Haemophilus influenzae type B-Neisseria meningitidis serogroups C (MenC) and Y (MenY)-tetanus toxoid (Hib-MenCY-TT, MenHibrix) vaccine has been approved by the Food and Drug Administration for an infant indication to be administered according to the standard 2-, 4-, 6-, and 12 months vaccine schedule in the United States as endorsed by the American Academy of Pediatrics (AAP), the American Academy of Family Physicians (AAFP), and the Centers for Disease Control and Prevention (CDC).

According to the presentation given at the CDC meeting Oct. 14, 2011, by Dr. Ismael Ortega-Sanchez, giving the vaccine could prevent 130 of the projected 377 (34.5%) cases of meningococcal infection in the 4-million-child birth cohort of the United States cumulatively to age 10 years. Also infant vaccination would prevent one death per 642,000 infants (seven deaths/year). The vaccine could be given along with a DTaP/inactivated polio vaccine/hepatitis b vaccine (DTaP/IPV/HepB, Pediarix) and the 13-valent pneumococcal conjugate vaccine (PCV13, Prevnar13) without increasing the total number of shots in a visit. The vaccine has been proven safe and effective.

Yet at the October meeting of the CDC Advisory Committee on Immunization Practices (ACIP), Hib-MenCY-TT (MenHibrix) vaccine was not recommended for universal use. Instead, it was recommended for high risk children as previously defined as complement deficient and asplenic. Why the restricted recommendation?*

• It isn’t the right time. When the ACIP/AAP/AAFP endorsed meningococcal vaccination for 11- to 12-year-olds 7 years ago, the annual incidence of meningococcal disease was fivefold higher than it is now. The drop in incidence cannot be fully attributed to the initiation of our national vaccination campaign. It was known before the meningococcal conjugate vaccine was recommended that meningococcal disease had a cyclical pattern with high and low years of incidence. But, had the incidence been as low as it is now, then one might speculate that the vote to recommend universal vaccination might have been different. The passionate pleas of concerned parents and the desire by all of us in health care to protect every single adolescent against the devastation of meningococcal infections carried the day, even though the cost for prevention of those cases and deaths was the highest ever seen up to that time. So, if the incidence of meningococcal infections is now at an all time low, the calculations of cost to prevent cases and deaths would be a multiple of what it was 7 years ago.

• The vaccine doesn’t include all the serotypes. Hib-MenCY-TT has meningococcal serotypes C and Y. The vaccine does not include serotype A or serotype W-135 (because these serotypes are virtually absent and uncommon, respectively, in the United States and other developed countries. So, a concern could be that serotype replacement might occur over time as we have seen with Prevnar7, now replaced in the United States with Prevnar13 because of serotype replacement. But more importantly is the absence of serotype B in the vaccine. Serotype B meningococci cause 60%-65% of meningococcal disease in the United States in infants. That is why the number of cases projected to be prevented with Hib-MenCY-TT is about one-third of all cases among infants.

• The total number of shots goes up per visit unless GlaxoSmithKline vaccines are preferentially used. Hib-MenCY-TT was developed and is licensed by GlaxoSmithKline, a world leader in pediatric vaccines, and they are building a portfolio of vaccines that can fit together well. There is nothing wrong with that – it is good marketing. Sanofi Pasteur Vaccines is doing the same thing and, as more products are forthcoming from Pfizer Vaccines, Novartis Vaccines, and others, we can expect the same strategy. However, the CDC, AAP, and AAFP do not want to endorse products that limit choices and/or provide any single company with a competitive advantage. So, to endorse Hib-MenCY-TT that clearly fits best with only GlaxoSmithKline vaccine products may be an unspoken concern.

• The National Immunization Program cannot afford it. Going back to the presentation to ACIP at the CDC in October 2011, a key aspect was the cost of vaccination calculated against cases prevented and lives saved. The calculation for Quality-Adjusted Life Year (QALY) saved for a two-dose schedule among adolescents came out to $157,000/case. For the infant vaccination, the numbers were pretty staggering at $3.6 million/case, based on the current incidence of meningococcal infections in the United States (see sidebar). Even if the incidence of meningococcal infections were currently as high as they were back in 1997-1999, the cost would be $0.5 million/case. For those thinking about the option of toddler vaccination with the quadrivalent meningococcal conjugate vaccine (Menactra), the calculations for QALYs concluded that such a strategy prevented half as many cases at half the cost.

So where do we go from here? The lack of an endorsement by ACIP/AAP/AAFP for universal use* normally means that the vaccine will not be available within the Vaccines for Children free program, and it will not be covered by commercial health insurance plans except for the specific indications endorsed by the recommending bodies.* So these are huge barriers to use. Nevertheless, it is a licensed vaccine and it is safe and effective, just not perfect and not cost-effective for widespread public use at government expense. How much is a child’s life worth? If it is your child, then the life is priceless. But in public health there are limits to what can be afforded. We will see more of these types of issues in the future. Another unspoken concern of the ACIP/AAP/AAFP is that a two-tiered vaccine access situation develops. In other words, for those who can afford to pay, Hib-MenCY-TT is available and, if they can pay for it out-of-pocket, then they can buy it to protect their child.

The following are cost-effectiveness analysis conclusions that were presented to the CDC:

• Vaccinating infants or toddlers with meningococcal vaccine has a high cost per case prevented – even at a low vaccine price.

• Cost estimates are much higher than prior analyses because of declining incidence and shorter duration of protection.

• Infant vaccination prevents twice as many cases as toddler vaccination but at twice the cost – cost per QALY saved is similar for both strategies.

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Rochester (N.Y.) General Hospital Research Institute. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero disclosed that in the past 3 years, he has served as a consultant to Sanofi Pasteur, Pfizer, Novartis, and Crucell for their vaccines currently licensed and in development. Dr. Pichichero also disclosed that in the past 3 years, his academic institution has received research grants to support vaccine work from GlaxoSmithKline, Sanofi Pasteur, Pfizer, Novartis, and Crucell, including studies involving Hib-MenCY-TT produced by GlaxoSmithKline and Quadrivalent meningococcal vaccine by Sanofi Pasteur and Novartis.

* This article was updated on 10/26/12.

Haemophilus influenzae type B-Neisseria meningitidis serogroups C (MenC) and Y (MenY)-tetanus toxoid (Hib-MenCY-TT, MenHibrix) vaccine has been approved by the Food and Drug Administration for an infant indication to be administered according to the standard 2-, 4-, 6-, and 12 months vaccine schedule in the United States as endorsed by the American Academy of Pediatrics (AAP), the American Academy of Family Physicians (AAFP), and the Centers for Disease Control and Prevention (CDC).

According to the presentation given at the CDC meeting Oct. 14, 2011, by Dr. Ismael Ortega-Sanchez, giving the vaccine could prevent 130 of the projected 377 (34.5%) cases of meningococcal infection in the 4-million-child birth cohort of the United States cumulatively to age 10 years. Also infant vaccination would prevent one death per 642,000 infants (seven deaths/year). The vaccine could be given along with a DTaP/inactivated polio vaccine/hepatitis b vaccine (DTaP/IPV/HepB, Pediarix) and the 13-valent pneumococcal conjugate vaccine (PCV13, Prevnar13) without increasing the total number of shots in a visit. The vaccine has been proven safe and effective.

Yet at the October meeting of the CDC Advisory Committee on Immunization Practices (ACIP), Hib-MenCY-TT (MenHibrix) vaccine was not recommended for universal use. Instead, it was recommended for high risk children as previously defined as complement deficient and asplenic. Why the restricted recommendation?*

• It isn’t the right time. When the ACIP/AAP/AAFP endorsed meningococcal vaccination for 11- to 12-year-olds 7 years ago, the annual incidence of meningococcal disease was fivefold higher than it is now. The drop in incidence cannot be fully attributed to the initiation of our national vaccination campaign. It was known before the meningococcal conjugate vaccine was recommended that meningococcal disease had a cyclical pattern with high and low years of incidence. But, had the incidence been as low as it is now, then one might speculate that the vote to recommend universal vaccination might have been different. The passionate pleas of concerned parents and the desire by all of us in health care to protect every single adolescent against the devastation of meningococcal infections carried the day, even though the cost for prevention of those cases and deaths was the highest ever seen up to that time. So, if the incidence of meningococcal infections is now at an all time low, the calculations of cost to prevent cases and deaths would be a multiple of what it was 7 years ago.

• The vaccine doesn’t include all the serotypes. Hib-MenCY-TT has meningococcal serotypes C and Y. The vaccine does not include serotype A or serotype W-135 (because these serotypes are virtually absent and uncommon, respectively, in the United States and other developed countries. So, a concern could be that serotype replacement might occur over time as we have seen with Prevnar7, now replaced in the United States with Prevnar13 because of serotype replacement. But more importantly is the absence of serotype B in the vaccine. Serotype B meningococci cause 60%-65% of meningococcal disease in the United States in infants. That is why the number of cases projected to be prevented with Hib-MenCY-TT is about one-third of all cases among infants.

• The total number of shots goes up per visit unless GlaxoSmithKline vaccines are preferentially used. Hib-MenCY-TT was developed and is licensed by GlaxoSmithKline, a world leader in pediatric vaccines, and they are building a portfolio of vaccines that can fit together well. There is nothing wrong with that – it is good marketing. Sanofi Pasteur Vaccines is doing the same thing and, as more products are forthcoming from Pfizer Vaccines, Novartis Vaccines, and others, we can expect the same strategy. However, the CDC, AAP, and AAFP do not want to endorse products that limit choices and/or provide any single company with a competitive advantage. So, to endorse Hib-MenCY-TT that clearly fits best with only GlaxoSmithKline vaccine products may be an unspoken concern.

• The National Immunization Program cannot afford it. Going back to the presentation to ACIP at the CDC in October 2011, a key aspect was the cost of vaccination calculated against cases prevented and lives saved. The calculation for Quality-Adjusted Life Year (QALY) saved for a two-dose schedule among adolescents came out to $157,000/case. For the infant vaccination, the numbers were pretty staggering at $3.6 million/case, based on the current incidence of meningococcal infections in the United States (see sidebar). Even if the incidence of meningococcal infections were currently as high as they were back in 1997-1999, the cost would be $0.5 million/case. For those thinking about the option of toddler vaccination with the quadrivalent meningococcal conjugate vaccine (Menactra), the calculations for QALYs concluded that such a strategy prevented half as many cases at half the cost.

So where do we go from here? The lack of an endorsement by ACIP/AAP/AAFP for universal use* normally means that the vaccine will not be available within the Vaccines for Children free program, and it will not be covered by commercial health insurance plans except for the specific indications endorsed by the recommending bodies.* So these are huge barriers to use. Nevertheless, it is a licensed vaccine and it is safe and effective, just not perfect and not cost-effective for widespread public use at government expense. How much is a child’s life worth? If it is your child, then the life is priceless. But in public health there are limits to what can be afforded. We will see more of these types of issues in the future. Another unspoken concern of the ACIP/AAP/AAFP is that a two-tiered vaccine access situation develops. In other words, for those who can afford to pay, Hib-MenCY-TT is available and, if they can pay for it out-of-pocket, then they can buy it to protect their child.

The following are cost-effectiveness analysis conclusions that were presented to the CDC:

• Vaccinating infants or toddlers with meningococcal vaccine has a high cost per case prevented – even at a low vaccine price.

• Cost estimates are much higher than prior analyses because of declining incidence and shorter duration of protection.

• Infant vaccination prevents twice as many cases as toddler vaccination but at twice the cost – cost per QALY saved is similar for both strategies.

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Rochester (N.Y.) General Hospital Research Institute. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero disclosed that in the past 3 years, he has served as a consultant to Sanofi Pasteur, Pfizer, Novartis, and Crucell for their vaccines currently licensed and in development. Dr. Pichichero also disclosed that in the past 3 years, his academic institution has received research grants to support vaccine work from GlaxoSmithKline, Sanofi Pasteur, Pfizer, Novartis, and Crucell, including studies involving Hib-MenCY-TT produced by GlaxoSmithKline and Quadrivalent meningococcal vaccine by Sanofi Pasteur and Novartis.

* This article was updated on 10/26/12.

Haemophilus influenzae type B-Neisseria meningitidis serogroups C (MenC) and Y (MenY)-tetanus toxoid (Hib-MenCY-TT, MenHibrix) vaccine has been approved by the Food and Drug Administration for an infant indication to be administered according to the standard 2-, 4-, 6-, and 12 months vaccine schedule in the United States as endorsed by the American Academy of Pediatrics (AAP), the American Academy of Family Physicians (AAFP), and the Centers for Disease Control and Prevention (CDC).

According to the presentation given at the CDC meeting Oct. 14, 2011, by Dr. Ismael Ortega-Sanchez, giving the vaccine could prevent 130 of the projected 377 (34.5%) cases of meningococcal infection in the 4-million-child birth cohort of the United States cumulatively to age 10 years. Also infant vaccination would prevent one death per 642,000 infants (seven deaths/year). The vaccine could be given along with a DTaP/inactivated polio vaccine/hepatitis b vaccine (DTaP/IPV/HepB, Pediarix) and the 13-valent pneumococcal conjugate vaccine (PCV13, Prevnar13) without increasing the total number of shots in a visit. The vaccine has been proven safe and effective.

Yet at the October meeting of the CDC Advisory Committee on Immunization Practices (ACIP), Hib-MenCY-TT (MenHibrix) vaccine was not recommended for universal use. Instead, it was recommended for high risk children as previously defined as complement deficient and asplenic. Why the restricted recommendation?*

• It isn’t the right time. When the ACIP/AAP/AAFP endorsed meningococcal vaccination for 11- to 12-year-olds 7 years ago, the annual incidence of meningococcal disease was fivefold higher than it is now. The drop in incidence cannot be fully attributed to the initiation of our national vaccination campaign. It was known before the meningococcal conjugate vaccine was recommended that meningococcal disease had a cyclical pattern with high and low years of incidence. But, had the incidence been as low as it is now, then one might speculate that the vote to recommend universal vaccination might have been different. The passionate pleas of concerned parents and the desire by all of us in health care to protect every single adolescent against the devastation of meningococcal infections carried the day, even though the cost for prevention of those cases and deaths was the highest ever seen up to that time. So, if the incidence of meningococcal infections is now at an all time low, the calculations of cost to prevent cases and deaths would be a multiple of what it was 7 years ago.

• The vaccine doesn’t include all the serotypes. Hib-MenCY-TT has meningococcal serotypes C and Y. The vaccine does not include serotype A or serotype W-135 (because these serotypes are virtually absent and uncommon, respectively, in the United States and other developed countries. So, a concern could be that serotype replacement might occur over time as we have seen with Prevnar7, now replaced in the United States with Prevnar13 because of serotype replacement. But more importantly is the absence of serotype B in the vaccine. Serotype B meningococci cause 60%-65% of meningococcal disease in the United States in infants. That is why the number of cases projected to be prevented with Hib-MenCY-TT is about one-third of all cases among infants.

• The total number of shots goes up per visit unless GlaxoSmithKline vaccines are preferentially used. Hib-MenCY-TT was developed and is licensed by GlaxoSmithKline, a world leader in pediatric vaccines, and they are building a portfolio of vaccines that can fit together well. There is nothing wrong with that – it is good marketing. Sanofi Pasteur Vaccines is doing the same thing and, as more products are forthcoming from Pfizer Vaccines, Novartis Vaccines, and others, we can expect the same strategy. However, the CDC, AAP, and AAFP do not want to endorse products that limit choices and/or provide any single company with a competitive advantage. So, to endorse Hib-MenCY-TT that clearly fits best with only GlaxoSmithKline vaccine products may be an unspoken concern.

• The National Immunization Program cannot afford it. Going back to the presentation to ACIP at the CDC in October 2011, a key aspect was the cost of vaccination calculated against cases prevented and lives saved. The calculation for Quality-Adjusted Life Year (QALY) saved for a two-dose schedule among adolescents came out to $157,000/case. For the infant vaccination, the numbers were pretty staggering at $3.6 million/case, based on the current incidence of meningococcal infections in the United States (see sidebar). Even if the incidence of meningococcal infections were currently as high as they were back in 1997-1999, the cost would be $0.5 million/case. For those thinking about the option of toddler vaccination with the quadrivalent meningococcal conjugate vaccine (Menactra), the calculations for QALYs concluded that such a strategy prevented half as many cases at half the cost.

So where do we go from here? The lack of an endorsement by ACIP/AAP/AAFP for universal use* normally means that the vaccine will not be available within the Vaccines for Children free program, and it will not be covered by commercial health insurance plans except for the specific indications endorsed by the recommending bodies.* So these are huge barriers to use. Nevertheless, it is a licensed vaccine and it is safe and effective, just not perfect and not cost-effective for widespread public use at government expense. How much is a child’s life worth? If it is your child, then the life is priceless. But in public health there are limits to what can be afforded. We will see more of these types of issues in the future. Another unspoken concern of the ACIP/AAP/AAFP is that a two-tiered vaccine access situation develops. In other words, for those who can afford to pay, Hib-MenCY-TT is available and, if they can pay for it out-of-pocket, then they can buy it to protect their child.

The following are cost-effectiveness analysis conclusions that were presented to the CDC:

• Vaccinating infants or toddlers with meningococcal vaccine has a high cost per case prevented – even at a low vaccine price.

• Cost estimates are much higher than prior analyses because of declining incidence and shorter duration of protection.

• Infant vaccination prevents twice as many cases as toddler vaccination but at twice the cost – cost per QALY saved is similar for both strategies.

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Rochester (N.Y.) General Hospital Research Institute. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero disclosed that in the past 3 years, he has served as a consultant to Sanofi Pasteur, Pfizer, Novartis, and Crucell for their vaccines currently licensed and in development. Dr. Pichichero also disclosed that in the past 3 years, his academic institution has received research grants to support vaccine work from GlaxoSmithKline, Sanofi Pasteur, Pfizer, Novartis, and Crucell, including studies involving Hib-MenCY-TT produced by GlaxoSmithKline and Quadrivalent meningococcal vaccine by Sanofi Pasteur and Novartis.

* This article was updated on 10/26/12.

In our understanding of family systems, we have long known that dysfunctional relational patterns often lie at the root of our patients’ problems. But to what extent should family diagnoses be incorporated into the DSM?

I sat down with Dr. Marianne Z. Wamboldt to explore these issues. Dr. Wamboldt, a child psychiatrist, is chair of the board of the Family Process Institute. She also holds the Leslie and William Vollbracht Family Chair in Stress and Anxiety Disorders at the University of Colorado, Denver, and serves as professor and vice chair in the department of psychiatry in the medical school.

Marianne Wamboldt: So why exactly do you oppose the inclusion of family diagnoses in the DSM?

Alison Heru: I don’t like the labeling of families. I like helping families understand their strengths and helping them work out their problems. I don’t see family problems as psychiatric problems.

MW: I think it is important that we have a way of measuring and classifying what we see, so that we know what we are talking about and that we can measure whether or not we have success in what we are doing.

AH: I agree that these goals are important. However, I think we can use tools like the GARF (Global Assessment of Relational Functioning) or other measuring devices, to do this. I don’t think we need to go as far as including measurements of family functioning in the DSM.

MW: Did you know the GARF is included in DSM-IV-TR already? What is the difference between the GARF and the DSM?

AH: The GARF is good and useful, like the GAF (Global Assessment Scale) in that it gives you a way to describe functioning on a range from healthy to unhealthy, without defining a pathological state. When you put something in the DSM, you are saying it is a disease. You are saying something about etiology.

MW: Not necessarily. In the DSM-IV, ADHD is a description of behavior; there is no attempt to talk about causality. We had hoped that the DSM-5 could start talking about causality, but most of the research is not yet ready. In the meantime, having a clear definition of what we are treating is useful for researchers as well as clinicians. Having a universal description is helpful for everyone.

AH: I agree that a universal description is good, but I still think that more harm than good comes from including family diagnoses in the DSM. I just don’t see families needing to be labeled as pathological. I understand your point, but I think that the repercussions of having a family diagnosis in the DSM outweigh the benefits. The DSM is used in all kinds of ways. In the court system, it is described as "The Psychiatrist’s Bible." If a family diagnosis is in the DSM, then it becomes an "illness" with all the repercussions that come from that label.

MW: However, if it is not in the DSM, many insurance companies won’t pay for the treatment, and persons in the family get labeled with some other diagnosis in order to get therapy. Moreover, if you label something and talk about it, stigma is reduced. Think about cancer and how we used to think about it. It used to be feared, and people with cancer were isolated. That is not what we want for psychiatry and family problems.

AH: I understand that view, but I think that the analogy with cancer is not accurate. Cancer research is well funded, and cancer in many instances can be cured. Mental illnesses have not seen this kind of support, funding, or understanding. In fact, funding has been drastically cut, and the prisons are full of people with mental illness. People now think about mental illness and crime together.

MW: When cancer research started, it was first to try to find commonalities among the many illnesses people with cancer had. The first treatment efforts improved conditions only a very little, but it was by using each effort and tweaking treatment again and again that the field moved forward to where it is today.

AH: I also heard (from Dr. Carl C. Bell of the University of Illinois at Chicago) about a study that showed that stigma was actually increased after the community was educated that psychiatric illnesses are biological illnesses. Before the educational intervention, people with mental illness were seen in the community as odd or quirky and accepted as "different." After the study, these same people were shunned by the community as having an immutable biological disease.

MW: What about child mistreatment? Don’t you think that would be good to include in the DSM? What about domestic violence? And there is a big push to include parental alienation syndrome. What do you think about that?

AH: I don’t see these as psychiatric illnesses, [they are] more social or criminal problems. I don’t think couples with IPV [interpersonal violence] would come for treatment if they knew that they would be labeled by the insurance companies or doctors. I think the parental alienation syndrome is also not a good thing to put in the DSM, whatever the science (or not) behind it. It is a social problem that parents do bad things to their children. I do not see that as a psychiatric issue.

MW: But we treat these people. They come to us for help, and we try to help them. I think it is better to have clear definition that is well thought out and scientifically based, rather than just vague and impressionistic. Relational problems have been written about for years. There is a huge literature on this topic. I think that the evidence for many relational processes that lead to morbidity is at least as good, if not better, than many diagnoses in the DSM-IV.

AH: I agree. However, my conclusion is that we should take things OUT of the DSM that don’t belong there and prevent social or criminal diagnoses from going into the DSM.

MW: How are we going to measure and be scientific about our work?

AH: I think we can do that without using the DSM. Why is the DSM so important? I also don’t think we should let insurance companies dictate how we think about what we do.

MW: Insurance companies pay for treating persons with some diagnoses, but not other diagnoses. For example, in some states, they do not pay for treatment for ADHD, which is extensively researched to be a primarily heritable illness, responsive to medications more than even very intensive psychotherapeutic interventions, and quite disabling for some youth. The DSM has to be used for more than merely what insurance companies decide what to do with it. It originally began as a method of reliably describing patients that psychiatrists were treating, so as to share knowledge about the illnesses, what worked, and what did not work. The [people behind the] ICD-9, 10, and now 11, also think that relational disorders are important to include. We don’t want to be a country left behind!

AH: A good question is, "What is the DSM for?"

MW: To provide a framework for us to diagnose and treat mental illness.

AH: Should it not just focus on biological disease? That is my preference of a system that calls itself a disease manual.

MW: But that is not what the DSM is. It reflects the biopsychosocial model and includes behaviors and clusters of symptoms that are a focus of treatment.

AH: I am not a biological psychiatrist; (I’m) more of a social and family psychiatrist, but I see the DSM as being a biological manual. I think it is hard to categorize social and family behaviors that can be pathological in one situation or culture and not in another. Take expressed emotion (EE). Research in Japan has found that two components of high EE – high criticism and high overinvolvement – need to be parsed out and that families benefit from specific treatments, depending on which component of high EE is present. I don’t think that relational diagnoses are fixed enough. This is another argument.

MW: So how do you see us communicating and working on this problem without a good system of description?

AH: Well, I think we can continue as we have, using these constructs but not embedding them in the DSM. I don’t think that is necessary. I think it might be better to get diagnoses that are subjective or significantly influenced by the prevailing culture out of the DSM.

MW: I would argue that many illnesses, let alone psychiatric disorders in the DSM, are significantly influenced by the prevailing culture. Read "The Spirit Catches You and You Fall Down" (New York: Farrar, Straus and Giroux, 2012), which illustrates the different cultural beliefs of the Hmong (who think the spirit moves a child) from Western medicine (which diagnoses epilepsy). If relational diagnoses are not in the DSM, many therapists will not think about relationships and will not have them as a focus for change.

AH: I think that is an assumption that is not proven.

MW: If relational disorders are in the DSM, then practitioners are more likely to think of them, and faculty are more likely to teach them to new clinicians.

AH: Yes, but think of them as a pathological entity and then we are back where we were 50 years ago – pathologizing families.

MW: I disagree with that. With education and knowledge about effective family interventions, stigma can be reduced, and people can access the treatments they need!

AH: This is a good argument that our field needs to engage in. Better measurement and reduced stigma are the benefits that you see from including relational problems in the DSM.

MW: Yes, and you see this as unnecessary labeling that might be used against families.

AH: Yes. I also think that relational diagnoses are more fluid than biological diagnoses and that we are not ready, and may never be ready, to carve these out as definitive immutable constructs.

Dr. Heru is with the department of psychiatry at the University of Colorado at Denver. She has been a member of the Association of Family Psychiatrists since 2002 and currently serves as the organization’s treasurer. In addition, she is the coauthor of two books on working with families and is the author of numerous articles on this topic.

In our understanding of family systems, we have long known that dysfunctional relational patterns often lie at the root of our patients’ problems. But to what extent should family diagnoses be incorporated into the DSM?

I sat down with Dr. Marianne Z. Wamboldt to explore these issues. Dr. Wamboldt, a child psychiatrist, is chair of the board of the Family Process Institute. She also holds the Leslie and William Vollbracht Family Chair in Stress and Anxiety Disorders at the University of Colorado, Denver, and serves as professor and vice chair in the department of psychiatry in the medical school.

Marianne Wamboldt: So why exactly do you oppose the inclusion of family diagnoses in the DSM?

Alison Heru: I don’t like the labeling of families. I like helping families understand their strengths and helping them work out their problems. I don’t see family problems as psychiatric problems.

MW: I think it is important that we have a way of measuring and classifying what we see, so that we know what we are talking about and that we can measure whether or not we have success in what we are doing.

AH: I agree that these goals are important. However, I think we can use tools like the GARF (Global Assessment of Relational Functioning) or other measuring devices, to do this. I don’t think we need to go as far as including measurements of family functioning in the DSM.

MW: Did you know the GARF is included in DSM-IV-TR already? What is the difference between the GARF and the DSM?

AH: The GARF is good and useful, like the GAF (Global Assessment Scale) in that it gives you a way to describe functioning on a range from healthy to unhealthy, without defining a pathological state. When you put something in the DSM, you are saying it is a disease. You are saying something about etiology.

MW: Not necessarily. In the DSM-IV, ADHD is a description of behavior; there is no attempt to talk about causality. We had hoped that the DSM-5 could start talking about causality, but most of the research is not yet ready. In the meantime, having a clear definition of what we are treating is useful for researchers as well as clinicians. Having a universal description is helpful for everyone.

AH: I agree that a universal description is good, but I still think that more harm than good comes from including family diagnoses in the DSM. I just don’t see families needing to be labeled as pathological. I understand your point, but I think that the repercussions of having a family diagnosis in the DSM outweigh the benefits. The DSM is used in all kinds of ways. In the court system, it is described as "The Psychiatrist’s Bible." If a family diagnosis is in the DSM, then it becomes an "illness" with all the repercussions that come from that label.

MW: However, if it is not in the DSM, many insurance companies won’t pay for the treatment, and persons in the family get labeled with some other diagnosis in order to get therapy. Moreover, if you label something and talk about it, stigma is reduced. Think about cancer and how we used to think about it. It used to be feared, and people with cancer were isolated. That is not what we want for psychiatry and family problems.

AH: I understand that view, but I think that the analogy with cancer is not accurate. Cancer research is well funded, and cancer in many instances can be cured. Mental illnesses have not seen this kind of support, funding, or understanding. In fact, funding has been drastically cut, and the prisons are full of people with mental illness. People now think about mental illness and crime together.

MW: When cancer research started, it was first to try to find commonalities among the many illnesses people with cancer had. The first treatment efforts improved conditions only a very little, but it was by using each effort and tweaking treatment again and again that the field moved forward to where it is today.

AH: I also heard (from Dr. Carl C. Bell of the University of Illinois at Chicago) about a study that showed that stigma was actually increased after the community was educated that psychiatric illnesses are biological illnesses. Before the educational intervention, people with mental illness were seen in the community as odd or quirky and accepted as "different." After the study, these same people were shunned by the community as having an immutable biological disease.

MW: What about child mistreatment? Don’t you think that would be good to include in the DSM? What about domestic violence? And there is a big push to include parental alienation syndrome. What do you think about that?

AH: I don’t see these as psychiatric illnesses, [they are] more social or criminal problems. I don’t think couples with IPV [interpersonal violence] would come for treatment if they knew that they would be labeled by the insurance companies or doctors. I think the parental alienation syndrome is also not a good thing to put in the DSM, whatever the science (or not) behind it. It is a social problem that parents do bad things to their children. I do not see that as a psychiatric issue.

MW: But we treat these people. They come to us for help, and we try to help them. I think it is better to have clear definition that is well thought out and scientifically based, rather than just vague and impressionistic. Relational problems have been written about for years. There is a huge literature on this topic. I think that the evidence for many relational processes that lead to morbidity is at least as good, if not better, than many diagnoses in the DSM-IV.

AH: I agree. However, my conclusion is that we should take things OUT of the DSM that don’t belong there and prevent social or criminal diagnoses from going into the DSM.

MW: How are we going to measure and be scientific about our work?

AH: I think we can do that without using the DSM. Why is the DSM so important? I also don’t think we should let insurance companies dictate how we think about what we do.

MW: Insurance companies pay for treating persons with some diagnoses, but not other diagnoses. For example, in some states, they do not pay for treatment for ADHD, which is extensively researched to be a primarily heritable illness, responsive to medications more than even very intensive psychotherapeutic interventions, and quite disabling for some youth. The DSM has to be used for more than merely what insurance companies decide what to do with it. It originally began as a method of reliably describing patients that psychiatrists were treating, so as to share knowledge about the illnesses, what worked, and what did not work. The [people behind the] ICD-9, 10, and now 11, also think that relational disorders are important to include. We don’t want to be a country left behind!

AH: A good question is, "What is the DSM for?"

MW: To provide a framework for us to diagnose and treat mental illness.

AH: Should it not just focus on biological disease? That is my preference of a system that calls itself a disease manual.

MW: But that is not what the DSM is. It reflects the biopsychosocial model and includes behaviors and clusters of symptoms that are a focus of treatment.

AH: I am not a biological psychiatrist; (I’m) more of a social and family psychiatrist, but I see the DSM as being a biological manual. I think it is hard to categorize social and family behaviors that can be pathological in one situation or culture and not in another. Take expressed emotion (EE). Research in Japan has found that two components of high EE – high criticism and high overinvolvement – need to be parsed out and that families benefit from specific treatments, depending on which component of high EE is present. I don’t think that relational diagnoses are fixed enough. This is another argument.

MW: So how do you see us communicating and working on this problem without a good system of description?

AH: Well, I think we can continue as we have, using these constructs but not embedding them in the DSM. I don’t think that is necessary. I think it might be better to get diagnoses that are subjective or significantly influenced by the prevailing culture out of the DSM.

MW: I would argue that many illnesses, let alone psychiatric disorders in the DSM, are significantly influenced by the prevailing culture. Read "The Spirit Catches You and You Fall Down" (New York: Farrar, Straus and Giroux, 2012), which illustrates the different cultural beliefs of the Hmong (who think the spirit moves a child) from Western medicine (which diagnoses epilepsy). If relational diagnoses are not in the DSM, many therapists will not think about relationships and will not have them as a focus for change.

AH: I think that is an assumption that is not proven.

MW: If relational disorders are in the DSM, then practitioners are more likely to think of them, and faculty are more likely to teach them to new clinicians.

AH: Yes, but think of them as a pathological entity and then we are back where we were 50 years ago – pathologizing families.

MW: I disagree with that. With education and knowledge about effective family interventions, stigma can be reduced, and people can access the treatments they need!

AH: This is a good argument that our field needs to engage in. Better measurement and reduced stigma are the benefits that you see from including relational problems in the DSM.

MW: Yes, and you see this as unnecessary labeling that might be used against families.

AH: Yes. I also think that relational diagnoses are more fluid than biological diagnoses and that we are not ready, and may never be ready, to carve these out as definitive immutable constructs.

Dr. Heru is with the department of psychiatry at the University of Colorado at Denver. She has been a member of the Association of Family Psychiatrists since 2002 and currently serves as the organization’s treasurer. In addition, she is the coauthor of two books on working with families and is the author of numerous articles on this topic.

In our understanding of family systems, we have long known that dysfunctional relational patterns often lie at the root of our patients’ problems. But to what extent should family diagnoses be incorporated into the DSM?

I sat down with Dr. Marianne Z. Wamboldt to explore these issues. Dr. Wamboldt, a child psychiatrist, is chair of the board of the Family Process Institute. She also holds the Leslie and William Vollbracht Family Chair in Stress and Anxiety Disorders at the University of Colorado, Denver, and serves as professor and vice chair in the department of psychiatry in the medical school.

Marianne Wamboldt: So why exactly do you oppose the inclusion of family diagnoses in the DSM?

Alison Heru: I don’t like the labeling of families. I like helping families understand their strengths and helping them work out their problems. I don’t see family problems as psychiatric problems.

MW: I think it is important that we have a way of measuring and classifying what we see, so that we know what we are talking about and that we can measure whether or not we have success in what we are doing.

AH: I agree that these goals are important. However, I think we can use tools like the GARF (Global Assessment of Relational Functioning) or other measuring devices, to do this. I don’t think we need to go as far as including measurements of family functioning in the DSM.

MW: Did you know the GARF is included in DSM-IV-TR already? What is the difference between the GARF and the DSM?

AH: The GARF is good and useful, like the GAF (Global Assessment Scale) in that it gives you a way to describe functioning on a range from healthy to unhealthy, without defining a pathological state. When you put something in the DSM, you are saying it is a disease. You are saying something about etiology.

MW: Not necessarily. In the DSM-IV, ADHD is a description of behavior; there is no attempt to talk about causality. We had hoped that the DSM-5 could start talking about causality, but most of the research is not yet ready. In the meantime, having a clear definition of what we are treating is useful for researchers as well as clinicians. Having a universal description is helpful for everyone.

AH: I agree that a universal description is good, but I still think that more harm than good comes from including family diagnoses in the DSM. I just don’t see families needing to be labeled as pathological. I understand your point, but I think that the repercussions of having a family diagnosis in the DSM outweigh the benefits. The DSM is used in all kinds of ways. In the court system, it is described as "The Psychiatrist’s Bible." If a family diagnosis is in the DSM, then it becomes an "illness" with all the repercussions that come from that label.

MW: However, if it is not in the DSM, many insurance companies won’t pay for the treatment, and persons in the family get labeled with some other diagnosis in order to get therapy. Moreover, if you label something and talk about it, stigma is reduced. Think about cancer and how we used to think about it. It used to be feared, and people with cancer were isolated. That is not what we want for psychiatry and family problems.

AH: I understand that view, but I think that the analogy with cancer is not accurate. Cancer research is well funded, and cancer in many instances can be cured. Mental illnesses have not seen this kind of support, funding, or understanding. In fact, funding has been drastically cut, and the prisons are full of people with mental illness. People now think about mental illness and crime together.

MW: When cancer research started, it was first to try to find commonalities among the many illnesses people with cancer had. The first treatment efforts improved conditions only a very little, but it was by using each effort and tweaking treatment again and again that the field moved forward to where it is today.

AH: I also heard (from Dr. Carl C. Bell of the University of Illinois at Chicago) about a study that showed that stigma was actually increased after the community was educated that psychiatric illnesses are biological illnesses. Before the educational intervention, people with mental illness were seen in the community as odd or quirky and accepted as "different." After the study, these same people were shunned by the community as having an immutable biological disease.

MW: What about child mistreatment? Don’t you think that would be good to include in the DSM? What about domestic violence? And there is a big push to include parental alienation syndrome. What do you think about that?

AH: I don’t see these as psychiatric illnesses, [they are] more social or criminal problems. I don’t think couples with IPV [interpersonal violence] would come for treatment if they knew that they would be labeled by the insurance companies or doctors. I think the parental alienation syndrome is also not a good thing to put in the DSM, whatever the science (or not) behind it. It is a social problem that parents do bad things to their children. I do not see that as a psychiatric issue.

MW: But we treat these people. They come to us for help, and we try to help them. I think it is better to have clear definition that is well thought out and scientifically based, rather than just vague and impressionistic. Relational problems have been written about for years. There is a huge literature on this topic. I think that the evidence for many relational processes that lead to morbidity is at least as good, if not better, than many diagnoses in the DSM-IV.

AH: I agree. However, my conclusion is that we should take things OUT of the DSM that don’t belong there and prevent social or criminal diagnoses from going into the DSM.

MW: How are we going to measure and be scientific about our work?

AH: I think we can do that without using the DSM. Why is the DSM so important? I also don’t think we should let insurance companies dictate how we think about what we do.

MW: Insurance companies pay for treating persons with some diagnoses, but not other diagnoses. For example, in some states, they do not pay for treatment for ADHD, which is extensively researched to be a primarily heritable illness, responsive to medications more than even very intensive psychotherapeutic interventions, and quite disabling for some youth. The DSM has to be used for more than merely what insurance companies decide what to do with it. It originally began as a method of reliably describing patients that psychiatrists were treating, so as to share knowledge about the illnesses, what worked, and what did not work. The [people behind the] ICD-9, 10, and now 11, also think that relational disorders are important to include. We don’t want to be a country left behind!

AH: A good question is, "What is the DSM for?"

MW: To provide a framework for us to diagnose and treat mental illness.

AH: Should it not just focus on biological disease? That is my preference of a system that calls itself a disease manual.

MW: But that is not what the DSM is. It reflects the biopsychosocial model and includes behaviors and clusters of symptoms that are a focus of treatment.

AH: I am not a biological psychiatrist; (I’m) more of a social and family psychiatrist, but I see the DSM as being a biological manual. I think it is hard to categorize social and family behaviors that can be pathological in one situation or culture and not in another. Take expressed emotion (EE). Research in Japan has found that two components of high EE – high criticism and high overinvolvement – need to be parsed out and that families benefit from specific treatments, depending on which component of high EE is present. I don’t think that relational diagnoses are fixed enough. This is another argument.

MW: So how do you see us communicating and working on this problem without a good system of description?

AH: Well, I think we can continue as we have, using these constructs but not embedding them in the DSM. I don’t think that is necessary. I think it might be better to get diagnoses that are subjective or significantly influenced by the prevailing culture out of the DSM.

MW: I would argue that many illnesses, let alone psychiatric disorders in the DSM, are significantly influenced by the prevailing culture. Read "The Spirit Catches You and You Fall Down" (New York: Farrar, Straus and Giroux, 2012), which illustrates the different cultural beliefs of the Hmong (who think the spirit moves a child) from Western medicine (which diagnoses epilepsy). If relational diagnoses are not in the DSM, many therapists will not think about relationships and will not have them as a focus for change.

AH: I think that is an assumption that is not proven.

MW: If relational disorders are in the DSM, then practitioners are more likely to think of them, and faculty are more likely to teach them to new clinicians.

AH: Yes, but think of them as a pathological entity and then we are back where we were 50 years ago – pathologizing families.

MW: I disagree with that. With education and knowledge about effective family interventions, stigma can be reduced, and people can access the treatments they need!

AH: This is a good argument that our field needs to engage in. Better measurement and reduced stigma are the benefits that you see from including relational problems in the DSM.

MW: Yes, and you see this as unnecessary labeling that might be used against families.

AH: Yes. I also think that relational diagnoses are more fluid than biological diagnoses and that we are not ready, and may never be ready, to carve these out as definitive immutable constructs.

Dr. Heru is with the department of psychiatry at the University of Colorado at Denver. She has been a member of the Association of Family Psychiatrists since 2002 and currently serves as the organization’s treasurer. In addition, she is the coauthor of two books on working with families and is the author of numerous articles on this topic.

VIENNA – Mixed results in phase II and III clinical trials leave open the question of whether lapatinib can prevent brain metastases in women with HER2-positive breast cancer.

Lapatinib (Tykerb) did not decrease the development of brain metastases when compared with trastuzumab (Herceptin) – each added to capecitabine (Xeloda) – in the open-label phase III CEREBREL trial. The results were inconclusive, however, for the primary end point of the incidence of central nervous system events as a first sign of relapse.

Favorable findings were reported from the 45-patient phase II LANDSCAPE study. Two-thirds of patients had an objective CNS response to up-front lapatinib plus capecitabine in the single-arm study.

Investigators from both trials reported outcomes at the European Society for Medical Oncology Congress.

‘No Conclusion Can Be Made...’

In the CEREBREL trial, 251 women were treated with lapatinib in combination with capecitabine. Eight (3%) exhibited CNS progression as the first site of relapse. In comparison, 12 (5%) of 250 women given trastuzumab plus capecitabine exhibited CNS progression (P = .360).

The incidence of CNS progression at any time (7% vs. 6%, respectively) and the median time to first CNS progression (5.7 vs. 4.4 months) also did not differ significantly.

Sara Freeman/IMNG Medical Media

"No conclusion should be made from these results," said Dr. Xavier Pivot of the Université de Franche-Comté in Besançon, France.

Dr. Pivot noted that a very low rate of CNS events had occurred in the trial because of the stringent accrual process, undermining the conclusions that can be drawn.

Trial Excluded Asymptomatic Brain Metastases

"The CEREBREL study was a front-line study, but the problem was that asymptomatic brain metastases were being screened out of the population," Dr. Stephen Johnston, who was not involved the study, commented in an interview.

"The overall incidence of brain metastases that they found in the study was a lot lower than they were anticipating, so they were never going to meet their end point," added Dr. Johnston, a consultant medical oncologist and director of clinical research and development at the Royal Marsden and the Institute of Cancer Research in London.

CEREBREL enrolled 540 of a planned 650 women with HER2-positive metastatic breast cancer who had received prior treatment with an anthracycline or taxane but who had no CNS metastases. To ensure that no metastases were present, patients had a baseline MRI scan, with 20% of women excluded because they had asymptomatic lesions.

In total, 271 women received lapatinib (1,250 mg/day) plus capecitabine (2,000 mg/m²/day on days 1-14 every 21 days) and 269 trastuzumab (6 mg/kg every 21 days) plus capecitabine (2,500 mg/m²/day on days 1-14 every 21 days).

PFS Longer with Trastuzumab and Capecitabine

The trial results also showed that median progression-free survival (PFS) was longer in patients who received trastuzumab in combination with the chemotherapy than in those who received lapatinib (8 months vs. 6.6 months, hazard ratio 1.3, P = .021).

This effect dissipated, however, when prior treatment with trastuzumab was considered; it had been received by 62% of patients in the lapatinib-containing arm and 59% of patients in the trastuzumab-containing arm.

While there was no difference in PFS among patients who had previously been treated with trastuzumab, those who had never received the drug before the trial appeared to obtain a greater benefit.

Commenting on these data, Dr. Johnston noted that they do seem to suggest that the combination of lapatinib and capecitabine was not equivalent and was actually inferior to trastuzumab plus capecitabine.

Nevertheless, "I think the question about the effects of lapatinib on brain metastases is still relevant," he said.

"We’re doing a trial [LANTERN] of lapatinib-capecitabine versus continuing the trastuzumab and adding in capecitabine, to see if switching the HER2-targeting keeps the brain disease under control for longer," Dr. Johnston explained. "This is where lapatinib may still have a role."

LANDSCAPE Results Favorable

The primary hypothesis of the phase II LANDSCAPE study was that up-front treatment with lapatinib might help prevent brain metastasis in HER2-positive metastatic breast cancer and delay the need for whole-brain radiation and its associated neurotoxicity, said study investigator Dr. Thomas Bachelot, on behalf of the Unicancer Federation Française group.

Dr. Bachelot of INSERM in Lyon said the response and overall survival results compared favorably with published data for whole-brain radiotherapy (WBRT).

Two thirds (66%) of patients treated with lapatinib and capecitabine exhibited a CNS objective response: 46% achieved a reduction in brain metastases of 50%-80%, and 20% exhibited a reduction in brain metastases of 80% or more. The median time to progression was 5.5 months, and the median time to WBRT was 7.8 months. Median overall survival was 17 months.

"This strategy could help delay whole-brain radiotherapy and its associated [neurological] toxicity," Dr. Bachelot concluded, noting that the up-front use of lapatinib and capecitabine warrants further evaluation.

The first analysis of the LANDSCAPE trial was presented at the American Society of Clinical Oncology (ASCO) in 2011.

Both the CEREBREL and LANDSCAPE studies were supported by funding from GlaxoSmithKline. All authors have received research support or consultancy fees from GlaxoSmithKline and Roche. Dr. Bachelot and Dr. Johnston have also received consultancy fees from Novartis.

VIENNA – Mixed results in phase II and III clinical trials leave open the question of whether lapatinib can prevent brain metastases in women with HER2-positive breast cancer.

Lapatinib (Tykerb) did not decrease the development of brain metastases when compared with trastuzumab (Herceptin) – each added to capecitabine (Xeloda) – in the open-label phase III CEREBREL trial. The results were inconclusive, however, for the primary end point of the incidence of central nervous system events as a first sign of relapse.

Favorable findings were reported from the 45-patient phase II LANDSCAPE study. Two-thirds of patients had an objective CNS response to up-front lapatinib plus capecitabine in the single-arm study.

Investigators from both trials reported outcomes at the European Society for Medical Oncology Congress.

‘No Conclusion Can Be Made...’

In the CEREBREL trial, 251 women were treated with lapatinib in combination with capecitabine. Eight (3%) exhibited CNS progression as the first site of relapse. In comparison, 12 (5%) of 250 women given trastuzumab plus capecitabine exhibited CNS progression (P = .360).

The incidence of CNS progression at any time (7% vs. 6%, respectively) and the median time to first CNS progression (5.7 vs. 4.4 months) also did not differ significantly.

Sara Freeman/IMNG Medical Media

"No conclusion should be made from these results," said Dr. Xavier Pivot of the Université de Franche-Comté in Besançon, France.

Dr. Pivot noted that a very low rate of CNS events had occurred in the trial because of the stringent accrual process, undermining the conclusions that can be drawn.

Trial Excluded Asymptomatic Brain Metastases

"The CEREBREL study was a front-line study, but the problem was that asymptomatic brain metastases were being screened out of the population," Dr. Stephen Johnston, who was not involved the study, commented in an interview.

"The overall incidence of brain metastases that they found in the study was a lot lower than they were anticipating, so they were never going to meet their end point," added Dr. Johnston, a consultant medical oncologist and director of clinical research and development at the Royal Marsden and the Institute of Cancer Research in London.

CEREBREL enrolled 540 of a planned 650 women with HER2-positive metastatic breast cancer who had received prior treatment with an anthracycline or taxane but who had no CNS metastases. To ensure that no metastases were present, patients had a baseline MRI scan, with 20% of women excluded because they had asymptomatic lesions.

In total, 271 women received lapatinib (1,250 mg/day) plus capecitabine (2,000 mg/m²/day on days 1-14 every 21 days) and 269 trastuzumab (6 mg/kg every 21 days) plus capecitabine (2,500 mg/m²/day on days 1-14 every 21 days).

PFS Longer with Trastuzumab and Capecitabine

The trial results also showed that median progression-free survival (PFS) was longer in patients who received trastuzumab in combination with the chemotherapy than in those who received lapatinib (8 months vs. 6.6 months, hazard ratio 1.3, P = .021).

This effect dissipated, however, when prior treatment with trastuzumab was considered; it had been received by 62% of patients in the lapatinib-containing arm and 59% of patients in the trastuzumab-containing arm.

While there was no difference in PFS among patients who had previously been treated with trastuzumab, those who had never received the drug before the trial appeared to obtain a greater benefit.

Commenting on these data, Dr. Johnston noted that they do seem to suggest that the combination of lapatinib and capecitabine was not equivalent and was actually inferior to trastuzumab plus capecitabine.

Nevertheless, "I think the question about the effects of lapatinib on brain metastases is still relevant," he said.

"We’re doing a trial [LANTERN] of lapatinib-capecitabine versus continuing the trastuzumab and adding in capecitabine, to see if switching the HER2-targeting keeps the brain disease under control for longer," Dr. Johnston explained. "This is where lapatinib may still have a role."

LANDSCAPE Results Favorable

The primary hypothesis of the phase II LANDSCAPE study was that up-front treatment with lapatinib might help prevent brain metastasis in HER2-positive metastatic breast cancer and delay the need for whole-brain radiation and its associated neurotoxicity, said study investigator Dr. Thomas Bachelot, on behalf of the Unicancer Federation Française group.

Dr. Bachelot of INSERM in Lyon said the response and overall survival results compared favorably with published data for whole-brain radiotherapy (WBRT).

Two thirds (66%) of patients treated with lapatinib and capecitabine exhibited a CNS objective response: 46% achieved a reduction in brain metastases of 50%-80%, and 20% exhibited a reduction in brain metastases of 80% or more. The median time to progression was 5.5 months, and the median time to WBRT was 7.8 months. Median overall survival was 17 months.

"This strategy could help delay whole-brain radiotherapy and its associated [neurological] toxicity," Dr. Bachelot concluded, noting that the up-front use of lapatinib and capecitabine warrants further evaluation.

The first analysis of the LANDSCAPE trial was presented at the American Society of Clinical Oncology (ASCO) in 2011.

Both the CEREBREL and LANDSCAPE studies were supported by funding from GlaxoSmithKline. All authors have received research support or consultancy fees from GlaxoSmithKline and Roche. Dr. Bachelot and Dr. Johnston have also received consultancy fees from Novartis.

VIENNA – Mixed results in phase II and III clinical trials leave open the question of whether lapatinib can prevent brain metastases in women with HER2-positive breast cancer.

Lapatinib (Tykerb) did not decrease the development of brain metastases when compared with trastuzumab (Herceptin) – each added to capecitabine (Xeloda) – in the open-label phase III CEREBREL trial. The results were inconclusive, however, for the primary end point of the incidence of central nervous system events as a first sign of relapse.

Favorable findings were reported from the 45-patient phase II LANDSCAPE study. Two-thirds of patients had an objective CNS response to up-front lapatinib plus capecitabine in the single-arm study.

Investigators from both trials reported outcomes at the European Society for Medical Oncology Congress.

‘No Conclusion Can Be Made...’

In the CEREBREL trial, 251 women were treated with lapatinib in combination with capecitabine. Eight (3%) exhibited CNS progression as the first site of relapse. In comparison, 12 (5%) of 250 women given trastuzumab plus capecitabine exhibited CNS progression (P = .360).

The incidence of CNS progression at any time (7% vs. 6%, respectively) and the median time to first CNS progression (5.7 vs. 4.4 months) also did not differ significantly.

Sara Freeman/IMNG Medical Media

"No conclusion should be made from these results," said Dr. Xavier Pivot of the Université de Franche-Comté in Besançon, France.

Dr. Pivot noted that a very low rate of CNS events had occurred in the trial because of the stringent accrual process, undermining the conclusions that can be drawn.

Trial Excluded Asymptomatic Brain Metastases

"The CEREBREL study was a front-line study, but the problem was that asymptomatic brain metastases were being screened out of the population," Dr. Stephen Johnston, who was not involved the study, commented in an interview.

"The overall incidence of brain metastases that they found in the study was a lot lower than they were anticipating, so they were never going to meet their end point," added Dr. Johnston, a consultant medical oncologist and director of clinical research and development at the Royal Marsden and the Institute of Cancer Research in London.

CEREBREL enrolled 540 of a planned 650 women with HER2-positive metastatic breast cancer who had received prior treatment with an anthracycline or taxane but who had no CNS metastases. To ensure that no metastases were present, patients had a baseline MRI scan, with 20% of women excluded because they had asymptomatic lesions.

In total, 271 women received lapatinib (1,250 mg/day) plus capecitabine (2,000 mg/m²/day on days 1-14 every 21 days) and 269 trastuzumab (6 mg/kg every 21 days) plus capecitabine (2,500 mg/m²/day on days 1-14 every 21 days).

PFS Longer with Trastuzumab and Capecitabine

The trial results also showed that median progression-free survival (PFS) was longer in patients who received trastuzumab in combination with the chemotherapy than in those who received lapatinib (8 months vs. 6.6 months, hazard ratio 1.3, P = .021).

This effect dissipated, however, when prior treatment with trastuzumab was considered; it had been received by 62% of patients in the lapatinib-containing arm and 59% of patients in the trastuzumab-containing arm.

While there was no difference in PFS among patients who had previously been treated with trastuzumab, those who had never received the drug before the trial appeared to obtain a greater benefit.

Commenting on these data, Dr. Johnston noted that they do seem to suggest that the combination of lapatinib and capecitabine was not equivalent and was actually inferior to trastuzumab plus capecitabine.

Nevertheless, "I think the question about the effects of lapatinib on brain metastases is still relevant," he said.

"We’re doing a trial [LANTERN] of lapatinib-capecitabine versus continuing the trastuzumab and adding in capecitabine, to see if switching the HER2-targeting keeps the brain disease under control for longer," Dr. Johnston explained. "This is where lapatinib may still have a role."

LANDSCAPE Results Favorable

The primary hypothesis of the phase II LANDSCAPE study was that up-front treatment with lapatinib might help prevent brain metastasis in HER2-positive metastatic breast cancer and delay the need for whole-brain radiation and its associated neurotoxicity, said study investigator Dr. Thomas Bachelot, on behalf of the Unicancer Federation Française group.

Dr. Bachelot of INSERM in Lyon said the response and overall survival results compared favorably with published data for whole-brain radiotherapy (WBRT).

Two thirds (66%) of patients treated with lapatinib and capecitabine exhibited a CNS objective response: 46% achieved a reduction in brain metastases of 50%-80%, and 20% exhibited a reduction in brain metastases of 80% or more. The median time to progression was 5.5 months, and the median time to WBRT was 7.8 months. Median overall survival was 17 months.

"This strategy could help delay whole-brain radiotherapy and its associated [neurological] toxicity," Dr. Bachelot concluded, noting that the up-front use of lapatinib and capecitabine warrants further evaluation.

The first analysis of the LANDSCAPE trial was presented at the American Society of Clinical Oncology (ASCO) in 2011.

Both the CEREBREL and LANDSCAPE studies were supported by funding from GlaxoSmithKline. All authors have received research support or consultancy fees from GlaxoSmithKline and Roche. Dr. Bachelot and Dr. Johnston have also received consultancy fees from Novartis.

SHM has joined scores of medical societies pushing Congress to stop pending cuts to Medicare that would directly impact hospitalists.

Scheduled to go into effect at the start of the New Year, the cuts include sequestration, which would reduce hospitalists' Medicare payments by 2%, and slash funding to the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC). This is in addition to a 27% cut to Medicare physician payment rates resulting from Medicare's sustainable growth rate (SGR) formula.

In a letter last month to congressional leaders [PDF], and an accompanying note to society members, SHM said hospitalists need to lobby legislators "to find a reasonable and measured solution to deficit reduction that does not include arbitrary across-the-board cuts to Medicare providers."

"Congress needs to know we're not happy," says SHM board member Eric Siegal, MD, SFHM, board liaison SHM's Public Policy Committee. "The only way that we are going to get them to change their behavior is if enough of us mobilize, and make enough noise to make it clear that we are not going to stand for this anymore."

Dr. Siegal says that because Congress has repeatedly delayed draconian cuts, there is a general consensus that another delay is likely. But Dr. Siegal also notes lobbying is still necessary to ensure that will happen. SHM has previously supported a meaningful replacement to the SGR, which has yet to receive significant action in Congress.

"What the entire healthcare community needs to push for is a solution," Dr. Siegal adds. "It's very hard to develop any kind of a strategy for how you're going to deliver care if every X number of months you have to worry [whether] you're going to take a massive cut in your compensation."

SHM has joined scores of medical societies pushing Congress to stop pending cuts to Medicare that would directly impact hospitalists.

Scheduled to go into effect at the start of the New Year, the cuts include sequestration, which would reduce hospitalists' Medicare payments by 2%, and slash funding to the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC). This is in addition to a 27% cut to Medicare physician payment rates resulting from Medicare's sustainable growth rate (SGR) formula.

In a letter last month to congressional leaders [PDF], and an accompanying note to society members, SHM said hospitalists need to lobby legislators "to find a reasonable and measured solution to deficit reduction that does not include arbitrary across-the-board cuts to Medicare providers."

"Congress needs to know we're not happy," says SHM board member Eric Siegal, MD, SFHM, board liaison SHM's Public Policy Committee. "The only way that we are going to get them to change their behavior is if enough of us mobilize, and make enough noise to make it clear that we are not going to stand for this anymore."

Dr. Siegal says that because Congress has repeatedly delayed draconian cuts, there is a general consensus that another delay is likely. But Dr. Siegal also notes lobbying is still necessary to ensure that will happen. SHM has previously supported a meaningful replacement to the SGR, which has yet to receive significant action in Congress.

"What the entire healthcare community needs to push for is a solution," Dr. Siegal adds. "It's very hard to develop any kind of a strategy for how you're going to deliver care if every X number of months you have to worry [whether] you're going to take a massive cut in your compensation."

SHM has joined scores of medical societies pushing Congress to stop pending cuts to Medicare that would directly impact hospitalists.

Scheduled to go into effect at the start of the New Year, the cuts include sequestration, which would reduce hospitalists' Medicare payments by 2%, and slash funding to the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC). This is in addition to a 27% cut to Medicare physician payment rates resulting from Medicare's sustainable growth rate (SGR) formula.

In a letter last month to congressional leaders [PDF], and an accompanying note to society members, SHM said hospitalists need to lobby legislators "to find a reasonable and measured solution to deficit reduction that does not include arbitrary across-the-board cuts to Medicare providers."

"Congress needs to know we're not happy," says SHM board member Eric Siegal, MD, SFHM, board liaison SHM's Public Policy Committee. "The only way that we are going to get them to change their behavior is if enough of us mobilize, and make enough noise to make it clear that we are not going to stand for this anymore."

Dr. Siegal says that because Congress has repeatedly delayed draconian cuts, there is a general consensus that another delay is likely. But Dr. Siegal also notes lobbying is still necessary to ensure that will happen. SHM has previously supported a meaningful replacement to the SGR, which has yet to receive significant action in Congress.

"What the entire healthcare community needs to push for is a solution," Dr. Siegal adds. "It's very hard to develop any kind of a strategy for how you're going to deliver care if every X number of months you have to worry [whether] you're going to take a massive cut in your compensation."

Clinical question: What is the impact, and sustainability, of chlorhexidine bathing on central-venous-catheter-associated bloodstream infections?

Background: Chlorhexidine bathing has been associated with reductions in healthcare-associated bloodstream infections, including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. No prospective studies have evaluated the impact and sustainability of chlorhexidine bathing.

Study design: Prospective, three-phase study.

Setting: Medical-surgical ICUs and respiratory-care units at five New York hospitals.

Synopsis: In the pre-intervention phase (six to nine months, 1,808 admissions), patients were bathed with soap and water or nonmedicated bathing cloths. In the intervention phase (eight months, 1,832 admissions), patients were bathed with 2% chlorhexidine cloths. In the post-intervention phase (12 months, 2,834 admissions), chlorhexidine bathing was continued without oversight by researchers.

During the intervention phase, there were significantly fewer central-venous-catheter-associated bloodstream infections (2.6/1,000 catheter days vs. 6.4/1,000 pre-intervention). The reductions in bloodstream infections were sustained during the post-intervention period (2.9/1,000 catheter days). Compliance with chlorhexidine bathing was 82% and 88% during the intervention and post-intervention phases, and was well tolerated by the patients.

Limitations of this study include lack of patient-specific data and severity of illness data, as well as lack of randomization and blinding. Although not evaluated in this study, the savings associated with decreased bloodstream infections likely outweigh the cost of chlorhexidine bathing.

Bottom line: Chlorhexidine bathing is a well-tolerated, sustainable intervention that significantly reduces central-venous-catheter-associated bloodstream infections.

Citation: Montecalvo MA, McKenna D, Yarrish R, et al. Chlorhexidine bathing to reduce central venous catheter-associated bloodstream infection: impact and sustainability.Am J Med. 2012;125(5):505-511.

For more physician reviews of recent HM-relevant literature, visit our website.

Clinical question: What is the impact, and sustainability, of chlorhexidine bathing on central-venous-catheter-associated bloodstream infections?

Background: Chlorhexidine bathing has been associated with reductions in healthcare-associated bloodstream infections, including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. No prospective studies have evaluated the impact and sustainability of chlorhexidine bathing.

Study design: Prospective, three-phase study.

Setting: Medical-surgical ICUs and respiratory-care units at five New York hospitals.

Synopsis: In the pre-intervention phase (six to nine months, 1,808 admissions), patients were bathed with soap and water or nonmedicated bathing cloths. In the intervention phase (eight months, 1,832 admissions), patients were bathed with 2% chlorhexidine cloths. In the post-intervention phase (12 months, 2,834 admissions), chlorhexidine bathing was continued without oversight by researchers.

During the intervention phase, there were significantly fewer central-venous-catheter-associated bloodstream infections (2.6/1,000 catheter days vs. 6.4/1,000 pre-intervention). The reductions in bloodstream infections were sustained during the post-intervention period (2.9/1,000 catheter days). Compliance with chlorhexidine bathing was 82% and 88% during the intervention and post-intervention phases, and was well tolerated by the patients.

Limitations of this study include lack of patient-specific data and severity of illness data, as well as lack of randomization and blinding. Although not evaluated in this study, the savings associated with decreased bloodstream infections likely outweigh the cost of chlorhexidine bathing.

Bottom line: Chlorhexidine bathing is a well-tolerated, sustainable intervention that significantly reduces central-venous-catheter-associated bloodstream infections.

Citation: Montecalvo MA, McKenna D, Yarrish R, et al. Chlorhexidine bathing to reduce central venous catheter-associated bloodstream infection: impact and sustainability.Am J Med. 2012;125(5):505-511.

For more physician reviews of recent HM-relevant literature, visit our website.

Clinical question: What is the impact, and sustainability, of chlorhexidine bathing on central-venous-catheter-associated bloodstream infections?

Background: Chlorhexidine bathing has been associated with reductions in healthcare-associated bloodstream infections, including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. No prospective studies have evaluated the impact and sustainability of chlorhexidine bathing.

Study design: Prospective, three-phase study.

Setting: Medical-surgical ICUs and respiratory-care units at five New York hospitals.

Synopsis: In the pre-intervention phase (six to nine months, 1,808 admissions), patients were bathed with soap and water or nonmedicated bathing cloths. In the intervention phase (eight months, 1,832 admissions), patients were bathed with 2% chlorhexidine cloths. In the post-intervention phase (12 months, 2,834 admissions), chlorhexidine bathing was continued without oversight by researchers.

During the intervention phase, there were significantly fewer central-venous-catheter-associated bloodstream infections (2.6/1,000 catheter days vs. 6.4/1,000 pre-intervention). The reductions in bloodstream infections were sustained during the post-intervention period (2.9/1,000 catheter days). Compliance with chlorhexidine bathing was 82% and 88% during the intervention and post-intervention phases, and was well tolerated by the patients.

Limitations of this study include lack of patient-specific data and severity of illness data, as well as lack of randomization and blinding. Although not evaluated in this study, the savings associated with decreased bloodstream infections likely outweigh the cost of chlorhexidine bathing.

Bottom line: Chlorhexidine bathing is a well-tolerated, sustainable intervention that significantly reduces central-venous-catheter-associated bloodstream infections.

Citation: Montecalvo MA, McKenna D, Yarrish R, et al. Chlorhexidine bathing to reduce central venous catheter-associated bloodstream infection: impact and sustainability.Am J Med. 2012;125(5):505-511.

For more physician reviews of recent HM-relevant literature, visit our website.

Ustekinumab induced a clinical response in patients with moderate to severe Crohn’s disease that was resistant to tumor necrosis factor antagonists, in a phase IIb clinical trial published online Oct. 17 in the New England Journal of Medicine.

However, the agent did not improve remission rates, compared with placebo, said Dr. William J. Sandborn, professor of medicine and chief of the division of gastroenterology at the University of California San Diego, La Jolla, and his associates.

"A sizable proportion" of patients with moderate to severe Crohn’s disease do not respond to TNF antagonists, have an unsustained response, or must discontinue the medications because of adverse effects. After ustekinumab showed efficacy in such patients in a phase IIa clinical study, Dr. Sandborn and his colleagues performed a 36-week double-blind phase II2b trial in 526 adults at 153 medical centers in 12 countries.

Ustekinumab, a human IgG monoclonal antibody that inhibits the receptors for interleukin-12 and interleukin-23 on T cells, natural killer cells, and antigen-presenting cells, has Food and Drug Administration approval for use in plaque psoriasis. This clinical trial was sponsored by an affiliate of the manufacturer, Janssen Biotech.

During an 8-week induction phase, the study subjects were randomly assigned to receive intravenous placebo (132 patients) or ustekinumab in 1-mg/kg (131 patients), 3-mg/kg (132 patients), or 6-mg/kg (131 patients) doses. Then, during weeks 8-36, the study subjects who showed a response to induction therapy and those who did not show a response were separately randomized to receive either subcutaneous ustekinumab (90 mg) or placebo at week 8 and week 16, as maintenance therapy.

Treatment efficacy was assessed at week 22, and patients were followed through week 36 for a safety analysis. A total of 36.1% of the subjects discontinued the study before week 36.

The primary end point was a clinical response, defined as a decrease of 100 points or more on the Crohn’s Disease Activity Index (CDAI) score.

A total of 39.7% of patients receiving the 6-mg induction dose showed a clinical response, which was significantly greater than the 23.5% of patients receiving placebo, the investigators said (New Engl. J. Med. 2012 [doi:10.1056/NEJMoa1203572]).

A greater number of patients receiving the lower doses of ustekinumab than receiving placebo showed a clinical response, but the differences between these low-dose groups and the placebo group did not reach statistical significance.

The 6-mg/kg dose was effective across most demographic and disease characteristics, judging from the findings of a subgroup analysis. It was consistently effective in patients who had failed on their first attempt at therapy with TNF antagonists, patients who had failed on two or more TNF antagonists, and patients who had only had a transient response to TNF antagonists.

However, rates of clinical remission did not differ significantly between patients receiving ustekinumab and those receiving placebo, Dr. Sandborn and his associates said.

At all follow-up visits, the proportion of patients who had a 70-point clinical response was significantly higher, the reductions in mean CDAI scores were significantly greater, and the reductions in C-reactive protein levels were significantly greater in patients receiving 6 mg per kg of ustekinumab than in the placebo group.

As a maintenance therapy, 90 mg of subcutaneous ustekinumab appeared to be effective in patients who responded to the induction dose of the agent. The proportion of patients who showed a clinical response at week 22 was 69.4% in those receiving maintenance ustekinumab, significantly greater than the 42.5% response rate among those receiving maintenance placebo.

Among patients who responded to induction-phase ustekinumab, 41.7% of those who also received maintenance ustekinumab achieved clinical remission at week 22, compared with only 27.4% of those who received maintenance placebo.

Similarly, among patients who showed a response to induction ustekinumab, reductions in both CDAI scores and CRP levels were sustained if they continued on maintenance ustekinumab but were not sustained if they continued on placebo for the maintenance period.

However, patients who did not show a response to induction ustekinumab also did not benefit from additional ustekinumab in the maintenance phase of the study.

The results of the safety analysis were "somewhat limited" by the small sample size and the short duration of treatment. No deaths, serious opportunistic infections, or major adverse cardiovascular events were reported, "but large studies of longer duration are needed to assess uncommon adverse events," the investigators said.

Of note, one patient receiving ustekinumab as both induction and maintenance therapy developed a basal cell carcinoma. Among patients taking ustekinumab in the induction phase of the study, six developed serious infections: Clostridium difficile, viral gastroenteritis, UTI, anal abscess, vaginal abscess, and a staph infection of a central catheter.

This study was sponsored by Janssen Research and Development; Janssen Biotech makes ustekinumab. Dr. Sandborn and his associates reported numerous ties to industry sources.

Ustekinumab induced a clinical response in patients with moderate to severe Crohn’s disease that was resistant to tumor necrosis factor antagonists, in a phase IIb clinical trial published online Oct. 17 in the New England Journal of Medicine.

However, the agent did not improve remission rates, compared with placebo, said Dr. William J. Sandborn, professor of medicine and chief of the division of gastroenterology at the University of California San Diego, La Jolla, and his associates.

"A sizable proportion" of patients with moderate to severe Crohn’s disease do not respond to TNF antagonists, have an unsustained response, or must discontinue the medications because of adverse effects. After ustekinumab showed efficacy in such patients in a phase IIa clinical study, Dr. Sandborn and his colleagues performed a 36-week double-blind phase II2b trial in 526 adults at 153 medical centers in 12 countries.

Ustekinumab, a human IgG monoclonal antibody that inhibits the receptors for interleukin-12 and interleukin-23 on T cells, natural killer cells, and antigen-presenting cells, has Food and Drug Administration approval for use in plaque psoriasis. This clinical trial was sponsored by an affiliate of the manufacturer, Janssen Biotech.

During an 8-week induction phase, the study subjects were randomly assigned to receive intravenous placebo (132 patients) or ustekinumab in 1-mg/kg (131 patients), 3-mg/kg (132 patients), or 6-mg/kg (131 patients) doses. Then, during weeks 8-36, the study subjects who showed a response to induction therapy and those who did not show a response were separately randomized to receive either subcutaneous ustekinumab (90 mg) or placebo at week 8 and week 16, as maintenance therapy.

Treatment efficacy was assessed at week 22, and patients were followed through week 36 for a safety analysis. A total of 36.1% of the subjects discontinued the study before week 36.

The primary end point was a clinical response, defined as a decrease of 100 points or more on the Crohn’s Disease Activity Index (CDAI) score.

A total of 39.7% of patients receiving the 6-mg induction dose showed a clinical response, which was significantly greater than the 23.5% of patients receiving placebo, the investigators said (New Engl. J. Med. 2012 [doi:10.1056/NEJMoa1203572]).

A greater number of patients receiving the lower doses of ustekinumab than receiving placebo showed a clinical response, but the differences between these low-dose groups and the placebo group did not reach statistical significance.

The 6-mg/kg dose was effective across most demographic and disease characteristics, judging from the findings of a subgroup analysis. It was consistently effective in patients who had failed on their first attempt at therapy with TNF antagonists, patients who had failed on two or more TNF antagonists, and patients who had only had a transient response to TNF antagonists.

However, rates of clinical remission did not differ significantly between patients receiving ustekinumab and those receiving placebo, Dr. Sandborn and his associates said.

At all follow-up visits, the proportion of patients who had a 70-point clinical response was significantly higher, the reductions in mean CDAI scores were significantly greater, and the reductions in C-reactive protein levels were significantly greater in patients receiving 6 mg per kg of ustekinumab than in the placebo group.

As a maintenance therapy, 90 mg of subcutaneous ustekinumab appeared to be effective in patients who responded to the induction dose of the agent. The proportion of patients who showed a clinical response at week 22 was 69.4% in those receiving maintenance ustekinumab, significantly greater than the 42.5% response rate among those receiving maintenance placebo.

Among patients who responded to induction-phase ustekinumab, 41.7% of those who also received maintenance ustekinumab achieved clinical remission at week 22, compared with only 27.4% of those who received maintenance placebo.

Similarly, among patients who showed a response to induction ustekinumab, reductions in both CDAI scores and CRP levels were sustained if they continued on maintenance ustekinumab but were not sustained if they continued on placebo for the maintenance period.

However, patients who did not show a response to induction ustekinumab also did not benefit from additional ustekinumab in the maintenance phase of the study.

The results of the safety analysis were "somewhat limited" by the small sample size and the short duration of treatment. No deaths, serious opportunistic infections, or major adverse cardiovascular events were reported, "but large studies of longer duration are needed to assess uncommon adverse events," the investigators said.

Of note, one patient receiving ustekinumab as both induction and maintenance therapy developed a basal cell carcinoma. Among patients taking ustekinumab in the induction phase of the study, six developed serious infections: Clostridium difficile, viral gastroenteritis, UTI, anal abscess, vaginal abscess, and a staph infection of a central catheter.

This study was sponsored by Janssen Research and Development; Janssen Biotech makes ustekinumab. Dr. Sandborn and his associates reported numerous ties to industry sources.

Ustekinumab induced a clinical response in patients with moderate to severe Crohn’s disease that was resistant to tumor necrosis factor antagonists, in a phase IIb clinical trial published online Oct. 17 in the New England Journal of Medicine.

However, the agent did not improve remission rates, compared with placebo, said Dr. William J. Sandborn, professor of medicine and chief of the division of gastroenterology at the University of California San Diego, La Jolla, and his associates.

"A sizable proportion" of patients with moderate to severe Crohn’s disease do not respond to TNF antagonists, have an unsustained response, or must discontinue the medications because of adverse effects. After ustekinumab showed efficacy in such patients in a phase IIa clinical study, Dr. Sandborn and his colleagues performed a 36-week double-blind phase II2b trial in 526 adults at 153 medical centers in 12 countries.

Ustekinumab, a human IgG monoclonal antibody that inhibits the receptors for interleukin-12 and interleukin-23 on T cells, natural killer cells, and antigen-presenting cells, has Food and Drug Administration approval for use in plaque psoriasis. This clinical trial was sponsored by an affiliate of the manufacturer, Janssen Biotech.

During an 8-week induction phase, the study subjects were randomly assigned to receive intravenous placebo (132 patients) or ustekinumab in 1-mg/kg (131 patients), 3-mg/kg (132 patients), or 6-mg/kg (131 patients) doses. Then, during weeks 8-36, the study subjects who showed a response to induction therapy and those who did not show a response were separately randomized to receive either subcutaneous ustekinumab (90 mg) or placebo at week 8 and week 16, as maintenance therapy.

Treatment efficacy was assessed at week 22, and patients were followed through week 36 for a safety analysis. A total of 36.1% of the subjects discontinued the study before week 36.

The primary end point was a clinical response, defined as a decrease of 100 points or more on the Crohn’s Disease Activity Index (CDAI) score.

A total of 39.7% of patients receiving the 6-mg induction dose showed a clinical response, which was significantly greater than the 23.5% of patients receiving placebo, the investigators said (New Engl. J. Med. 2012 [doi:10.1056/NEJMoa1203572]).

A greater number of patients receiving the lower doses of ustekinumab than receiving placebo showed a clinical response, but the differences between these low-dose groups and the placebo group did not reach statistical significance.

The 6-mg/kg dose was effective across most demographic and disease characteristics, judging from the findings of a subgroup analysis. It was consistently effective in patients who had failed on their first attempt at therapy with TNF antagonists, patients who had failed on two or more TNF antagonists, and patients who had only had a transient response to TNF antagonists.

However, rates of clinical remission did not differ significantly between patients receiving ustekinumab and those receiving placebo, Dr. Sandborn and his associates said.

At all follow-up visits, the proportion of patients who had a 70-point clinical response was significantly higher, the reductions in mean CDAI scores were significantly greater, and the reductions in C-reactive protein levels were significantly greater in patients receiving 6 mg per kg of ustekinumab than in the placebo group.

As a maintenance therapy, 90 mg of subcutaneous ustekinumab appeared to be effective in patients who responded to the induction dose of the agent. The proportion of patients who showed a clinical response at week 22 was 69.4% in those receiving maintenance ustekinumab, significantly greater than the 42.5% response rate among those receiving maintenance placebo.

Among patients who responded to induction-phase ustekinumab, 41.7% of those who also received maintenance ustekinumab achieved clinical remission at week 22, compared with only 27.4% of those who received maintenance placebo.

Similarly, among patients who showed a response to induction ustekinumab, reductions in both CDAI scores and CRP levels were sustained if they continued on maintenance ustekinumab but were not sustained if they continued on placebo for the maintenance period.

However, patients who did not show a response to induction ustekinumab also did not benefit from additional ustekinumab in the maintenance phase of the study.

The results of the safety analysis were "somewhat limited" by the small sample size and the short duration of treatment. No deaths, serious opportunistic infections, or major adverse cardiovascular events were reported, "but large studies of longer duration are needed to assess uncommon adverse events," the investigators said.

Of note, one patient receiving ustekinumab as both induction and maintenance therapy developed a basal cell carcinoma. Among patients taking ustekinumab in the induction phase of the study, six developed serious infections: Clostridium difficile, viral gastroenteritis, UTI, anal abscess, vaginal abscess, and a staph infection of a central catheter.

This study was sponsored by Janssen Research and Development; Janssen Biotech makes ustekinumab. Dr. Sandborn and his associates reported numerous ties to industry sources.

There seems to be a cruel irony at work: It is generally recognized that a primary care physician–based accountable care organization stands the greatest chance of successfully squeezing the waste out of our health care system – yet that same system has historically deprived primary care of the means to finance an ACO.

Worse, most of the payments that are necessary to fund and sustain ACOs are deferred for more than a year, because they come from savings created during the prior year. It is the proverbial "you can’t get there from here" problem.

How do we avoid this "Catch-22," in which the primary care–driven ACO model is best suited to meet the goals of ACOs but often is least able to afford the costs of creating ACOs?

The answer may be the federal government. There are several viable options available to have the government effectively fund 100% of your ACO start-up costs.

Consider the following:

• Meaningful use incentives. Why not have the government pay for your ACO technology platform? If you think ahead, the health information exchange you will want for your ACO will likely qualify you for stage 2 and stage 3 meaningful use incentives. You can earn up to $44,000 over 5 years from Medicare, or up to $63,750 over 6 years from Medicaid. Instead of data being a burden under fee for service, access to and exchange capability of data will be a huge asset.

You will need to make these investments anyway. If you have your ACO game plan in place, much of what you and your colleagues do to meet the meaningful use criteria can be used to fund your ACO.

• Advance payment model program. The Centers for Medicare and Medicaid Services apparently recognized the "you can’t get there from here" dilemma by creating the advance payment model program. Physician-run ACOs in rural areas have been singled out to receive enough up-front funding to completely pay for the development and implementation of the Medicare Shared Savings Program (MSSP) ACO until shared savings payments kick in.

In addition to the MSSP application, ACOs that wish to receive advance funding from the CMS Innovation Center must also complete the advance payment model application. The advance payment model is open to only two types of ACOs: ACOs that do not include any inpatient facilities and have less than $50 million in total annual revenue; and ACOs in which the only inpatient facilities are critical access hospitals and/or Medicare low-volume rural hospitals, and that have less than $80 million in total annual revenue. ACOs that are co-owned with a health plan will be ineligible, regardless of whether they also fall into one of the above categories.

The advance payment model application consists of two primary sections: the ACO’s financial characteristics; and the ACO’s investment plan.

With respect to the financial characteristics, the ACO will need to list the total annual revenue and total Medicaid revenue for each ACO participant during the preceding 3 years. The information submitted by the ACO will need to be based on either federal tax returns or audited financial statements.

The second key section of the advance payment model application is the ACO investment plan. The ACO must explain how it intends to use the advance payment funds awarded from CMS.

Specifically, the investment plan must include:

• A description of the types of staffing and infrastructure that the ACO will acquire and/or expand using the funding available through the advance payment model.

• The timing of such acquisitions or expansions, and the estimated unit costs.

• A description of how such investments build on staff and infrastructure the ACO already has or plans to acquire through its own upcoming investments.

• An explanation of how each investment will support the ACO in achieving the three-part aim of better health, better health care, and lower per capita costs for Medicare beneficiaries.

The advance payment model money may not be renewed once the initial $1 billion budgeted amount is exhausted. But if the results and return on investment are as powerful as predicted for the targeted ACOs, this could be viewed as a sound investment by CMS.

At current levels, an ACO will receive an up-front fixed amount of $250,000, a variable $36/member, and then $8/member per month. This will be repaid if there are ACO shared savings later on.

Beyond the dollars and cents impact, the APM program is vivid evidence for primary care physicians of just how promising CMS believes physician-directed ACOs are.

Primary care physicians are starting to understand the professional and financial rewards behind ACOs. They should not be dismayed by lack of funding. The payers know that funding these ACOs is a smart "investment" in reforming our inefficient and wasteful current system.

Mr. Bobbitt is a senior partner and head of the Health Law Group at the Smith Anderson law firm in Raleigh, N.C. He has many years’ experience assisting physicians forming integrated delivery systems. He has spoken and written nationally to primary care physicians on the strategies and practicalities of forming or joining ACOs. This article is meant to be educational and does not constitute legal advice. For additional information, readers may contact the author at bbobbitt@smithlaw.com or 919-821-6612.

There seems to be a cruel irony at work: It is generally recognized that a primary care physician–based accountable care organization stands the greatest chance of successfully squeezing the waste out of our health care system – yet that same system has historically deprived primary care of the means to finance an ACO.

Worse, most of the payments that are necessary to fund and sustain ACOs are deferred for more than a year, because they come from savings created during the prior year. It is the proverbial "you can’t get there from here" problem.

How do we avoid this "Catch-22," in which the primary care–driven ACO model is best suited to meet the goals of ACOs but often is least able to afford the costs of creating ACOs?

The answer may be the federal government. There are several viable options available to have the government effectively fund 100% of your ACO start-up costs.

Consider the following:

• Meaningful use incentives. Why not have the government pay for your ACO technology platform? If you think ahead, the health information exchange you will want for your ACO will likely qualify you for stage 2 and stage 3 meaningful use incentives. You can earn up to $44,000 over 5 years from Medicare, or up to $63,750 over 6 years from Medicaid. Instead of data being a burden under fee for service, access to and exchange capability of data will be a huge asset.

You will need to make these investments anyway. If you have your ACO game plan in place, much of what you and your colleagues do to meet the meaningful use criteria can be used to fund your ACO.

• Advance payment model program. The Centers for Medicare and Medicaid Services apparently recognized the "you can’t get there from here" dilemma by creating the advance payment model program. Physician-run ACOs in rural areas have been singled out to receive enough up-front funding to completely pay for the development and implementation of the Medicare Shared Savings Program (MSSP) ACO until shared savings payments kick in.

In addition to the MSSP application, ACOs that wish to receive advance funding from the CMS Innovation Center must also complete the advance payment model application. The advance payment model is open to only two types of ACOs: ACOs that do not include any inpatient facilities and have less than $50 million in total annual revenue; and ACOs in which the only inpatient facilities are critical access hospitals and/or Medicare low-volume rural hospitals, and that have less than $80 million in total annual revenue. ACOs that are co-owned with a health plan will be ineligible, regardless of whether they also fall into one of the above categories.

The advance payment model application consists of two primary sections: the ACO’s financial characteristics; and the ACO’s investment plan.

With respect to the financial characteristics, the ACO will need to list the total annual revenue and total Medicaid revenue for each ACO participant during the preceding 3 years. The information submitted by the ACO will need to be based on either federal tax returns or audited financial statements.

The second key section of the advance payment model application is the ACO investment plan. The ACO must explain how it intends to use the advance payment funds awarded from CMS.

Specifically, the investment plan must include:

• A description of the types of staffing and infrastructure that the ACO will acquire and/or expand using the funding available through the advance payment model.

• The timing of such acquisitions or expansions, and the estimated unit costs.

• A description of how such investments build on staff and infrastructure the ACO already has or plans to acquire through its own upcoming investments.

• An explanation of how each investment will support the ACO in achieving the three-part aim of better health, better health care, and lower per capita costs for Medicare beneficiaries.

The advance payment model money may not be renewed once the initial $1 billion budgeted amount is exhausted. But if the results and return on investment are as powerful as predicted for the targeted ACOs, this could be viewed as a sound investment by CMS.

At current levels, an ACO will receive an up-front fixed amount of $250,000, a variable $36/member, and then $8/member per month. This will be repaid if there are ACO shared savings later on.

Beyond the dollars and cents impact, the APM program is vivid evidence for primary care physicians of just how promising CMS believes physician-directed ACOs are.

Primary care physicians are starting to understand the professional and financial rewards behind ACOs. They should not be dismayed by lack of funding. The payers know that funding these ACOs is a smart "investment" in reforming our inefficient and wasteful current system.

Mr. Bobbitt is a senior partner and head of the Health Law Group at the Smith Anderson law firm in Raleigh, N.C. He has many years’ experience assisting physicians forming integrated delivery systems. He has spoken and written nationally to primary care physicians on the strategies and practicalities of forming or joining ACOs. This article is meant to be educational and does not constitute legal advice. For additional information, readers may contact the author at bbobbitt@smithlaw.com or 919-821-6612.

There seems to be a cruel irony at work: It is generally recognized that a primary care physician–based accountable care organization stands the greatest chance of successfully squeezing the waste out of our health care system – yet that same system has historically deprived primary care of the means to finance an ACO.

Worse, most of the payments that are necessary to fund and sustain ACOs are deferred for more than a year, because they come from savings created during the prior year. It is the proverbial "you can’t get there from here" problem.

How do we avoid this "Catch-22," in which the primary care–driven ACO model is best suited to meet the goals of ACOs but often is least able to afford the costs of creating ACOs?

The answer may be the federal government. There are several viable options available to have the government effectively fund 100% of your ACO start-up costs.

Consider the following:

• Meaningful use incentives. Why not have the government pay for your ACO technology platform? If you think ahead, the health information exchange you will want for your ACO will likely qualify you for stage 2 and stage 3 meaningful use incentives. You can earn up to $44,000 over 5 years from Medicare, or up to $63,750 over 6 years from Medicaid. Instead of data being a burden under fee for service, access to and exchange capability of data will be a huge asset.

You will need to make these investments anyway. If you have your ACO game plan in place, much of what you and your colleagues do to meet the meaningful use criteria can be used to fund your ACO.

• Advance payment model program. The Centers for Medicare and Medicaid Services apparently recognized the "you can’t get there from here" dilemma by creating the advance payment model program. Physician-run ACOs in rural areas have been singled out to receive enough up-front funding to completely pay for the development and implementation of the Medicare Shared Savings Program (MSSP) ACO until shared savings payments kick in.

In addition to the MSSP application, ACOs that wish to receive advance funding from the CMS Innovation Center must also complete the advance payment model application. The advance payment model is open to only two types of ACOs: ACOs that do not include any inpatient facilities and have less than $50 million in total annual revenue; and ACOs in which the only inpatient facilities are critical access hospitals and/or Medicare low-volume rural hospitals, and that have less than $80 million in total annual revenue. ACOs that are co-owned with a health plan will be ineligible, regardless of whether they also fall into one of the above categories.

The advance payment model application consists of two primary sections: the ACO’s financial characteristics; and the ACO’s investment plan.

With respect to the financial characteristics, the ACO will need to list the total annual revenue and total Medicaid revenue for each ACO participant during the preceding 3 years. The information submitted by the ACO will need to be based on either federal tax returns or audited financial statements.

The second key section of the advance payment model application is the ACO investment plan. The ACO must explain how it intends to use the advance payment funds awarded from CMS.

Specifically, the investment plan must include:

• A description of the types of staffing and infrastructure that the ACO will acquire and/or expand using the funding available through the advance payment model.

• The timing of such acquisitions or expansions, and the estimated unit costs.

• A description of how such investments build on staff and infrastructure the ACO already has or plans to acquire through its own upcoming investments.

• An explanation of how each investment will support the ACO in achieving the three-part aim of better health, better health care, and lower per capita costs for Medicare beneficiaries.

The advance payment model money may not be renewed once the initial $1 billion budgeted amount is exhausted. But if the results and return on investment are as powerful as predicted for the targeted ACOs, this could be viewed as a sound investment by CMS.

At current levels, an ACO will receive an up-front fixed amount of $250,000, a variable $36/member, and then $8/member per month. This will be repaid if there are ACO shared savings later on.

Beyond the dollars and cents impact, the APM program is vivid evidence for primary care physicians of just how promising CMS believes physician-directed ACOs are.

Primary care physicians are starting to understand the professional and financial rewards behind ACOs. They should not be dismayed by lack of funding. The payers know that funding these ACOs is a smart "investment" in reforming our inefficient and wasteful current system.

Mr. Bobbitt is a senior partner and head of the Health Law Group at the Smith Anderson law firm in Raleigh, N.C. He has many years’ experience assisting physicians forming integrated delivery systems. He has spoken and written nationally to primary care physicians on the strategies and practicalities of forming or joining ACOs. This article is meant to be educational and does not constitute legal advice. For additional information, readers may contact the author at bbobbitt@smithlaw.com or 919-821-6612.

ATLANTA – Applying the topical fluorocarbon perfluorodecalin prior to Q-switched laser treatment for tattoo removal allows for immediate retreatment of the tattoo, thereby improving results while decreasing overall treatment time, according to Dr. Roy Geronemus.

The findings have important implications for improving outcomes and patient satisfaction, given that tattoo removal can require 10-20 sessions, depending on factors such as the age and colors of the tattoo, and that tattoos – and thus tattoo removal – continue to increase in popularity, he said. "For a busy practice or impatient patients like we have in New York, this has been a nice advance," Dr. Geronemus said at the annual meeting of the American Society for Dermatologic Surgery.

Courtesy Wikimedia/gemteck1/Creative Commons License

The approach builds on the "R20 technique" described earlier this year in a study published in the Journal of the American Academy of Dermatology. R20 involves the use of multiple treatment passes that are made at 20-minute intervals.

Typically, after an initial pass, tiny white bubbles form in the superficial papillary dermis, appearing as a whitening of the skin. Retreatment while these bubbles are present elicits a limited reaction.

The R20 technique was developed when investigators found that the bubbles disappear after 20 minutes, and, thus, tested the technique in a study of 12 adults. The patients were randomized to a single treatment pass with a Q-switched alexandrite laser (5.5 J/cm², 755 nm, 100-nanosecond pulse duration, 3-mm spot size) or to four passes at 20 minute intervals.

The first treatment caused an immediate whitening reaction, but little or no whitening occurred after subsequent passes at 20-minute intervals. However, at 90-day follow-up, significant improvement was seen in the R20 group, compared with the single-treatment group, and light microscopy demonstrated greater dispersion of tattoo ink with the R20 approach. (J. Am. Acad. Dermatol. 2012;66:271-7).

Despite the increased efficacy using this approach, the time required to complete four passes at 20-minute intervals makes it impractical in the clinical setting, said Dr. Geronemus, a dermatologist in private practice in New York.

"So with this idea in mind, we began to look at a concept that would allow us to re-treat tattoos immediately without waiting 20 minutes," he said, explaining that topical perfluorodecalin helps dissolve the gas seen after the application of the Q-switched laser and speeds the resolution of the whitening.

"Rather than waiting 20 minutes, the gas dissolves almost immediately, allowing you to re-treat, and we’re now re-treating three or four times in a matter of minutes rather than waiting the 80 minutes that the R20 technique would take for a four-time treatment session," he said.

In his experience, results with perfluorodecalin are comparable to those seen with the R20 technique – but with greater convenience for the patient.

His observations were confirmed on optical coherence tomography scanning, which demonstrated that cavitation levels are indeed reduced by the use of perfluorodecalin.

Dr. Geronemus is an investigator for Cutera, Cynosure, Palomar, Solta Medical, and Syneron. He is also on the medical advisory board for Cynosure, Lumenis, Photomedex, Syneron, and Zeltiq. He reported that he is a Zeltiq shareholder.

ATLANTA – Applying the topical fluorocarbon perfluorodecalin prior to Q-switched laser treatment for tattoo removal allows for immediate retreatment of the tattoo, thereby improving results while decreasing overall treatment time, according to Dr. Roy Geronemus.

The findings have important implications for improving outcomes and patient satisfaction, given that tattoo removal can require 10-20 sessions, depending on factors such as the age and colors of the tattoo, and that tattoos – and thus tattoo removal – continue to increase in popularity, he said. "For a busy practice or impatient patients like we have in New York, this has been a nice advance," Dr. Geronemus said at the annual meeting of the American Society for Dermatologic Surgery.

Courtesy Wikimedia/gemteck1/Creative Commons License

The approach builds on the "R20 technique" described earlier this year in a study published in the Journal of the American Academy of Dermatology. R20 involves the use of multiple treatment passes that are made at 20-minute intervals.

Typically, after an initial pass, tiny white bubbles form in the superficial papillary dermis, appearing as a whitening of the skin. Retreatment while these bubbles are present elicits a limited reaction.

The R20 technique was developed when investigators found that the bubbles disappear after 20 minutes, and, thus, tested the technique in a study of 12 adults. The patients were randomized to a single treatment pass with a Q-switched alexandrite laser (5.5 J/cm², 755 nm, 100-nanosecond pulse duration, 3-mm spot size) or to four passes at 20 minute intervals.

The first treatment caused an immediate whitening reaction, but little or no whitening occurred after subsequent passes at 20-minute intervals. However, at 90-day follow-up, significant improvement was seen in the R20 group, compared with the single-treatment group, and light microscopy demonstrated greater dispersion of tattoo ink with the R20 approach. (J. Am. Acad. Dermatol. 2012;66:271-7).

Despite the increased efficacy using this approach, the time required to complete four passes at 20-minute intervals makes it impractical in the clinical setting, said Dr. Geronemus, a dermatologist in private practice in New York.

"So with this idea in mind, we began to look at a concept that would allow us to re-treat tattoos immediately without waiting 20 minutes," he said, explaining that topical perfluorodecalin helps dissolve the gas seen after the application of the Q-switched laser and speeds the resolution of the whitening.

"Rather than waiting 20 minutes, the gas dissolves almost immediately, allowing you to re-treat, and we’re now re-treating three or four times in a matter of minutes rather than waiting the 80 minutes that the R20 technique would take for a four-time treatment session," he said.

In his experience, results with perfluorodecalin are comparable to those seen with the R20 technique – but with greater convenience for the patient.

His observations were confirmed on optical coherence tomography scanning, which demonstrated that cavitation levels are indeed reduced by the use of perfluorodecalin.

Dr. Geronemus is an investigator for Cutera, Cynosure, Palomar, Solta Medical, and Syneron. He is also on the medical advisory board for Cynosure, Lumenis, Photomedex, Syneron, and Zeltiq. He reported that he is a Zeltiq shareholder.

ATLANTA – Applying the topical fluorocarbon perfluorodecalin prior to Q-switched laser treatment for tattoo removal allows for immediate retreatment of the tattoo, thereby improving results while decreasing overall treatment time, according to Dr. Roy Geronemus.

The findings have important implications for improving outcomes and patient satisfaction, given that tattoo removal can require 10-20 sessions, depending on factors such as the age and colors of the tattoo, and that tattoos – and thus tattoo removal – continue to increase in popularity, he said. "For a busy practice or impatient patients like we have in New York, this has been a nice advance," Dr. Geronemus said at the annual meeting of the American Society for Dermatologic Surgery.

Courtesy Wikimedia/gemteck1/Creative Commons License

The approach builds on the "R20 technique" described earlier this year in a study published in the Journal of the American Academy of Dermatology. R20 involves the use of multiple treatment passes that are made at 20-minute intervals.

Typically, after an initial pass, tiny white bubbles form in the superficial papillary dermis, appearing as a whitening of the skin. Retreatment while these bubbles are present elicits a limited reaction.

The R20 technique was developed when investigators found that the bubbles disappear after 20 minutes, and, thus, tested the technique in a study of 12 adults. The patients were randomized to a single treatment pass with a Q-switched alexandrite laser (5.5 J/cm², 755 nm, 100-nanosecond pulse duration, 3-mm spot size) or to four passes at 20 minute intervals.

The first treatment caused an immediate whitening reaction, but little or no whitening occurred after subsequent passes at 20-minute intervals. However, at 90-day follow-up, significant improvement was seen in the R20 group, compared with the single-treatment group, and light microscopy demonstrated greater dispersion of tattoo ink with the R20 approach. (J. Am. Acad. Dermatol. 2012;66:271-7).

Despite the increased efficacy using this approach, the time required to complete four passes at 20-minute intervals makes it impractical in the clinical setting, said Dr. Geronemus, a dermatologist in private practice in New York.

"So with this idea in mind, we began to look at a concept that would allow us to re-treat tattoos immediately without waiting 20 minutes," he said, explaining that topical perfluorodecalin helps dissolve the gas seen after the application of the Q-switched laser and speeds the resolution of the whitening.

"Rather than waiting 20 minutes, the gas dissolves almost immediately, allowing you to re-treat, and we’re now re-treating three or four times in a matter of minutes rather than waiting the 80 minutes that the R20 technique would take for a four-time treatment session," he said.

In his experience, results with perfluorodecalin are comparable to those seen with the R20 technique – but with greater convenience for the patient.

His observations were confirmed on optical coherence tomography scanning, which demonstrated that cavitation levels are indeed reduced by the use of perfluorodecalin.

Dr. Geronemus is an investigator for Cutera, Cynosure, Palomar, Solta Medical, and Syneron. He is also on the medical advisory board for Cynosure, Lumenis, Photomedex, Syneron, and Zeltiq. He reported that he is a Zeltiq shareholder.

SAN FRANCISCO – A side-by-side comparison of three bedside tools used to identify severe cases of Clostridium difficile infection yielded no clear winner, a reminder that judgment at diagnosis is still the clinician’s best bet.

Criteria from the Infectious Diseases Society of America were more sensitive but the least specific than both the Hines Veterans Affairs (VA) and the ATLAS severity scoring systems, Thien-Ly Doan, Pharm.D. explained in an interview at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

Sherry E. Boschert/IMNG Medical Media

The Hines VA system for stratifying patients missed 19 of 44 severe/complicated cases of C. difficile infection. The ATLAS scoring system (which incorporates five parameters: age, temperature, leukocytosis, albumin, and systemic concomitant antibiotic use) missed 14 of the 44 cases in a retrospective chart review of 109 patients hospitalized for more than a day with confirmed C. difficile infection.

The IDSA guidelines missed only 5 of the 44 severe/complicated infections, but they cast such a wide net that anyone with a white count above 15,000 cells/mm³ or an elevated creatinine (1.5 times or greater than the premorbid level) is considered to have severe C. difficile infection, she said.

Use of the IDSA guidelines could increase unnecessary use of vancomycin instead of metronidazole, said Dr. Doan, a clinical coordinator at Long Island Jewish Medical Center, New Hyde Park, N.Y.

The IDSA criteria suggested that nearly 60% of the 109 patients had severe infection. However, the 44 severe/complicated C. difficile patients comprised just 40% of the study population. They were defined in the study as patients who were in critical care or whose infections were refractory to treatment and who had ileus, severe pancolitis/toxic megacolon, a WBC of 15,000 cells/mL with hypotension, surgery related to C. difficile infection, or who had died from infection.

Dr. Doan and her associates compared the three stratification systems in evaluating the charts of adults with C. difficile infection at the medical center, who had a mean age of 71 years. A total of 74% of patients were on the medicine service, 22% were in critical care, and 4% were on the surgical service; 34% were female.

The Centers for Disease Control and Prevention also offer severity criteria, but these require the observation of clinical end points and thus are ineffective for assessing patients at initial presentation, she said in a poster presentation at the meeting, sponsored by the American Society for Microbiology.

The Hines VA scoring system, in addition to missing the most severe cases, also gives a great deal of weight to diagnostic imaging, which "makes it impractical at our institution," she said. The Hines VA tool incorporates temperature, the presence of ileus, systolic blood pressure, leukocytosis, and abnormal CT findings to stratify patients by severity.

"We’re going to continue relying on the clinician’s assessment at the bedside at the time of diagnosis to evaluate whether cases are severe or not severe, and not use any of these tools that are available," Dr. Doan said.

A good bedside tool sure would be nice, though, to have a good, objective way of identifying severe C. difficile infection, she added. In a large health system, order sets could be developed based on the tool’s findings "so that everybody would be on the same page in terms of treatment," she said. None of the current tools are good enough for that.

Severe cases of C. difficile are on the rise because of increasing prevalence of the hypervirulent NAP1/BI/027 strain, she noted.

A number of clinicians at the meeting approached her with their own versions of bedside tools for identifying severe C. difficile infection, which Dr. Doan and her associates may evaluate next. They also may compare the tools on different subpopulations of patients with severe infection, such as only patients whose death or surgery was related to C. difficile infection.

Dr. Doan reported having no financial disclosures.

SAN FRANCISCO – A side-by-side comparison of three bedside tools used to identify severe cases of Clostridium difficile infection yielded no clear winner, a reminder that judgment at diagnosis is still the clinician’s best bet.

Criteria from the Infectious Diseases Society of America were more sensitive but the least specific than both the Hines Veterans Affairs (VA) and the ATLAS severity scoring systems, Thien-Ly Doan, Pharm.D. explained in an interview at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

Sherry E. Boschert/IMNG Medical Media

The Hines VA system for stratifying patients missed 19 of 44 severe/complicated cases of C. difficile infection. The ATLAS scoring system (which incorporates five parameters: age, temperature, leukocytosis, albumin, and systemic concomitant antibiotic use) missed 14 of the 44 cases in a retrospective chart review of 109 patients hospitalized for more than a day with confirmed C. difficile infection.

The IDSA guidelines missed only 5 of the 44 severe/complicated infections, but they cast such a wide net that anyone with a white count above 15,000 cells/mm³ or an elevated creatinine (1.5 times or greater than the premorbid level) is considered to have severe C. difficile infection, she said.

Use of the IDSA guidelines could increase unnecessary use of vancomycin instead of metronidazole, said Dr. Doan, a clinical coordinator at Long Island Jewish Medical Center, New Hyde Park, N.Y.

The IDSA criteria suggested that nearly 60% of the 109 patients had severe infection. However, the 44 severe/complicated C. difficile patients comprised just 40% of the study population. They were defined in the study as patients who were in critical care or whose infections were refractory to treatment and who had ileus, severe pancolitis/toxic megacolon, a WBC of 15,000 cells/mL with hypotension, surgery related to C. difficile infection, or who had died from infection.

Dr. Doan and her associates compared the three stratification systems in evaluating the charts of adults with C. difficile infection at the medical center, who had a mean age of 71 years. A total of 74% of patients were on the medicine service, 22% were in critical care, and 4% were on the surgical service; 34% were female.

The Centers for Disease Control and Prevention also offer severity criteria, but these require the observation of clinical end points and thus are ineffective for assessing patients at initial presentation, she said in a poster presentation at the meeting, sponsored by the American Society for Microbiology.

The Hines VA scoring system, in addition to missing the most severe cases, also gives a great deal of weight to diagnostic imaging, which "makes it impractical at our institution," she said. The Hines VA tool incorporates temperature, the presence of ileus, systolic blood pressure, leukocytosis, and abnormal CT findings to stratify patients by severity.

"We’re going to continue relying on the clinician’s assessment at the bedside at the time of diagnosis to evaluate whether cases are severe or not severe, and not use any of these tools that are available," Dr. Doan said.

A good bedside tool sure would be nice, though, to have a good, objective way of identifying severe C. difficile infection, she added. In a large health system, order sets could be developed based on the tool’s findings "so that everybody would be on the same page in terms of treatment," she said. None of the current tools are good enough for that.

Severe cases of C. difficile are on the rise because of increasing prevalence of the hypervirulent NAP1/BI/027 strain, she noted.

A number of clinicians at the meeting approached her with their own versions of bedside tools for identifying severe C. difficile infection, which Dr. Doan and her associates may evaluate next. They also may compare the tools on different subpopulations of patients with severe infection, such as only patients whose death or surgery was related to C. difficile infection.

Dr. Doan reported having no financial disclosures.

SAN FRANCISCO – A side-by-side comparison of three bedside tools used to identify severe cases of Clostridium difficile infection yielded no clear winner, a reminder that judgment at diagnosis is still the clinician’s best bet.

Criteria from the Infectious Diseases Society of America were more sensitive but the least specific than both the Hines Veterans Affairs (VA) and the ATLAS severity scoring systems, Thien-Ly Doan, Pharm.D. explained in an interview at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

Sherry E. Boschert/IMNG Medical Media

The Hines VA system for stratifying patients missed 19 of 44 severe/complicated cases of C. difficile infection. The ATLAS scoring system (which incorporates five parameters: age, temperature, leukocytosis, albumin, and systemic concomitant antibiotic use) missed 14 of the 44 cases in a retrospective chart review of 109 patients hospitalized for more than a day with confirmed C. difficile infection.

The IDSA guidelines missed only 5 of the 44 severe/complicated infections, but they cast such a wide net that anyone with a white count above 15,000 cells/mm³ or an elevated creatinine (1.5 times or greater than the premorbid level) is considered to have severe C. difficile infection, she said.

Use of the IDSA guidelines could increase unnecessary use of vancomycin instead of metronidazole, said Dr. Doan, a clinical coordinator at Long Island Jewish Medical Center, New Hyde Park, N.Y.

The IDSA criteria suggested that nearly 60% of the 109 patients had severe infection. However, the 44 severe/complicated C. difficile patients comprised just 40% of the study population. They were defined in the study as patients who were in critical care or whose infections were refractory to treatment and who had ileus, severe pancolitis/toxic megacolon, a WBC of 15,000 cells/mL with hypotension, surgery related to C. difficile infection, or who had died from infection.

Dr. Doan and her associates compared the three stratification systems in evaluating the charts of adults with C. difficile infection at the medical center, who had a mean age of 71 years. A total of 74% of patients were on the medicine service, 22% were in critical care, and 4% were on the surgical service; 34% were female.

The Centers for Disease Control and Prevention also offer severity criteria, but these require the observation of clinical end points and thus are ineffective for assessing patients at initial presentation, she said in a poster presentation at the meeting, sponsored by the American Society for Microbiology.

The Hines VA scoring system, in addition to missing the most severe cases, also gives a great deal of weight to diagnostic imaging, which "makes it impractical at our institution," she said. The Hines VA tool incorporates temperature, the presence of ileus, systolic blood pressure, leukocytosis, and abnormal CT findings to stratify patients by severity.

"We’re going to continue relying on the clinician’s assessment at the bedside at the time of diagnosis to evaluate whether cases are severe or not severe, and not use any of these tools that are available," Dr. Doan said.

A good bedside tool sure would be nice, though, to have a good, objective way of identifying severe C. difficile infection, she added. In a large health system, order sets could be developed based on the tool’s findings "so that everybody would be on the same page in terms of treatment," she said. None of the current tools are good enough for that.

Severe cases of C. difficile are on the rise because of increasing prevalence of the hypervirulent NAP1/BI/027 strain, she noted.

A number of clinicians at the meeting approached her with their own versions of bedside tools for identifying severe C. difficile infection, which Dr. Doan and her associates may evaluate next. They also may compare the tools on different subpopulations of patients with severe infection, such as only patients whose death or surgery was related to C. difficile infection.

Dr. Doan reported having no financial disclosures.