RANBP2 and CLTC are involved in ALK rearrangements in inflammatory myofibroblastic tumors

Inflammatory myofibroblastic tumors (IMTs) are rare soft tissue tumors occurring primarily in children and young adults. ALK gene rearrangements have been identified in this neoplasm, with fusion of the ALK gene at 2p23 to a number of different partner genes. Metaphase cytogenetic analyses of these tumors have been relatively few, however, and may help to identify additional variant partners. We report on an IMT from a 2-year-old boy with a karyotype of 45,XY,der(2)inv(2)(p23q12)del(2)(p11.1p11.2),-22. FISH showed ALK-RANBP2 fusion in this tumor. The breakpoint was cloned and the fusion was confirmed, making this the third reported case of IMT with ALK-RANBP2 fusion. In addition, we identified the ALK fusion partner in a previously reported IMT with t(2;17)(p23;q23) as CLTC, a gene reported to be involved in four other IMTs, and showed that the breakpoint involved a novel ALK-CLTC fusion. FISH evaluation of nine other IMTs identified CLTC as the fusion partner in one additional case, but RANBP2 was not involved in the remaining eight IMTs, suggesting that the variant partners involved in ALK rearrangements in IMTs are diverse.     

Management of access to branded psychotropic medications in private health plans

BACKGROUND: In the past decade, health insurers have increased their reliance on cost control policies such as prior authorization and 3-tier formularies. Little is known about how these policies are being applied to psychotropic medications, many of which have low rates of patient adherence. OBJECTIVE: This study reports on plans' cost-sharing tier placement and authorization policies for 12 brand only psychotropic medications in 3 classes: antidepressants, anti-psychotics, and medications for attention deficit/hyperactivity disorder (ADFID). METHODS: Data were from a nationally representative survey of private health plans regarding mental health and substance-abuse services in 2003; 368 plans responded (83% response rate). Results were weighted and represent national estimates of health-plan characteristics. RESULTS: The majority of insurance products provided unrestricted placement on Tier 2 (medium copayment) for at least 2 brand-only antidepressants and at least 2 brand-only antipsychotics. This approach allows clinicians some limited leeway in initial medication selection. However, most patients who did not respond to the Tier-2 options typically faced a substantial escalation in copayment (Tier 3), possibly leading to premature medication discontinuation. For ADHI)5 the options were considerably more limited, with 22.1% of products applying some restriction to all 3 medications and only 15.9% of products leaving all 3 medications unrestricted. Plans with specialty contracts for mental health were considerably more likely to use Tier 3 (highest copayment) as their only restriction approach. CONCLUSIONS: Based on the results of this analysis,private plans were managing psychotropic costs using copayment incentives rather than administrative controls. This approach was less intrusive for clinicians, but resulting higher copayments could worsen already high rates of nonadherence; future research should examine this issue.     

Can we afford to ignore the biology of joint healing and graft incorporation after ACL reconstruction?

Anterior cruciate ligament (ACL) reconstruction is successful at restoring stability to return ACL injured patients to high-demand work, sports, and recreational activities. The development of posttraumatic osteoarthritis (OA) in roughly half of patients just 10–15 years after ACLR highlight the need to improve clinical care pathways. Graft failure and reinjury rates, which further increase OA risk, also remain high for younger and more active patients. The biological components of joint recovery and graft incorporation, therefore, impact short- and long-term clinical outcomes. Biochemical and magnetic resonance imaging (MRI) data show substantial compromise of articular cartilage metabolism and matrix composition after ACL injury and reconstructive surgery suggesting a potential need for activity modulation in early recovery. Furthermore, joint recovery is variable with compositional MRI studies showing progressive cartilage degeneration 1 and 2 years after ACLR. Biopsy and MRI studies also show high variability in ACL graft characteristics within the 1st year after ACLR followed by continued graft maturation into the 2nd year and beyond. To improve the care of ACL injured patients, there is a critical need for clinical attention and scientific inquiry into timing the reintroduction of higher load activities in relationship to neuromuscular recovery, joint biology, and graft maturation. In addition to symptomatic and mechanical recovery, development and validation of biological markers for joint and cartilage homeostasis as well as ACL graft healing are needed for personalized decision making on rehabilitation needs, reduction of OA risk, and resumption of athletic, recreational, and vocational activities.     

Reliability and Extension of Quantitative Prediction of CYP3A4-Mediated Drug Interactions Based on Clinical Data

An approach was proposed in 2007 for quantitative predictions of cytochrome P450 (CYP)3A4-mediated drug-drug interactions. It is based on two characteristic parameters: the contribution ratio (CR; i.e., the fraction of victim drug clearance by CYP) and the inhibition ratio (IR) of the inhibitor. Knowledge of these parameters allows forecasting of the ratio between the area under the plasma concentration-time curve (AUC) of the victim drug when given with the inhibitor and the AUC of the victim drug when it is given alone. So far, these parameters were established for 21 substrates and 17 inhibitors. The goals of our study were to test the assumption of substrate independence of the potency of inhibitors in vivo and to estimate the CR and IR for an extended list of substrates and inhibitors of CYP3A4. The assumption of independence of IRs from the substrate was evaluated on a set of eight victim drugs and eight inhibitors. Forty-four AUC ratios were available. This assumption was rejected in four cases, but it did not result in more than a twofold error in AUC ratio predictions. The extended list of substrates and inhibitors was defined by a thorough literature search. Fifty-nine AUC ratios were available for the global analysis. Final estimates of CRs and IRs were obtained for 37 substrates and 25 inhibitors, respectively. The mean prediction error of the ratios was 0.02, while the mean absolute prediction error was 0.58. Predictive distributions for 917 possible interactions were obtained, giving detailed information on some drugs or inhibitors that have been poorly studied so far.     

The Alcoholics Anonymous Affiliation Scale: Development, Reliability, and Norms for Diverse Treated and Untreated Populations

Affiliation with Alcoholics Anonymous (AA) is an important variable to measure in many clinical and research activities. This paper reports on the development of an AA affiliation scale, and demonstrates its utility in a sample of 927 alcohol treatment seekers and 674 untreated problem drinkers. The scale is short (9 items), covers a range of AA experiences, and is internally consistent across diverse demographic groups, multiple health services settings, and treated and untreated populations. The validity of the scale is supported by the findings that treatment seekers report significantly higher AA affiliation than do untreated problem drinkers, and inpatients report higher affiliation than outpatients. Potential clinical and research applications of the scale are proposed.     

Long-term follow-up of two infants with an implanted cardiac pacemaker

The clinical course of two patients with congenital heart block who had pacemaker implantation at age 7 and 8 months, respectively, is reviewed. One patient at age 10 years has had nine pulse generators Inserted; the other has had six implantations, the most recent a lithium iodine pacemaker, during 81/2 years of observation. Both patients have shown normal physical development and emotional maturation despite multiple hospitalizations and pacemaker replacements, thus demonstrating that electrical pacing, initiated in infancy, can be maintained through childhood without adverse effects.