Ibrutinib downregulates a subset of miRNA leading to upregulation of tumor suppressors and inhibition of cell proliferation in chronic lymphocytic leukemia.

The lymph node (LN) is the site of chronic lymphocytic leukemia (CLL) cell activation and proliferation. Aberrant microRNA (miRNA) expression has been shown to have a role in CLL pathogenesis; however, a comparison of miRNA expression between CLL cells in the LN and the peripheral blood (PB) has previously not been reported. On the basis of the analysis of 17 paired LN and PB samples from CLL patients, we identify a panel of miRNAs that are increased in LN CLL cells correlating with an activation phenotype. When evaluated in CLL cells from 38 patients pre and post treatment with ibrutinib, a subset of these miRNAs (miR-22, miR-34a, miR-146b and miR-181b) was significantly decreased in response to ibrutinib. A concomitant increase in putative miRNA target transcripts (ARID1B, ARID2, ATM, CYLD, FOXP1, HDAC1, IBTK, PTEN and SMAD4) was also observed. Functional studies confirmed targets of ibrutinib-responsive miRNAs to include messenger RNA transcripts of multiple tumor suppressors. Knockdown of endogenous miR-34a and miR146b resulted in increased transcription of tumor suppressors and inhibition of cell proliferation. These findings demonstrate that ibrutinib downregulates the expression of a subset of miRNAs related to B-cell activation leading to increased expression of miRNA targets including tumor suppressors and a reduction in cell proliferation.

Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study.

Ibrutinib and other targeted inhibitors of B-cell receptor signaling achieve impressive clinical results for patients with chronic lymphocytic leukemia (CLL). A treatment-induced rise in absolute lymphocyte count (ALC) has emerged as a class effect of kinase inhibitors in CLL and warrants further investigation. Here we report correlative studies in 64 patients with CLL treated with ibrutinib. We quantified tumor burden in blood, lymph nodes (LNs), spleen and bone marrow, assessed phenotypic changes of circulating cells and measured whole-blood viscosity. With just one dose of ibrutinib, the average increase in ALC was 66%, and in>40% of patients the ALC peaked within 24 h of initiating treatment. Circulating CLL cells on day 2 showed increased Ki67 and CD38 expression, indicating an efflux of tumor cells from the tissue compartments into the blood. The kinetics and degree of the treatment-induced lymphocytosis was highly variable; interestingly, in patients with a high baseline ALC the relative increase was mild and resolution rapid. After two cycles of treatment the disease burden in the LN, bone marrow and spleen decreased irrespective of the relative change in ALC. Whole-blood viscosity was dependent on both ALC and hemoglobin. No adverse events were attributed to the lymphocytosis.

Modeling tumor-host interactions of chronic lymphocytic leukemia in xenografted mice to study tumor biology and evaluate targeted therapy.

Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental factors for proliferation and survival. In particular, the B-cell receptor (BCR) and nuclear factor- κB (NF-κB) pathways are activated in the lymph node (LN) microenvironment. Thus, model systems mimicking tumor-host interactions are important tools to study CLL biology and pathogenesis. We investigated whether the recently established NOD/scid/γc(null) (NSG) mouse xenograft model can recapitulate the effects of the human microenvironment. We assessed, therefore, tumor characteristics previously defined in LN-resident CLL cells, including proliferation, and activation of the BCR and NF-κB pathways. We found that the murine spleen (SP) microenvironment supported CLL cell proliferation and activation to a similar degree than the human LN, including induction of BCR and NF-κB signaling in the xenografted cells. Next, we used this model to study ibrutinib, a Bruton's tyrosine kinase inhibitor in clinical development. Ibrutinib inhibited BCR and NF-κB signaling induced by the microenvironment, decreased proliferation, induced apoptosis and reduced the tumor burden in vivo. Thus, our data demonstrate that the SP of xenografted NSG mice can, in part, recapitulate the role of the human LN for CLL cells. In addition, we show that ibrutinib effectively disrupts tumor-host interactions essential for CLL cell proliferation and survival in vivo.

Longitudinal effects of integrated treatment on alcohol use for persons with serious mental illness and substance use disorders.

A randomized experimental design was used to assign participants to an integrated mental health and substance use treatment program or to standard hospital treatment. A multilevel, nonlinear model was used to estimate hospital treatment effects on days of alcohol use for persons with serious mental illness and substance use disorders over 18 months. The integrated treatment program had a significant effect on the rate of alcohol use at 2 months postdischarge, reducing the rate of use by 54%. Motivation for sobriety at hospital discharge, posttreatment self-help attendance, and social support for sobriety were also found to reduce the rate of use during the follow-up period. Implications for mental health treatment and aftercare support are discussed.

Methods of ensuring high follow-up rates: lessons from a longitudinal study of dual diagnosed participants.

Despite growing research interest in co-occurring psychiatric and substance misuse disorders, relatively few longitudinal studies have been conducted with dual diagnosis populations. Many of the longitudinal studies that have been done have experienced excessive attrition. Thus, investigators have noted that one of the primary difficulties of conducting longitudinal studies with this population is successfully minimizing attrition during follow-up. This study, conducted in 1991 1993, describes retention and tracking methods employed in a longitudinal study of 485 dual diagnosis participants. Follow-up interview completion rates at the 2-, 6-, 10-, 14-, and 18-month interviews were 86.7, 85.6, 85.1, 84.5, and 88.4%, respectively. Several case studies are provided that document some of the challenges facing project staff and successful strategies for handling them. A notable finding from this study was that participants reported that the relationship established with the interviewer was more important than material incentives in preventing study attrition.

Exploring the link between service quality and outcomes. Parents' assessments of family support programs.

Relationships among consumer-generated quality factors, satisfaction, and outcome measures were examined for family support services provided by Michigan's public mental health system. Parents focused on structural and procedural aspects of program accessibility and attended less to program administration issues. Parents who gave the services the highest quality ratings also were the most satisfied with services, saw the services as more effective, had fewer family problems, and rated their time and child-related resources as more adequate. Implications for evaluation practice are discussed.

Immediate outcomes of substance use treatment within a state psychiatric hospital.

Outcomes of an integrated inpatient treatment program for persons with serious mental illness and substance use disorders are examined in relationship to five stages of treatment--stabilization, engagement, persuasion/awareness, active treatment, and relapse prevention. The study used a randomized design with participants assigned to an integrated mental health and substance abuse treatment program or standard psychiatric hospital treatment. At discharge, participants in the integrated treatment program indicated more active engagement in treatment and greater awareness of mental health issues, substance use issues, and the 12-step program than those who received standard hospital treatment. Participants in the integrated treatment program also saw their treatment as being more effective and had more motivation to stay healthy and sober. The integrated treatment program was not equally effective at each treatment stage with all participants. The implications of the program's success overall and at each treatment stage are discussed.

Perceptions of services and resources as mediators of depression among parents of children with developmental disabilities.

Path analysis was used to test the effects of resource perceptions and respite use in a theoretical model of parental adaptation to children with disabilities The amount and quality of respite indirectly affected parental depression via parent's perceptions of the adequacy of baby sitting and the time the parent had for herself or himself. Both quality and respite use were related to the helpfulness of the parent's social network. The strongest predictor of depression was the parent's perception of time resources, which was influenced by the amount of care the child required, the adequacy of money, and baby sitting resources.

Correlates of functioning in a population with dual diagnoses: an examination of diagnosis and problem history.

This study examines the relationship between diagnosis and life functioning using the Addiction Severity Index (ASI) with 467 hospitalized individuals with mental illness and substance abuse problems. Persons diagnosed with schizophrenia were the best functioning group across most of the ASI domains except employment and psychiatric functioning. More robust relationships were found between problem history (i.e., prior symptomatology or treatment) and current functioning. Respondents with histories of drug treatment, prior experience of anxiety and depression, self-injurious behavior, or violence control problems experienced more severe medical, drug, alcohol, psychiatric, legal, and family/social problems at the time of hospitalization. Violence control problems were related to drug use and criminal involvement, whereas self-injurious behavior was more often related to alcohol use and psychiatric distress. These findings suggest that problem history may be a stronger predictor of treatment need at the time of hospital entry than are more commonly used indexes, such as diagnosis.

Exploring the diversity of dual diagnosis: utility of cluster analysis for program planning.

This study demonstrates the utility of using cluster analysis to explore the heterogeneity of dual diagnosis populations so as to facilitate planning and implementation of individualized treatment programs. A sample of 467 persons admitted to a state psychiatric hospital with DSM-III-R psychiatric diagnoses and substance abuse problems were interviewed on the Addiction Severity Index (ASI) and other measures to assess psychological, social, and community functioning. Scores on seven ASI severity ratings (medical, employment, alcohol, drug, legal, family, and psychiatric functioning) were used to group patients into seven homogeneous subgroups using cluster analysis: best functioning, unhealthy alcohol abuse, functioning alcohol abuse, drug abuse, functioning polyabuse, criminal polyabuse, and unhealthy polyabuse. Cluster reliability and validity were demonstrated using split-half tests as well as cross-sectional and longitudinal analyses. Results illustrate the extreme heterogeneity of dual diagnosis and are suggestive of how individualized treatment programs can be matched to the particular needs of patients with dual diagnoses.

Parents' perspectives on quality in family support programs.

Support services for families who have a member with developmental disabilities are a growing component of many state mental health systems. Family empowerment is a key principle of these programs, but parents and the staff who work with them are often challenged in their efforts to have parents participate in policy development, program management, and evaluation of programs. The use of nominal group techniques is described as a means of identifying factors parents believe characterize quality family support programs. Parents' identified factors are then compared with factors from a theoretical framework for quality. Parents stressed access to information, adherence to empowerment philosophy, and the importance of interpersonal relationships with staff. Parents placed less emphasis on factors generally found in accreditation criteria.

Families' perceptions of their resources for caring for children with developmental disabilities.

Factors related to families' perceptions of internal resources when raising children with developmental disabilities were examined. Families enrolled in a Cash Subsidy Program were surveyed about their resources, use of services, and helpfulness of social supports. Parents saw their basic resources for daily life as adequate. However, they reported that their time, discretionary money, and child-care resources were not adequate for caring for their children. Helpfulness of social supports, the children's characteristics, and income were related to perception of resource adequacy. Findings suggest that support services must be flexible in the types and amounts of services provided.

Cash subsidy program: family satisfaction and need.

Families of children with severe developmental disabilities who were participating in a cash subsidy program were surveyed about their satisfaction with the program. They were also asked about their need for a variety of other services. Families were satisfied with the operation of the program and with the amount of the subsidy they received. Families indicated a need for more respite care or sitters more often than any other service. Respondents were found to use their subsidy for the types of services they said they needed.

A comparison of how families and their service providers rate family generated quality of service factors.

This paper presents a method which was utilized to obtain family consensus around the criteria which should be used to evaluate family support programs. Twelve family members of persons with developmental disabilities were selected in each of six different sites to participate in a group process to identify the factors which distinguish quality family support programs. Content analysis of the results of the six meetings resulted in a final list of 15 quality factors. Two hundred and sixty one families and their family support coordinators (N = 65) were asked to rate the importance of each factor on a 10 point scale. Analysis revealed that there was high agreement between families and their coordinators on the importance of all 15 factors. The applicability of the method used to obtain family consensus regarding evaluation criteria for community mental health agencies is discussed.

Evaluation of family support services: changes in availability and accessibility.

Changes in availability and accessibility of family support services were studied by surveying county mental health authorities in Michigan before and after the implementation of new policy on and funding for such programs. An overall increase in the availability of family support services was found. Access to services as measured by length of time families waited for services remained unchanged following the increase in funds. Policy and funding implications of the study were discussed.

Use and impact of a cash subsidy program.

The use and impact of a $256.74 monthly cash subsidy by 1,283 families with children who have severe disabilities were examined. Families reported a variety of uses, including the purchase of clothing, toys, sitters, diapers, special foods, adaptive equipment, and professional services. Families at lower income levels used the subsidy to meet basic needs more often than did families at higher income levels. Families indicated that the subsidy was very helpful in meeting special needs and had improved family life, eased financial worries, and reduced stress. The influence of the availability of the subsidy on continuing family-based care was examined.

Client typology based on functioning level assessments: utility for service planning and monitoring.

Cluster analysis was used to develop a six-group typology based on level of functioning data from 2,447 clients with serious mental illness served by the Michigan public mental health system. The groups are described in terms of level of functioning in 16 domains, global functioning, diagnosis, demographic characteristics and services used. A group of older, poor functioning clients with high health needs was identified. A second group of highly dysfunctional clients with few health needs was also found. Two groups of young adult "chronic" clients were found: one with extensive substance abuse problems and one with moderate substance abuse problems and extreme levels of suicidal and aggressive behavior. Two groups of relatively good functioning clients were also identified: one with some problems in many areas and a second with functional problems in a number of life areas and pronounced symptoms of depression and demoralization. The results point to the utility of cluster analysis as a mechanism to organize and identify patterns within the rich array of information provided by multidimensional level of functioning assessments. The uses of empirically derived client types in planning and monitoring mental health services are discussed.

Characteristics of seriously mentally ill adults in a public mental health system.

To aid in planning mental health services, the state of Michigan collected sociodemographic and clinical information on a sample of 2,447 mental health system clientele in both hospital and community settings. Hospitalized patients were found to have poorer functioning and higher levels of disability than clients treated in community settings. Younger patients were more likely to be male, to exhibit more self-destructive behaviors, and to be more aggressive and demoralized. Older patients were more likely to be women, to have a high degree of physical health care needs, and to possess poor skills in self-care and community living. The heterogeneous nature of the population and the presence of complicating problems not traditionally served by mental health systems, such as medical illness and substance abuse, point to a need for interagency planning to address the needs of seriously mentally ill adults.

Evaluation approaches in mental health: implications of the new federalism.

Since the introduction of federal mental health legislation in 1963, there has been a changing emphasis on evaluation and accountability. With direct federal funding of community mental health services, accountability demands were met through expectations for local agency evaluation activities which were overseen by federal authorities. The advent of the New Federalism and the shift to block grant funding of mental health services to state mental health authorities have shifted responsibility for evaluation to the states and local programs. This paper reviews federal mental health statutes to trace the extent and locus of required evaluation activities and discusses two approaches to carrying out program evaluation: "top-down" where the evaluation topic, method, and data collection are mandated by an administering or funding body; and "bottom-up" approaches where the subject, method of study, and data to be collected are developed in response to a felt need at the local agency level. A case study of each approach as used at the state level in mental health is examined. Based on the literature and the case studies, conclusions are presented on the pro's and con's of each method in meeting accountability demands and the barriers which must be overcome for either method to be successful.