatology at the University of California, Davis, and director of the center for healthy aging at UC Davis.

While no interventions are approved yet, there are braces and special shoes that may support the knee. In addition, ongoing research is evaluating gait interventions. “They may be efficacious if the interventions are initiated earlier in the disease state,” according to Dr. Lane.

Individuals were included if they had symptomatic OA of the hip, as defined by the American College of Rheumatology's Clinical Criteria for Classification. They also had to have at least 30 mm of pain (on a 100-mm scale) while walking – which corresponds to question 1 of the visual analog format of the hip-directed WOMAC (Western Ontario and McMaster Universities Arthritis) Index. OA was confirmed radiographically.

Exclusion criteria included symptomatic OA of the contralateral hip or either knee with the presence of pain defined as 30 mm (on a 100-mm scale) while walking. They were also excluded if they had radiographic evidence of OA of the contralateral hip or either of the knees, in excess of grade 3, according to the modified Kellgren-Lawrence (KL) scale.

A total of 62 individuals met the study criteria and completed the study. The mean age was 62 years, and more women (60%) were included than men. A total of 55 individuals had both appropriate gait data and evaluation of bone density at bilateral knees.

All individuals had anterior-posterior radiographs of the pelvis, which were evaluated for KL grade at the hips. They also underwent anterior-posterior standing knee radiographs that were evaluated for KL grade at the knees. All participants completed the WOMAC visual analog scale for pain at both knees and both hips. The WOMAC scores were normalized to a 100-mm scale.

Participants also underwent gait analysis to collect three-dimensional kinematics and ground reaction forces using optoelectronic cameras with passive markers and a multicomponent force plate. Passive markers were placed at the lateral-most aspect of the superior iliac crest, the superior aspect of the greater trochanter, the lateral knee joint line, the lateral malleolus, the lateral calcaneus, and the head of the fifth metatarsal.

DXA was used to scan the bilateral proximal tibia and determine BMD. Software was used to determine the subperiostial surface of the tibia. Cortical bone of the subchondral plate was excluded from the measurements, as sclerosis in this region can alter BMD. Therefore, the medial and lateral regions of interest include subchondral trabecular bone.

The primary end point was the PAddM, which is a validated gait parameter that reflects the load at the medial compartment of the knee. This measure has been associated with pain, radiographic severity, and progression of knee OA. The PAddM was defined as the external adduction moment of greatest magnitude during the stance phase of the gait cycle in this study. The coprimary end points were total loading of the medial compartment and medial compartment BMD.

Both primary gait outcomes at the knees – the PAddM and the total medial knee load – were significantly greater for the contralateral knee relative to the ipsilateral knee. Lateral compartment load was also greater for the contralateral knee. In addition, the medial tibial plateau BMD was significantly greater at the contralateral knee relative to the ipsilateral knee, though there were no significant differences at the lateral tibial plateau.

Interestingly, the ratio of the contralateral-to-ipsilateral medial compartment knee BMD was directly correlated with contralateral-to-ipsilateral knee PAddM and contralateral-to-ipsilateral knee medial compartment load, the investigators noted.

In addition, the significant asymmetries observed in the proximal tibial BMD of the contralateral vs. ipsilateral knees provide evidence of substantially altered load history in the knees as well.

“The current study demonstrates that loading asymmetries at the knees begin early in the disease course of hip OA to end-stage disease. These results may have implications for interventional strategies targeted in those with unilateral hip OA in order to prevent or minimize these asymmetries early in the disease course,” the researchers concluded.

The authors and Dr. Lane reported that they have no relevant financial disclosures. The study was sponsored by the National Institutes of Health and the Schweppe Foundation.

Unilateral hip arthritis may cause alterations in the joint loading of the contralateral knee before the onset of symptomatic osteoarthritis in that knee, a small study has shown.

This finding could open up the possibility of interventions that could prevent or slow the progression of knee osteoarthritis (OA) in those with unilateral hip arthritis.

The results come from a study of 55 participants, who underwent gait analysis of dynamic joint loading and dual-energy x-ray absorptiometry (DXA) to determine bone mineral density (BMD) of the tibial plateau (Arthritis Rheum. 2011 30 Aug. [doi:10.1002/art.30626]).

“This study demonstrates that in unilateral hip OA, the contralateral knee is subjected to significantly higher dynamic joint loading, as assessed by PAddM [peak external knee adduction moment] and by total medial compartment loads, relative to the ipsilateral knee. Importantly, this asymmetry of knee loading is observed even though the knees are asymptomatic and do not have clinical evidence of OA,” wrote Dr. Najia Shakoor and her coinvestigators at Rush Medical College, Chicago.

Asked to comment on the findings, Dr. Nancy E. Lane noted that “it is not a surprise that changes in gait are present before the disease becomes clinically symptomatic.

“The more we can study gait to provide early detection of OA, we might be able to provide an intervention that might slow the progression of the disease,” noted Dr. Lane, professor of medicine and rheumatology at the University of California, Davis, and director of the center for healthy aging at UC Davis.

While no interventions are approved yet, there are braces and special shoes that may support the knee. In addition, ongoing research is evaluating gait interventions. “They may be efficacious if the interventions are initiated earlier in the disease state,” according to Dr. Lane.

Individuals were included if they had symptomatic OA of the hip, as defined by the American College of Rheumatology's Clinical Criteria for Classification. They also had to have at least 30 mm of pain (on a 100-mm scale) while walking – which corresponds to question 1 of the visual analog format of the hip-directed WOMAC (Western Ontario and McMaster Universities Arthritis) Index. OA was confirmed radiographically.

Exclusion criteria included symptomatic OA of the contralateral hip or either knee with the presence of pain defined as 30 mm (on a 100-mm scale) while walking. They were also excluded if they had radiographic evidence of OA of the contralateral hip or either of the knees, in excess of grade 3, according to the modified Kellgren-Lawrence (KL) scale.

A total of 62 individuals met the study criteria and completed the study. The mean age was 62 years, and more women (60%) were included than men. A total of 55 individuals had both appropriate gait data and evaluation of bone density at bilateral knees.

All individuals had anterior-posterior radiographs of the pelvis, which were evaluated for KL grade at the hips. They also underwent anterior-posterior standing knee radiographs that were evaluated for KL grade at the knees. All participants completed the WOMAC visual analog scale for pain at both knees and both hips. The WOMAC scores were normalized to a 100-mm scale.

Participants also underwent gait analysis to collect three-dimensional kinematics and ground reaction forces using optoelectronic cameras with passive markers and a multicomponent force plate. Passive markers were placed at the lateral-most aspect of the superior iliac crest, the superior aspect of the greater trochanter, the lateral knee joint line, the lateral malleolus, the lateral calcaneus, and the head of the fifth metatarsal.

DXA was used to scan the bilateral proximal tibia and determine BMD. Software was used to determine the subperiostial surface of the tibia. Cortical bone of the subchondral plate was excluded from the measurements, as sclerosis in this region can alter BMD. Therefore, the medial and lateral regions of interest include subchondral trabecular bone.

The primary end point was the PAddM, which is a validated gait parameter that reflects the load at the medial compartment of the knee. This measure has been associated with pain, radiographic severity, and progression of knee OA. The PAddM was defined as the external adduction moment of greatest magnitude during the stance phase of the gait cycle in this study. The coprimary end points were total loading of the medial compartment and medial compartment BMD.

Both primary gait outcomes at the knees – the PAddM and the total medial knee load – were significantly greater for the contralateral knee relative to the ipsilateral knee. Lateral compartment load was also greater for the contralateral knee. In addition, the medial tibial plateau BMD was significantly greater at the contralateral knee relative to the ipsilateral knee, though there were no significant differences at the lateral tibial plateau.

Interestingly, the ratio of the contralateral-to-ipsilateral medial compartment knee BMD was directly correlated with contralateral-to-ipsilateral knee PAddM and contralateral-to-ipsilateral knee medial compartment load, the investigators noted.

In addition, the significant asymmetries observed in the proximal tibial BMD of the contralateral vs. ipsilateral knees provide evidence of substantially altered load history in the knees as well.

“The current study demonstrates that loading asymmetries at the knees begin early in the disease course of hip OA to end-stage disease. These results may have implications for interventional strategies targeted in those with unilateral hip OA in order to prevent or minimize these asymmetries early in the disease course,” the researchers concluded.

The authors and Dr. Lane reported that they have no relevant financial disclosures. The study was sponsored by the National Institutes of Health and the Schweppe Foundation.

Unilateral hip arthritis may cause alterations in the joint loading of the contralateral knee before the onset of symptomatic osteoarthritis in that knee, a small study has shown.

This finding could open up the possibility of interventions that could prevent or slow the progression of knee osteoarthritis (OA) in those with unilateral hip arthritis.

The results come from a study of 55 participants, who underwent gait analysis of dynamic joint loading and dual-energy x-ray absorptiometry (DXA) to determine bone mineral density (BMD) of the tibial plateau (Arthritis Rheum. 2011 30 Aug. [doi:10.1002/art.30626]).

“This study demonstrates that in unilateral hip OA, the contralateral knee is subjected to significantly higher dynamic joint loading, as assessed by PAddM [peak external knee adduction moment] and by total medial compartment loads, relative to the ipsilateral knee. Importantly, this asymmetry of knee loading is observed even though the knees are asymptomatic and do not have clinical evidence of OA,” wrote Dr. Najia Shakoor and her coinvestigators at Rush Medical College, Chicago.

Asked to comment on the findings, Dr. Nancy E. Lane noted that “it is not a surprise that changes in gait are present before the disease becomes clinically symptomatic.

“The more we can study gait to provide early detection of OA, we might be able to provide an intervention that might slow the progression of the disease,” noted Dr. Lane, professor of medicine and rheumatology at the University of California, Davis, and director of the center for healthy aging at UC Davis.

While no interventions are approved yet, there are braces and special shoes that may support the knee. In addition, ongoing research is evaluating gait interventions. “They may be efficacious if the interventions are initiated earlier in the disease state,” according to Dr. Lane.

Individuals were included if they had symptomatic OA of the hip, as defined by the American College of Rheumatology's Clinical Criteria for Classification. They also had to have at least 30 mm of pain (on a 100-mm scale) while walking – which corresponds to question 1 of the visual analog format of the hip-directed WOMAC (Western Ontario and McMaster Universities Arthritis) Index. OA was confirmed radiographically.

Exclusion criteria included symptomatic OA of the contralateral hip or either knee with the presence of pain defined as 30 mm (on a 100-mm scale) while walking. They were also excluded if they had radiographic evidence of OA of the contralateral hip or either of the knees, in excess of grade 3, according to the modified Kellgren-Lawrence (KL) scale.

A total of 62 individuals met the study criteria and completed the study. The mean age was 62 years, and more women (60%) were included than men. A total of 55 individuals had both appropriate gait data and evaluation of bone density at bilateral knees.

All individuals had anterior-posterior radiographs of the pelvis, which were evaluated for KL grade at the hips. They also underwent anterior-posterior standing knee radiographs that were evaluated for KL grade at the knees. All participants completed the WOMAC visual analog scale for pain at both knees and both hips. The WOMAC scores were normalized to a 100-mm scale.

Participants also underwent gait analysis to collect three-dimensional kinematics and ground reaction forces using optoelectronic cameras with passive markers and a multicomponent force plate. Passive markers were placed at the lateral-most aspect of the superior iliac crest, the superior aspect of the greater trochanter, the lateral knee joint line, the lateral malleolus, the lateral calcaneus, and the head of the fifth metatarsal.

DXA was used to scan the bilateral proximal tibia and determine BMD. Software was used to determine the subperiostial surface of the tibia. Cortical bone of the subchondral plate was excluded from the measurements, as sclerosis in this region can alter BMD. Therefore, the medial and lateral regions of interest include subchondral trabecular bone.

The primary end point was the PAddM, which is a validated gait parameter that reflects the load at the medial compartment of the knee. This measure has been associated with pain, radiographic severity, and progression of knee OA. The PAddM was defined as the external adduction moment of greatest magnitude during the stance phase of the gait cycle in this study. The coprimary end points were total loading of the medial compartment and medial compartment BMD.

Both primary gait outcomes at the knees – the PAddM and the total medial knee load – were significantly greater for the contralateral knee relative to the ipsilateral knee. Lateral compartment load was also greater for the contralateral knee. In addition, the medial tibial plateau BMD was significantly greater at the contralateral knee relative to the ipsilateral knee, though there were no significant differences at the lateral tibial plateau.

Interestingly, the ratio of the contralateral-to-ipsilateral medial compartment knee BMD was directly correlated with contralateral-to-ipsilateral knee PAddM and contralateral-to-ipsilateral knee medial compartment load, the investigators noted.

In addition, the significant asymmetries observed in the proximal tibial BMD of the contralateral vs. ipsilateral knees provide evidence of substantially altered load history in the knees as well.

“The current study demonstrates that loading asymmetries at the knees begin early in the disease course of hip OA to end-stage disease. These results may have implications for interventional strategies targeted in those with unilateral hip OA in order to prevent or minimize these asymmetries early in the disease course,” the researchers concluded.

The authors and Dr. Lane reported that they have no relevant financial disclosures. The study was sponsored by the National Institutes of Health and the Schweppe Foundation.

European researchers have confirmed a new independent susceptibility allele for psoriatic arthritis that could possibly represent a new candidate pharmacogenetic marker for the disease.

"In this collaborative work, we replicated the association of TNF*-857T as a susceptibility allele for [psoriatic arthritis (PsA)] independent of the main PSORS1 risk allele," wrote Emiliano Giardina, Ph.D., of the University of Rome, and his colleagues in an article published online in Arthritis & Rheumatism (doi:10.1002/art.30591).

It’s long been known that the strongest and most replicated susceptibility region for psoriatic vulgaris – and by extension PsA – is within the major histocompatibility complex (MHC) region (PSORS1-psoriasis susceptibility region). "This locus maps to chromosome 6p21.3, comprising many different class I antigens associated with disease expression. Human leukocyte antigen (HLA)-C was repetitively reported as the PSORS1 gene and HLA-Cw*06:02 as the susceptibility allele," they noted.

In this study, the researchers attempted to confirm this finding by assessing allele and genotype frequencies of TNF*-857 in three independent cohorts. They included a German cohort (374 cases and 561 controls), an Italian cohort (400 cases and 400 controls), and a British cohort (135 cases and 354 controls.

The overall cohort of 2,224 individuals of European ancestry was assessed for distribution of HLA-Cw*06:02/PSORS1 risk allele and also was typed for TNF*-857T. The overall allele frequency of TNF*-857T was significantly higher in individuals with PsA (27%) than in control individuals (20%).

The researchers calculated the genotype frequencies of TNF*-857T in samples that were positive and negative for the PSORS1 risk allele, in order to verify the existence of an association independent of the PSORS1 risk allele.

"Overall, the frequency of heterozygous or homozygous carriers of TNF*-857T (TT/CT) in individuals negative for the PSORS1/HLA-C risk allele was significantly higher in PsA patients (30%) than in control subjects (21%)," they reported. This yielded an odds ratio of 1.35

"As expected, the haplotype analysis confirmed TNF*-857T as a susceptibility factor independent of the PSORS1/HLA-C risk allele," they wrote. Association of PsA to TNF*-857T was significant in individuals not carrying the PSORS1/HLA-C risk allele, with an odds ratio of 1.27.

"Although the functional role of TNF*-857T remains to be determined, previous data could show that the allele T increases the transcription of TNF-alpha." In addition, tumor necrosis factor–alpha is known to play a pivotal role in both the activation and extravasation of T-cells in the highly vascularized synovium, as well as in subchondral osteoclastogenesis promoting bone erosions." Genes encoding for TNF-alpha, along with other cytokines, could be candidate pharmacogenetic markers.

The study was supported by a research grant from the Italian Association for the Defense of Psoriatic Patients; the Interdisciplinary Centre for Clinical Research at the University of Erlangen-Nuremberg, Germany; and the Bath Institute for Rheumatic Diseases. Two researchers were received grants from Wyeth-Pharm GmbH (Germany).

European researchers have confirmed a new independent susceptibility allele for psoriatic arthritis that could possibly represent a new candidate pharmacogenetic marker for the disease.

"In this collaborative work, we replicated the association of TNF*-857T as a susceptibility allele for [psoriatic arthritis (PsA)] independent of the main PSORS1 risk allele," wrote Emiliano Giardina, Ph.D., of the University of Rome, and his colleagues in an article published online in Arthritis & Rheumatism (doi:10.1002/art.30591).

It’s long been known that the strongest and most replicated susceptibility region for psoriatic vulgaris – and by extension PsA – is within the major histocompatibility complex (MHC) region (PSORS1-psoriasis susceptibility region). "This locus maps to chromosome 6p21.3, comprising many different class I antigens associated with disease expression. Human leukocyte antigen (HLA)-C was repetitively reported as the PSORS1 gene and HLA-Cw*06:02 as the susceptibility allele," they noted.

In this study, the researchers attempted to confirm this finding by assessing allele and genotype frequencies of TNF*-857 in three independent cohorts. They included a German cohort (374 cases and 561 controls), an Italian cohort (400 cases and 400 controls), and a British cohort (135 cases and 354 controls.

The overall cohort of 2,224 individuals of European ancestry was assessed for distribution of HLA-Cw*06:02/PSORS1 risk allele and also was typed for TNF*-857T. The overall allele frequency of TNF*-857T was significantly higher in individuals with PsA (27%) than in control individuals (20%).

The researchers calculated the genotype frequencies of TNF*-857T in samples that were positive and negative for the PSORS1 risk allele, in order to verify the existence of an association independent of the PSORS1 risk allele.

"Overall, the frequency of heterozygous or homozygous carriers of TNF*-857T (TT/CT) in individuals negative for the PSORS1/HLA-C risk allele was significantly higher in PsA patients (30%) than in control subjects (21%)," they reported. This yielded an odds ratio of 1.35

"As expected, the haplotype analysis confirmed TNF*-857T as a susceptibility factor independent of the PSORS1/HLA-C risk allele," they wrote. Association of PsA to TNF*-857T was significant in individuals not carrying the PSORS1/HLA-C risk allele, with an odds ratio of 1.27.

"Although the functional role of TNF*-857T remains to be determined, previous data could show that the allele T increases the transcription of TNF-alpha." In addition, tumor necrosis factor–alpha is known to play a pivotal role in both the activation and extravasation of T-cells in the highly vascularized synovium, as well as in subchondral osteoclastogenesis promoting bone erosions." Genes encoding for TNF-alpha, along with other cytokines, could be candidate pharmacogenetic markers.

The study was supported by a research grant from the Italian Association for the Defense of Psoriatic Patients; the Interdisciplinary Centre for Clinical Research at the University of Erlangen-Nuremberg, Germany; and the Bath Institute for Rheumatic Diseases. Two researchers were received grants from Wyeth-Pharm GmbH (Germany).

European researchers have confirmed a new independent susceptibility allele for psoriatic arthritis that could possibly represent a new candidate pharmacogenetic marker for the disease.

"In this collaborative work, we replicated the association of TNF*-857T as a susceptibility allele for [psoriatic arthritis (PsA)] independent of the main PSORS1 risk allele," wrote Emiliano Giardina, Ph.D., of the University of Rome, and his colleagues in an article published online in Arthritis & Rheumatism (doi:10.1002/art.30591).

It’s long been known that the strongest and most replicated susceptibility region for psoriatic vulgaris – and by extension PsA – is within the major histocompatibility complex (MHC) region (PSORS1-psoriasis susceptibility region). "This locus maps to chromosome 6p21.3, comprising many different class I antigens associated with disease expression. Human leukocyte antigen (HLA)-C was repetitively reported as the PSORS1 gene and HLA-Cw*06:02 as the susceptibility allele," they noted.

In this study, the researchers attempted to confirm this finding by assessing allele and genotype frequencies of TNF*-857 in three independent cohorts. They included a German cohort (374 cases and 561 controls), an Italian cohort (400 cases and 400 controls), and a British cohort (135 cases and 354 controls.

The overall cohort of 2,224 individuals of European ancestry was assessed for distribution of HLA-Cw*06:02/PSORS1 risk allele and also was typed for TNF*-857T. The overall allele frequency of TNF*-857T was significantly higher in individuals with PsA (27%) than in control individuals (20%).

The researchers calculated the genotype frequencies of TNF*-857T in samples that were positive and negative for the PSORS1 risk allele, in order to verify the existence of an association independent of the PSORS1 risk allele.

"Overall, the frequency of heterozygous or homozygous carriers of TNF*-857T (TT/CT) in individuals negative for the PSORS1/HLA-C risk allele was significantly higher in PsA patients (30%) than in control subjects (21%)," they reported. This yielded an odds ratio of 1.35

"As expected, the haplotype analysis confirmed TNF*-857T as a susceptibility factor independent of the PSORS1/HLA-C risk allele," they wrote. Association of PsA to TNF*-857T was significant in individuals not carrying the PSORS1/HLA-C risk allele, with an odds ratio of 1.27.

"Although the functional role of TNF*-857T remains to be determined, previous data could show that the allele T increases the transcription of TNF-alpha." In addition, tumor necrosis factor–alpha is known to play a pivotal role in both the activation and extravasation of T-cells in the highly vascularized synovium, as well as in subchondral osteoclastogenesis promoting bone erosions." Genes encoding for TNF-alpha, along with other cytokines, could be candidate pharmacogenetic markers.

The study was supported by a research grant from the Italian Association for the Defense of Psoriatic Patients; the Interdisciplinary Centre for Clinical Research at the University of Erlangen-Nuremberg, Germany; and the Bath Institute for Rheumatic Diseases. Two researchers were received grants from Wyeth-Pharm GmbH (Germany).

STOCKHOLM – Novel antibody-guided trastuzumab emtansine therapy not only improved progression-free survival by 5 months in women with HER2-positive metastatic breast cancer, but it also had an impressively tame side effect profile, according to Dr. Sara Hurvitz.*

Treatment with trastuzumab emtansine (T-DM1) resulted in a median progression-free survival of 14 months vs. 9 months with trastuzumab (Herceptin) and docetaxel (Taxotere) in a phase II open-label study with 137 women. T-DM1 reduced the relative risk of disease progression by 41% with a hazard ratio of 0.59 (P = .0353), she reported at the European Multidisciplinary Cancer Congress.

"These results validate the hypothesis that the unique properties of T-DM1 may lead to an improved therapeutic index," said Dr. Hurvitz of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

An antibody drug conjugate, T-DM1 retains the targeting properties of monoclonal antibody trastuzumab in HER2-positive breast cancer while transporting a potent cytotoxic agent (DM1) that inhibits tubulin polymerization and microtubule dynamics into cancer cells.

Invited discussant Dr. Martine J. Piccart-Gebhart talked excitedly about the results, but also urged caution.

"You have to remember that this is an open-label study. I am saying that because I believe that T-DM1 is the magic drug for medical oncologists – the drug that we have been waiting for, for so many years. It is a clever drug. It brings the cytotoxic agent inside the cancer cell," said Dr. Piccart-Gebhart of the Jules Bordet Institute at the Université Libre de Bruxelles in Belgium.

However, "in an open-label study, you have to worry a little bit because we want to give this T-DM1 drug to our patients," so it may be tempting to interpret the results too favorably, she told attendees at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

The researchers recruited 137 women with HER2-positive, recurrent locally advanced breast cancer or metastatic breast cancer. The patients were randomized to receive either trastuzumab and docetaxel or T-DM1 alone.

Trastuzumab was given as an 8-mg/kg loading dose and then as 6 mg/kg every 3 weeks. Docetaxel was given in a dose of 75 mg/m² or 100 mg/m² for 3 weeks. T-DM1 was given intravenously at a dose of 3.6 mg/kg every 3 weeks. In all, 70 women received trastuzumab and docetaxel and 67 received T-DM1.

The primary end points were progression-free survival by investigator assessment and safety. Data analyses were based on clinical data as of Nov. 15, 2010, and prior to any T-DM1 crossover. Overall survival data are expected in 2012. Quality of life data will be presented as a poster at the San Antonio Breast Cancer Symposium this December.

Most of the patients in each group (85%) had centrally confirmed HER2-positive breast cancer. "Relatively few patients had received neoadjuvant or adjuvant trastuzumab. This was likely owing to the international nature of the study and the lack of availability at some centers for trastuzumab in the adjuvant setting," said Dr. Hurvitz.

Dr. Piccart-Gebhart observed that one-third of patients in this study were stage IV at diagnosis and only 20%-25% were exposed to adjuvant trastuzumab. These numbers are likely to change with time, as more patients are exposed to trastuzumab.

At the time of data cutoff, 21% of patients on trastuzumab and docetaxel were still on the treatment, compared with 43% of those in the T-DM1 arm. "The majority of patients came off of treatment for disease progression," she said.

The objective response rate was similar – 58% for the T-DM1 arm vs. 64% for the control arm. Patients in the trastuzumab/docetaxel arm had a median duration of response of 9.5 months. The duration of response in the T-DM1 arm has not yet been reached.

"In terms of safety and tolerability, it is very clear that the safety profile of T-DM1 is far better than the one for docetaxel and trastuzumab," said Dr. Piccart-Gebhart. Patients who received T-DM1 had many fewer adverse events of grade 3 or greater – 32 vs. 59.

Among hematologic adverse events, neutropenia of any grade was more common in the control arm – 63.6% compared with 17.4% – but any grade thrombocytopenia was more common in the T-DM1 arm (30% vs. 6%).

Among nonhematologic events, any grade alopecia was less than 4% for the T-DM1 arm compared with 67% for the control arm. Likewise, the incidence of any grade diarrhea was much lower in the T-DM1 arm – 16% for those on T-DM1 compared with 46% for those on the trastuzumab/docetaxel. Peripheral edema of any grade was also much lower in the T-DM1 arm (10% vs. 44%).

"Cardiac safety is important to look at whenever you’re talking about HER-2 targeting agent," said Dr. Hurvitz.

Adjuvant anthracyclines were given to 45% and 49% of patients in the T-DM1 arm and control arm. On local assessment two patients in the control arm, compared with none in the T-DM1 arm, had a postbaseline left ventricular ejection fraction of 40% or less.

"There were no clinically significant cardiac events reported," she noted.

Dr. Hurvitz and Dr. Piccart-Gebhart agreed that large phase III trials are needed to confirm these findings. The drug is being evaluated in three large phase III clinical trials for HER2-postive metastatic breast cancer.

The study was funded by F. Hoffmann-La Roche. Dr. Hurvitz reported that she has no relevant financial disclosures. Dr. Piccart-Gebhart has previously reported that she is a consultant for and has received research support from several pharmaceutical companies, including Roche.

* Clarification, 9/29/2011: The original version of this article stated that trastuzumab emtansine improved disease-free progression. However, it is more accurate to say that it improved progression-free survival. This version has been updated.

STOCKHOLM – Novel antibody-guided trastuzumab emtansine therapy not only improved progression-free survival by 5 months in women with HER2-positive metastatic breast cancer, but it also had an impressively tame side effect profile, according to Dr. Sara Hurvitz.*

Treatment with trastuzumab emtansine (T-DM1) resulted in a median progression-free survival of 14 months vs. 9 months with trastuzumab (Herceptin) and docetaxel (Taxotere) in a phase II open-label study with 137 women. T-DM1 reduced the relative risk of disease progression by 41% with a hazard ratio of 0.59 (P = .0353), she reported at the European Multidisciplinary Cancer Congress.

"These results validate the hypothesis that the unique properties of T-DM1 may lead to an improved therapeutic index," said Dr. Hurvitz of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

An antibody drug conjugate, T-DM1 retains the targeting properties of monoclonal antibody trastuzumab in HER2-positive breast cancer while transporting a potent cytotoxic agent (DM1) that inhibits tubulin polymerization and microtubule dynamics into cancer cells.

Invited discussant Dr. Martine J. Piccart-Gebhart talked excitedly about the results, but also urged caution.

"You have to remember that this is an open-label study. I am saying that because I believe that T-DM1 is the magic drug for medical oncologists – the drug that we have been waiting for, for so many years. It is a clever drug. It brings the cytotoxic agent inside the cancer cell," said Dr. Piccart-Gebhart of the Jules Bordet Institute at the Université Libre de Bruxelles in Belgium.

However, "in an open-label study, you have to worry a little bit because we want to give this T-DM1 drug to our patients," so it may be tempting to interpret the results too favorably, she told attendees at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

The researchers recruited 137 women with HER2-positive, recurrent locally advanced breast cancer or metastatic breast cancer. The patients were randomized to receive either trastuzumab and docetaxel or T-DM1 alone.

Trastuzumab was given as an 8-mg/kg loading dose and then as 6 mg/kg every 3 weeks. Docetaxel was given in a dose of 75 mg/m² or 100 mg/m² for 3 weeks. T-DM1 was given intravenously at a dose of 3.6 mg/kg every 3 weeks. In all, 70 women received trastuzumab and docetaxel and 67 received T-DM1.

The primary end points were progression-free survival by investigator assessment and safety. Data analyses were based on clinical data as of Nov. 15, 2010, and prior to any T-DM1 crossover. Overall survival data are expected in 2012. Quality of life data will be presented as a poster at the San Antonio Breast Cancer Symposium this December.

Most of the patients in each group (85%) had centrally confirmed HER2-positive breast cancer. "Relatively few patients had received neoadjuvant or adjuvant trastuzumab. This was likely owing to the international nature of the study and the lack of availability at some centers for trastuzumab in the adjuvant setting," said Dr. Hurvitz.

Dr. Piccart-Gebhart observed that one-third of patients in this study were stage IV at diagnosis and only 20%-25% were exposed to adjuvant trastuzumab. These numbers are likely to change with time, as more patients are exposed to trastuzumab.

At the time of data cutoff, 21% of patients on trastuzumab and docetaxel were still on the treatment, compared with 43% of those in the T-DM1 arm. "The majority of patients came off of treatment for disease progression," she said.

The objective response rate was similar – 58% for the T-DM1 arm vs. 64% for the control arm. Patients in the trastuzumab/docetaxel arm had a median duration of response of 9.5 months. The duration of response in the T-DM1 arm has not yet been reached.

"In terms of safety and tolerability, it is very clear that the safety profile of T-DM1 is far better than the one for docetaxel and trastuzumab," said Dr. Piccart-Gebhart. Patients who received T-DM1 had many fewer adverse events of grade 3 or greater – 32 vs. 59.

Among hematologic adverse events, neutropenia of any grade was more common in the control arm – 63.6% compared with 17.4% – but any grade thrombocytopenia was more common in the T-DM1 arm (30% vs. 6%).

Among nonhematologic events, any grade alopecia was less than 4% for the T-DM1 arm compared with 67% for the control arm. Likewise, the incidence of any grade diarrhea was much lower in the T-DM1 arm – 16% for those on T-DM1 compared with 46% for those on the trastuzumab/docetaxel. Peripheral edema of any grade was also much lower in the T-DM1 arm (10% vs. 44%).

"Cardiac safety is important to look at whenever you’re talking about HER-2 targeting agent," said Dr. Hurvitz.

Adjuvant anthracyclines were given to 45% and 49% of patients in the T-DM1 arm and control arm. On local assessment two patients in the control arm, compared with none in the T-DM1 arm, had a postbaseline left ventricular ejection fraction of 40% or less.

"There were no clinically significant cardiac events reported," she noted.

Dr. Hurvitz and Dr. Piccart-Gebhart agreed that large phase III trials are needed to confirm these findings. The drug is being evaluated in three large phase III clinical trials for HER2-postive metastatic breast cancer.

The study was funded by F. Hoffmann-La Roche. Dr. Hurvitz reported that she has no relevant financial disclosures. Dr. Piccart-Gebhart has previously reported that she is a consultant for and has received research support from several pharmaceutical companies, including Roche.

* Clarification, 9/29/2011: The original version of this article stated that trastuzumab emtansine improved disease-free progression. However, it is more accurate to say that it improved progression-free survival. This version has been updated.

STOCKHOLM – Novel antibody-guided trastuzumab emtansine therapy not only improved progression-free survival by 5 months in women with HER2-positive metastatic breast cancer, but it also had an impressively tame side effect profile, according to Dr. Sara Hurvitz.*

Treatment with trastuzumab emtansine (T-DM1) resulted in a median progression-free survival of 14 months vs. 9 months with trastuzumab (Herceptin) and docetaxel (Taxotere) in a phase II open-label study with 137 women. T-DM1 reduced the relative risk of disease progression by 41% with a hazard ratio of 0.59 (P = .0353), she reported at the European Multidisciplinary Cancer Congress.

"These results validate the hypothesis that the unique properties of T-DM1 may lead to an improved therapeutic index," said Dr. Hurvitz of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

An antibody drug conjugate, T-DM1 retains the targeting properties of monoclonal antibody trastuzumab in HER2-positive breast cancer while transporting a potent cytotoxic agent (DM1) that inhibits tubulin polymerization and microtubule dynamics into cancer cells.

Invited discussant Dr. Martine J. Piccart-Gebhart talked excitedly about the results, but also urged caution.

"You have to remember that this is an open-label study. I am saying that because I believe that T-DM1 is the magic drug for medical oncologists – the drug that we have been waiting for, for so many years. It is a clever drug. It brings the cytotoxic agent inside the cancer cell," said Dr. Piccart-Gebhart of the Jules Bordet Institute at the Université Libre de Bruxelles in Belgium.

However, "in an open-label study, you have to worry a little bit because we want to give this T-DM1 drug to our patients," so it may be tempting to interpret the results too favorably, she told attendees at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

The researchers recruited 137 women with HER2-positive, recurrent locally advanced breast cancer or metastatic breast cancer. The patients were randomized to receive either trastuzumab and docetaxel or T-DM1 alone.

Trastuzumab was given as an 8-mg/kg loading dose and then as 6 mg/kg every 3 weeks. Docetaxel was given in a dose of 75 mg/m² or 100 mg/m² for 3 weeks. T-DM1 was given intravenously at a dose of 3.6 mg/kg every 3 weeks. In all, 70 women received trastuzumab and docetaxel and 67 received T-DM1.

The primary end points were progression-free survival by investigator assessment and safety. Data analyses were based on clinical data as of Nov. 15, 2010, and prior to any T-DM1 crossover. Overall survival data are expected in 2012. Quality of life data will be presented as a poster at the San Antonio Breast Cancer Symposium this December.

Most of the patients in each group (85%) had centrally confirmed HER2-positive breast cancer. "Relatively few patients had received neoadjuvant or adjuvant trastuzumab. This was likely owing to the international nature of the study and the lack of availability at some centers for trastuzumab in the adjuvant setting," said Dr. Hurvitz.

Dr. Piccart-Gebhart observed that one-third of patients in this study were stage IV at diagnosis and only 20%-25% were exposed to adjuvant trastuzumab. These numbers are likely to change with time, as more patients are exposed to trastuzumab.

At the time of data cutoff, 21% of patients on trastuzumab and docetaxel were still on the treatment, compared with 43% of those in the T-DM1 arm. "The majority of patients came off of treatment for disease progression," she said.

The objective response rate was similar – 58% for the T-DM1 arm vs. 64% for the control arm. Patients in the trastuzumab/docetaxel arm had a median duration of response of 9.5 months. The duration of response in the T-DM1 arm has not yet been reached.

"In terms of safety and tolerability, it is very clear that the safety profile of T-DM1 is far better than the one for docetaxel and trastuzumab," said Dr. Piccart-Gebhart. Patients who received T-DM1 had many fewer adverse events of grade 3 or greater – 32 vs. 59.

Among hematologic adverse events, neutropenia of any grade was more common in the control arm – 63.6% compared with 17.4% – but any grade thrombocytopenia was more common in the T-DM1 arm (30% vs. 6%).

Among nonhematologic events, any grade alopecia was less than 4% for the T-DM1 arm compared with 67% for the control arm. Likewise, the incidence of any grade diarrhea was much lower in the T-DM1 arm – 16% for those on T-DM1 compared with 46% for those on the trastuzumab/docetaxel. Peripheral edema of any grade was also much lower in the T-DM1 arm (10% vs. 44%).

"Cardiac safety is important to look at whenever you’re talking about HER-2 targeting agent," said Dr. Hurvitz.

Adjuvant anthracyclines were given to 45% and 49% of patients in the T-DM1 arm and control arm. On local assessment two patients in the control arm, compared with none in the T-DM1 arm, had a postbaseline left ventricular ejection fraction of 40% or less.

"There were no clinically significant cardiac events reported," she noted.

Dr. Hurvitz and Dr. Piccart-Gebhart agreed that large phase III trials are needed to confirm these findings. The drug is being evaluated in three large phase III clinical trials for HER2-postive metastatic breast cancer.

The study was funded by F. Hoffmann-La Roche. Dr. Hurvitz reported that she has no relevant financial disclosures. Dr. Piccart-Gebhart has previously reported that she is a consultant for and has received research support from several pharmaceutical companies, including Roche.

* Clarification, 9/29/2011: The original version of this article stated that trastuzumab emtansine improved disease-free progression. However, it is more accurate to say that it improved progression-free survival. This version has been updated.

Unilateral hip arthritis may cause alterations in the joint loading of the contralateral knee before the onset of symptomatic osteoarthritis in that knee.

This finding could open up the possibility of interventions that could prevent or slow the progression of knee osteoarthritis (OA) in those with unilateral hip arthritis.

The results come from a small study of 55 participants, who underwent gait analysis of dynamic joint loading and dual-energy x-ray absorptiometry (DXA) to determine bone mineral density (BMD) of the tibial plateau (Arthritis & Rheumatism 2011 [doi:10.1002/art.30626]).

"This study demonstrates that in unilateral hip OA, the contralateral knee is subjected to significantly higher dynamic joint loading, as assessed by PAddM [peak external knee adduction moment] and by total medial compartment loads, relative to the ipsilateral knee. Importantly, this asymmetry of knee loading is observed even though the knees are asymptomatic and do not have clinical evidence of OA," wrote Dr. Najia Shakoor and her coinvestigators at Rush Medical College, Chicago.

Asked to comment on the findings, Dr. Nancy E. Lane noted that it is "not a surprise that changes in gait are present before the disease becomes clinically symptomatic.

"The more we can study gait to provide early detection of OA, we might be able to provide an intervention that might slow the progression of the disease," noted Dr. Lane, who is professor of medicine and rheumatology at the University of California, Davis, and director of the Center for Healthy Aging at UC Davis.

Individuals were included if they had symptomatic OA of the hip, as defined by the American College of Rheumatology’s Clinical Criteria for Classification. They also had to have at least 30 mm of pain (on a 100-mm scale) while walking – which corresponds to question 1 of the visual analog format of the hip-directed WOMAC (Western Ontario and McMaster Universities Arthritis) Index. OA was confirmed radiographically.

Exclusion criteria included symptomatic OA of the contralateral hip or either knee with the presence of pain defined as 30 mm (on a 100-mm scale) while walking. They were also excluded if they had radiographic evidence of OA of the contralateral hip or either of the knees, in excess of grade 3 according to the modified Kellgren-Lawrence (KL) scale.

A total of 62 individuals met the study criteria and completed the study. The mean age was 62 years and more women (60%) were included than men. A total of 55 individuals had both appropriate gait data and evaluation of bone density at bilateral knees.

All individuals had anterior-posterior radiographs of the pelvis, which were evaluated for KL grade at the hips. They also underwent anterior-posterior standing knee radiographs that were evaluated for KL grade at the knees. All participants completed the WOMAC visual analog scale for pain at both knees and both hips. The WOMAC scores were normalized to a 100-mm scale.

Participants also underwent gait analysis to collect three-dimensional kinematics and ground reaction forces using optoelectronic cameras with passive markers and a multicomponent force plate. Passive markers were placed at the lateral-most aspect of the superior iliac crest, the superior aspect of the greater trochanter, the lateral knee joint line, lateral malleolus, lateral calcaneus, and the head of the fifth metatarsal.

DXA was used to scan the bilateral proximal tibia and determine BMD. Software was used to determine the subperiostial surface of the tibia. Cortical bone of the subchondral plate was excluded from the measurements, as sclerosis in this region can alter BMD. Therefore, the medial and lateral regions of interest include subchondral trabecular bone.

The primary end point was the PAddM, which is a validated gait parameter that reflects the load at the medial compartment of the knee. This measure has been associated with pain, radiographic severity, and progression of knee OA. The PAddM was defined as the external adduction moment of greatest magnitude during the stance phase of the gait cycle in this study. The co-primary end points were total loading of the medial compartment and medial compartment BMD.

Both primary gait outcomes at the knees – the PAddM and the total medial knee load – were significantly greater for the contralateral knee relative to the ipsilateral knee. Lateral compartment load was also greater for the contralateral knee. In addition, the medial tibial plateau BMD was significantly greater at the contralateral knee relative to the ipsilateral knee, though there were no significant differences at the lateral tibial plateau.

Interestingly, the ratio of the contralateral-to-ipsilateral medial compartment knee BMD was directly correlated with contralateral-to-ipsilateral knee PAddM and contralateral-to-ipsilateral knee medial compartment load, the investigators noted.

In addition, the significant asymmetries observed in the proximal tibial BMD of the contralateral vs. ipsilateral knees provide evidence of substantially altered load history in the knees as well.

"The current study demonstrates that loading asymmetries at the knees begin early in the disease course of hip OA to end-stage disease. These results may have implications for interventional strategies targeted in those with unilateral hip OA in order to prevent or minimized these asymmetries early in the disease course," the researchers concluded

The authors and Dr. Lane reported that they have no conflicts of interest. The study was sponsored by the National Institutes of Health and the Schweppe Foundation.

Unilateral hip arthritis may cause alterations in the joint loading of the contralateral knee before the onset of symptomatic osteoarthritis in that knee.

This finding could open up the possibility of interventions that could prevent or slow the progression of knee osteoarthritis (OA) in those with unilateral hip arthritis.

The results come from a small study of 55 participants, who underwent gait analysis of dynamic joint loading and dual-energy x-ray absorptiometry (DXA) to determine bone mineral density (BMD) of the tibial plateau (Arthritis & Rheumatism 2011 [doi:10.1002/art.30626]).

"This study demonstrates that in unilateral hip OA, the contralateral knee is subjected to significantly higher dynamic joint loading, as assessed by PAddM [peak external knee adduction moment] and by total medial compartment loads, relative to the ipsilateral knee. Importantly, this asymmetry of knee loading is observed even though the knees are asymptomatic and do not have clinical evidence of OA," wrote Dr. Najia Shakoor and her coinvestigators at Rush Medical College, Chicago.

Asked to comment on the findings, Dr. Nancy E. Lane noted that it is "not a surprise that changes in gait are present before the disease becomes clinically symptomatic.

"The more we can study gait to provide early detection of OA, we might be able to provide an intervention that might slow the progression of the disease," noted Dr. Lane, who is professor of medicine and rheumatology at the University of California, Davis, and director of the Center for Healthy Aging at UC Davis.

Individuals were included if they had symptomatic OA of the hip, as defined by the American College of Rheumatology’s Clinical Criteria for Classification. They also had to have at least 30 mm of pain (on a 100-mm scale) while walking – which corresponds to question 1 of the visual analog format of the hip-directed WOMAC (Western Ontario and McMaster Universities Arthritis) Index. OA was confirmed radiographically.

Exclusion criteria included symptomatic OA of the contralateral hip or either knee with the presence of pain defined as 30 mm (on a 100-mm scale) while walking. They were also excluded if they had radiographic evidence of OA of the contralateral hip or either of the knees, in excess of grade 3 according to the modified Kellgren-Lawrence (KL) scale.

A total of 62 individuals met the study criteria and completed the study. The mean age was 62 years and more women (60%) were included than men. A total of 55 individuals had both appropriate gait data and evaluation of bone density at bilateral knees.

All individuals had anterior-posterior radiographs of the pelvis, which were evaluated for KL grade at the hips. They also underwent anterior-posterior standing knee radiographs that were evaluated for KL grade at the knees. All participants completed the WOMAC visual analog scale for pain at both knees and both hips. The WOMAC scores were normalized to a 100-mm scale.

Participants also underwent gait analysis to collect three-dimensional kinematics and ground reaction forces using optoelectronic cameras with passive markers and a multicomponent force plate. Passive markers were placed at the lateral-most aspect of the superior iliac crest, the superior aspect of the greater trochanter, the lateral knee joint line, lateral malleolus, lateral calcaneus, and the head of the fifth metatarsal.

DXA was used to scan the bilateral proximal tibia and determine BMD. Software was used to determine the subperiostial surface of the tibia. Cortical bone of the subchondral plate was excluded from the measurements, as sclerosis in this region can alter BMD. Therefore, the medial and lateral regions of interest include subchondral trabecular bone.

The primary end point was the PAddM, which is a validated gait parameter that reflects the load at the medial compartment of the knee. This measure has been associated with pain, radiographic severity, and progression of knee OA. The PAddM was defined as the external adduction moment of greatest magnitude during the stance phase of the gait cycle in this study. The co-primary end points were total loading of the medial compartment and medial compartment BMD.

Both primary gait outcomes at the knees – the PAddM and the total medial knee load – were significantly greater for the contralateral knee relative to the ipsilateral knee. Lateral compartment load was also greater for the contralateral knee. In addition, the medial tibial plateau BMD was significantly greater at the contralateral knee relative to the ipsilateral knee, though there were no significant differences at the lateral tibial plateau.

Interestingly, the ratio of the contralateral-to-ipsilateral medial compartment knee BMD was directly correlated with contralateral-to-ipsilateral knee PAddM and contralateral-to-ipsilateral knee medial compartment load, the investigators noted.

In addition, the significant asymmetries observed in the proximal tibial BMD of the contralateral vs. ipsilateral knees provide evidence of substantially altered load history in the knees as well.

"The current study demonstrates that loading asymmetries at the knees begin early in the disease course of hip OA to end-stage disease. These results may have implications for interventional strategies targeted in those with unilateral hip OA in order to prevent or minimized these asymmetries early in the disease course," the researchers concluded

The authors and Dr. Lane reported that they have no conflicts of interest. The study was sponsored by the National Institutes of Health and the Schweppe Foundation.

Unilateral hip arthritis may cause alterations in the joint loading of the contralateral knee before the onset of symptomatic osteoarthritis in that knee.

This finding could open up the possibility of interventions that could prevent or slow the progression of knee osteoarthritis (OA) in those with unilateral hip arthritis.

The results come from a small study of 55 participants, who underwent gait analysis of dynamic joint loading and dual-energy x-ray absorptiometry (DXA) to determine bone mineral density (BMD) of the tibial plateau (Arthritis & Rheumatism 2011 [doi:10.1002/art.30626]).

"This study demonstrates that in unilateral hip OA, the contralateral knee is subjected to significantly higher dynamic joint loading, as assessed by PAddM [peak external knee adduction moment] and by total medial compartment loads, relative to the ipsilateral knee. Importantly, this asymmetry of knee loading is observed even though the knees are asymptomatic and do not have clinical evidence of OA," wrote Dr. Najia Shakoor and her coinvestigators at Rush Medical College, Chicago.

Asked to comment on the findings, Dr. Nancy E. Lane noted that it is "not a surprise that changes in gait are present before the disease becomes clinically symptomatic.

"The more we can study gait to provide early detection of OA, we might be able to provide an intervention that might slow the progression of the disease," noted Dr. Lane, who is professor of medicine and rheumatology at the University of California, Davis, and director of the Center for Healthy Aging at UC Davis.

Individuals were included if they had symptomatic OA of the hip, as defined by the American College of Rheumatology’s Clinical Criteria for Classification. They also had to have at least 30 mm of pain (on a 100-mm scale) while walking – which corresponds to question 1 of the visual analog format of the hip-directed WOMAC (Western Ontario and McMaster Universities Arthritis) Index. OA was confirmed radiographically.

Exclusion criteria included symptomatic OA of the contralateral hip or either knee with the presence of pain defined as 30 mm (on a 100-mm scale) while walking. They were also excluded if they had radiographic evidence of OA of the contralateral hip or either of the knees, in excess of grade 3 according to the modified Kellgren-Lawrence (KL) scale.

A total of 62 individuals met the study criteria and completed the study. The mean age was 62 years and more women (60%) were included than men. A total of 55 individuals had both appropriate gait data and evaluation of bone density at bilateral knees.

All individuals had anterior-posterior radiographs of the pelvis, which were evaluated for KL grade at the hips. They also underwent anterior-posterior standing knee radiographs that were evaluated for KL grade at the knees. All participants completed the WOMAC visual analog scale for pain at both knees and both hips. The WOMAC scores were normalized to a 100-mm scale.

Participants also underwent gait analysis to collect three-dimensional kinematics and ground reaction forces using optoelectronic cameras with passive markers and a multicomponent force plate. Passive markers were placed at the lateral-most aspect of the superior iliac crest, the superior aspect of the greater trochanter, the lateral knee joint line, lateral malleolus, lateral calcaneus, and the head of the fifth metatarsal.

DXA was used to scan the bilateral proximal tibia and determine BMD. Software was used to determine the subperiostial surface of the tibia. Cortical bone of the subchondral plate was excluded from the measurements, as sclerosis in this region can alter BMD. Therefore, the medial and lateral regions of interest include subchondral trabecular bone.

The primary end point was the PAddM, which is a validated gait parameter that reflects the load at the medial compartment of the knee. This measure has been associated with pain, radiographic severity, and progression of knee OA. The PAddM was defined as the external adduction moment of greatest magnitude during the stance phase of the gait cycle in this study. The co-primary end points were total loading of the medial compartment and medial compartment BMD.

Both primary gait outcomes at the knees – the PAddM and the total medial knee load – were significantly greater for the contralateral knee relative to the ipsilateral knee. Lateral compartment load was also greater for the contralateral knee. In addition, the medial tibial plateau BMD was significantly greater at the contralateral knee relative to the ipsilateral knee, though there were no significant differences at the lateral tibial plateau.

Interestingly, the ratio of the contralateral-to-ipsilateral medial compartment knee BMD was directly correlated with contralateral-to-ipsilateral knee PAddM and contralateral-to-ipsilateral knee medial compartment load, the investigators noted.

In addition, the significant asymmetries observed in the proximal tibial BMD of the contralateral vs. ipsilateral knees provide evidence of substantially altered load history in the knees as well.

"The current study demonstrates that loading asymmetries at the knees begin early in the disease course of hip OA to end-stage disease. These results may have implications for interventional strategies targeted in those with unilateral hip OA in order to prevent or minimized these asymmetries early in the disease course," the researchers concluded

The authors and Dr. Lane reported that they have no conflicts of interest. The study was sponsored by the National Institutes of Health and the Schweppe Foundation.