Maintenance Phase Of Treatment Research Articles

General principles in the treatment of lupus nephritis with the prevention of cardiovascular events

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown etiology, which is characterized by the hyperproduction of organ-nonspecific autoantibodies to various components of the cell nucleus with the development of immunoinflammatory tissue and visceral damages. Kidney damage is one of the most common severe manifestations of SLE, which develops in 40–80% of patients and, in 15–20% of them, progresses to end-stage renal failure. A renal biopsy is recommended for all patients with lupus nephritis (LN) when choosing a successful treatment policy added by immunosuppressive therapy.The paper presents treatments for LN according to its morphological class with a dosage detailed description, a route of administration, and the duration of intake of different drug groups in the induction and maintenance phases of treatment, as well as the specific features of therapy for refractory LN. Taking into account that patients with SLE in general and those with LN in particular have an increased rate of cardiovascular events, the authors have proposed exposures to traditional and specific risk factors for cardiovascular diseases.

Childhood Acute Lymphoblastic Leukemia in Developing Countries, Barriers Against Better Outcome, Single Center Experience, EGYPT

The improvement in overall survival in children with acute lymphoblastic leukemia (ALL) over the last 5 decades has been considerable, with around 90% now surviving long term. Developing countries still suffering from infectious complications as added risk factor against better survival rate even during least risky maintenance phase of treatment.

Salivary Immunoglobulin A, E, and G4 Levels Specific to Dermatophagoides pteronyssinus in Allergic Rhinitis Patients Treated With Subcutaneous Immunotherapy.

Allergen-specific immunotherapy (AIT) is an effective treatment for allergic rhinitis (AR). During the course of AIT, many biomarkers in body fluids change. It is necessary to find effective indicators of AIT. To examine levels of salivary immunoglobulin A, E, and G4 (IgA, IgE, and IgG4, respectively) specific to Dermatophagoides pteronyssinus (Dp-IgA, Dp-IgE, and Dp-IgG4, respectively) and their changes in AR patients undergoing subcutaneous immunotherapy (SCIT). This study included 82 patients with AR sensitized only to Dp and 14 healthy controls. Among patients with AR, 30 patients were not treated with specific immunotherapy (group A), while the remainder (n = 52) received house dust mite SCIT in the up-dosing phase (n = 27; group B) or the maintenance treatment phase (n = 25; group C). Dp-IgA, Dp-IgE, and Dp-IgG4 levels in the saliva were measured using the enzyme-linked immunosorbent assay. Clinical symptoms, concomitant medication, and the Rhinoconjunctivitis Quality of Life Questionnaire score were recorded and correlated with immunoglobulin levels. Salivary Dp-IgG4 and Dp-IgA levels were significantly lower in AR patients than in healthy controls ( P < .001 for both), while Dp-IgE levels were significantly higher ( P < .001). SCIT resulted in sustained increases in Dp-IgG4 and Dp-IgA in the maintenance phase compared to the up-dosing phase ( P < .001 for both), whereas Dp-IgE only increased in the up-dosing phase ( P = .004, P < .0125). There was no correlation between the different salivary immunoglobulins and clinical scores during SCIT. This study shows that allergen-specific IgE levels are increased in the saliva of sensitized patients, suggesting that measuring salivary IgE testing should be further considered for the diagnosis of AR. Moreover, allergen-specific IgA and IgG4 in the saliva, which may play protective roles against allergy, may serve as objective indicators for evaluating treatment response to SCIT. However, none of the immunoglobulin reflects subjective symptoms.

Variants in TPMT, ITPA, ABCC4 and ABCB1 Genes As Predictors of 6-mercaptopurine Induced Toxicity in Children with Acute Lymphoblastic Leukemia.

SummaryBackgroundAcute lymphoblastic leukemia is the most common childhood malignancy. Optimal use of anti leukemic drugs has led to less toxicity and adverse reactions, and a higher survival rate. Thiopurine drugs, including 6-mercaptopurine, are mostly used as antileukemic medications in the maintenance phase of treatment for children with acute lymphoblastic leukemia. For those patients, TPMT genotype- tailored 6-mercaptopurine therapy is already implemented in the treatment protocols. We investigated the role of TPMT, ITPA, ABCC4 and ABCB1 genetic variants as predictors of outcome and 6-mercaptopurine induced toxicity during the maintenance phase of treatment in pediatric acute lymphoblastic leukemia.MethodsSixty-eight children with acute lymphoblastic leukemia were enrolled in this study. Patients have been treated according to ALL IC-BFM 2002 or ALL IC-BFM 2009 protocols. Toxicity and adverse events have been monitored via surrogate markers (off-therapy weeks, episodes of leu - ko penia and average 6-mercaptopurine dose) and a prob- abilistic model was employed to predict overall 6-mercaptopurine related toxicity.ResultsWe confirmed that patients with acute lymphoblastic leukemia that carry inactive TPMT allele(s) require 6- mercaptopurine dose reduction. ITPA and ABCC4 genetic variants failed to show an association with 6-mercapto - purine induced toxicity during the maintenance phase. Carriers of ABCB1 variant allele experienced greater hepatotoxicity. The probabilistic model Neural net which considered all the analysed genetic variants was assessed to be the best prediction model. It was able to discriminate ALL patients with good and poor 6-mercaptopurin tolerance in 71% of cases (AUC=0.71).ConclusionsThis study contributes to the design of a panel of pharmacogenetic markers for predicting thiopurineinduced toxicity in pediatric ALL.

Abstract LB-257: Tumor treating fields treatment for patients with newly diagnosed glioblastoma: A cost-effectiveness analysis

Abstract Objective: To estimate the potential cost-effectiveness of treating newly diagnosed glioblastoma patients with tumor treating fields (TTFields) and temozolomide (TMZ) based on data from the final analysis of the EF-14 Trial. Background: Glioblastoma (GBM) is the most aggressive form of primary brain cancer in adults. The EF-14 Trial in GBM patients reported a 5-year survival rate of 13% for newly diagnosed GBM patients treated with TTFields and maintenance temozolomide (TMZ) chemotherapy. The cost-effectiveness of adding TTFields to the maintainance phase of the first line treatment protocol for GBM patients has not been previously assessed from a U.S. health system perspective. Methods: The primary economic endpoint was the projected incremental cost-effectiveness ratio (ICER) for treatment of newly diagnosed GBM with TTFields and TMZ versus TMZ monotherapy alone during the maintenance phase of treatment. Patient outcomes were simulated using a 3-state area under the curve model including alive without progression, progressed disease, and death. Survival was modelled over a lifetime horizon by integrating the 5-year survival results reported in the EF-14 trial with long-term GBM epidemiology data and U.S. background mortality rates. Data on patient utilities used to calculate quality-adjusted life years (QALYs) were based on a previous analysis of GBM-specific health-state preferences. Costs and frequency of adverse events associated with TTFields and TMZ were estimated from the EF-14 trial. Supportive care cost estimates were derived from published literature. Future survival benefits and costs were discounted to present value at a rate of 3%. One-way and probabilistic sensitivity analyses were performed to assess result uncertainty due to parameter variability. Results: Use of TTFields plus TMZ were projected to increase in undiscounted mean survival of 1.8 life years versus TMZ alone. The resulting life years gained (LYG) and quality-adjusted life years (QALYs) were 1.3 and 1.0, respectively, after discounting. The incremental total cost was $188,870. The ICER was $150,638 per LYG and $198,032 per QALY gained. The probability of TTFields being cost-effective was 70.5% at a willingness-to-pay threshold of $200,000 per QALY. Conclusions: Treating newly diagnosed GBM patients with TTFields and TMZ has the potential to increase mean lifetime survival and quality-adjusted survival substantially compared to treatment with TMZ alone. TTFields therapy, even when evaluated at its full list price, demonstrated a high probability of cost-effectiveness at a willingness to pay threshold of $200,000. Citation Format: Gregory F. Guzauskas, Erqi L. Pollom, Volker W. Stieber, Bruce C. Wang, Lou Garrison. Tumor treating fields treatment for patients with newly diagnosed glioblastoma: A cost-effectiveness analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-257.

Asian consensus on assessment and management of mild to moderate plaque psoriasis with topical therapy.

A working group of dermatologists in Asian countries assessed the current status of psoriatic management in the region to prepare a consensus report on topical treatment in mild to moderate plaque psoriasis. Even though the association of psoriasis with systemic comorbidities is increasingly acknowledged, psoriasis is still lower in health‐care priority lists in the region. The psychosocial impact of psoriasis may be greater in Asian countries due to cultural norms and social discrimination. Non‐adherence to treatment is also common among Asians. The current care given to patients with mild to moderate psoriasis needs to be streamlined, enhanced and organized with a patient‐centered care approach to achieve better outcomes. A comprehensive assessment of the disease severity and its impact on a patient's life is required before initiating treatment. Education and active involvement of the patient in the treatment plan is an important part of psoriatic management. It is recommended to personalize topical treatment to meet the needs of the patient, depending on disease severity, psychosocial impact, the patient's expectations and, more importantly, the patient's willingness and ability to actively follow the treatment procedure. Fixed‐dose combination of corticosteroid and vitamin D analogs is the preferred topical medication for both initial and maintenance phases of treatment. The fast containment of the disease is the goal of the initial phase of 4–8 weeks and it demands a potent fast‐acting topical therapy. Satisfactory control of the disease and prevention of relapses should be achieved during the maintenance phase with twice a week or weekend applications.

Is lithium monitoring NICE? Lithium monitoring in a UK secondary care setting.

Lithium is widely used for the treatment of bipolar disorder. Owing to its narrow therapeutic index and side-effect profile, regular monitoring of serum levels, renal and thyroid function has been recommended by all major guidelines on lithium use. We investigated whether lithium monitoring during maintenance phase treatment in clinical practice meets the latest recommendation by the National Institute for Health and Clinical excellence (i.e. lithium levels between 0.6 and 1.0 mmol/L and lithium level, thyroid and renal function tests every 6 months) in one of the largest mental health organizations in Europe, the South London and Maudsley (SLaM) NHS Foundation Trust. Retrospective data were extracted from SLaM's Clinical Record Interactive Search (CRIS) system. Adult patients with a psychiatric disorder who were on lithium at any point during the period January 2012-January 2016 and had at least one lithium level test result in the system were included in the analyses. A total of 2639 lithium level tests results were retrieved for 412 patients. Overall, the serum level was within the recommended range in 50.7% of all tests, below the range in 42.4% and above in 6.9%. Lithium level, renal and thyroid function tests were performed at the recommended frequency of 6 months (or less) in 76.2%, 72.7% and 60.2% of patients, respectively. These data demonstrate that there is a gap between the NICE 2014 recommendation and lithium monitoring practice in secondary care, with a high number of lithium level results below the therapeutic minimum. Reminder strategies for secondary care practitioners, shared care agreements or a central registry for lithium users could improve monitoring performance.

Simultaneous Occurrence of Multifocal Osteomyelitis in a Child with Acute Lymphoblastic Leukemia: A Rare Manifestation During the Maintenance Phase of Treatment

Introduction: Acute lymphoblastic leukemia (ALL) has various clinical manifestations due to bone marrow or extra medullary involvement. Osteomyelitis may occur as the first presentation or relapsing sign of ALL. Multifocal osteomyelitis in non-neutropenic children with ALL is rare. Case Presentation: This study reported on an 8-year-old male with ALL during the maintenance phase of his treatment, who presented fever and generalized body pain. Bone scan showed multiple bones involvement and biopsy was in favor of osteomyelitis. Conclusions: Multifocal osteomyelitis should be kept in mind as a possible diagnosis in patients with leukemia, who are presented with prolonged fever.

Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders: bipolar disorder summary.

In December 2015, the Royal Australian and New Zealand College of Psychiatrists published a comprehensive set of mood disorder clinical practice guidelines for psychiatrists, psychologists and mental health professionals. This guideline summary, directed broadly at primary care physicians, is an abridged version that focuses on bipolar disorder. It is intended as an aid to the management of this complex disorder for primary care physicians working in collaboration with psychiatrists to implement successful long term management. Main recommendations: The guidelines address the main phases of bipolar disorder with a particular emphasis on long term management, and provide specific clinical recommendations. Mania: All physicians should be able to detect its early signs so that treatment can be initiated promptly. At the outset, taper and cease medications with mood-elevating properties and institute measures to reduce stimulation, and transfer the patient to specialist care. Bipolar depression: Treatment is complicated and may require trialling treatment combinations. Monotherapy with mood-stabilising agents or second generation antipsychotics has demonstrated efficacy but using combinations of these agents along with antidepressants is sometimes necessary to achieve remission. Commencing adjunctive structured psychosocial treatments in this phase is benign and likely effective. Long term management: Physicians should adjust treatment to prevent the recurrence of manic and/or depressive symptoms and optimise functional recovery. Closely monitor the efficacy of pharmacological and psychological treatments, adverse effects and compliance. Changes in management as a result of the guidelines: The guidelines position bipolar disorder as part of a spectrum of mood disorders and provide a longitudinal perspective for assessment and treatment. They provide new management algorithms for the maintenance phase of treatment that underscore the importance of ongoing monitoring to achieve prophylaxis. As a first line treatment, lithium remains the most effective medication for the prevention of relapse and potential suicide, but requires nuanced management from both general practitioners and specialists. The guidelines provide clarity and simplicity for the long term management of bipolar disorder, incorporating the use of new medications and therapies alongside established treatments.

Mood Stabilizers: Implementing Combined Treatment Regimens in Bipolar Disorder

Patients with bipolar disorders spend a greater proportion of their illness in a depressed or mixed state rather than experiencing either mania or hypomania. Over the past 20 years, most major pharmaceutical companies have either reduced or abandoned the research and development of novel psychiatric drugs, exiting the development of new, safe, efficacious, and tolerable treatment regimens for bipolar disorder. Therefore, optimizing the current treatments available is critical. We review studies of the last 15 years that provide guidance relevant to managing the maintenance phase of bipolar disorders. Based on these data, we provide recommendations for effective treatment planning and implementation, principally for the maintenance phase care of persons with bipolar disorder. We also discuss strategies for implementing medication regimens, differentiating strategies for maintenance phase treatment from those of acute phase treatment. Assessing key symptoms that are sensitive to change is critical for longitudinal assessments and treatment planning for patients with bipolar disorders. In most studies, only a subset of rating scale items differentiate patients with good responses from those without. Identified symptoms include racing thoughts, less need for sleep, hyperactivity, increased activity, and increased energy. We developed a procedure for using Multistate Outcome Analysis of Treatment (MOAT) in bipolar disorders. MOAT integrates efficacy and tolerability data during studies to provide information about the quantity and quality of time spent in distinct mood states. The protocol developed will be useful for assessing treatment strategies in bipolar disorder. This review contains 4 figures, 7 tables and 32 references Key words: bipolar, depression, lithium, mania, mixed, mood stabilizer, survival analysis, symptom domains, valproate

Efficacy of BPO 2.5% Gel in the Acute and Maintenance Periods for Moderate or Severe Facial Acne Vulgaris

Background and objective: There is no evidence of efficacy for concomitant use of benzoyl peroxide (BPO) gel, adapalene gel, and antimicrobial agents for external treatment of the inflammatory phase of acne vulgaris, and there is little evidence for the utility of BPO gel for the maintenance phase after remission of inflammatory acne. Therefore, we investigated the effect of concomitant use of BPO gel, adapalene gel, and an antimicrobial agent for topical use for inflammatory-phase acne vulgaris and the efficacy of BPO gel for the maintenance phase. Design and methods: The subjects were patients with moderate to severe acne vulgaris (6 to 30 inflammatory skin eruptions on one side of the face). A randomized 3 group parallel comparison study of inflammatory-phase treatment (step 1) was performed, followed by a randomized 2 group parallel comparison study of maintenancephase treatment (step 2). Results: In the inflammatory phase, both inflammatory and non-inflammatory skin eruptions were improved by concomitant use of BPO 2.5% gel+clindamycin 1%, concomitant use of BPO gel 2.5%+adapalene gel 0.1% and concomitant use of adapalene gel 0.1%+clindamycin 1%, respectively. For the maintenance phase, both adapalene 0.1% gel and BPO 2.5% gel were effective. Conclusion: These results confirm that concomitant treatment with BPO gel, adapalene gel, and an antimicrobial agent for topical use is useful for the inflammatory phase of severe facial acne vulgaris, and that treatment with BPO 2.5% gel alone is useful for the maintenance phase in Japanese acne patients.

Predictors of remission during acute treatment of first-episode schizophrenia patients involuntarily hospitalized and treated with algorithm-based pharmacotherapy: Secondary analysis of an observational study.

Early clinical response predicts symptomatic remission and recovery in the maintenance treatment phase of first-episode schizophrenia (FES). However, little is known about predictors of symptomatic remission during acute treatment of severely ill patients with FES. Here, we conducted a secondary analysis of our retrospective observational study, which examined response, remission and treatment-resistance rates in seriously ill patients with FES spectrum disorders involuntarily hospitalized and treated with algorithm-based pharmacotherapy. We performed a retrospective chart review of 131 involuntarily admitted patients with schizophrenia or schizoaffective disorder. Our algorithm aimed to delay olanzapine treatment, standardize medications and suggest initiation of clozapine after failure of third-line antipsychotic treatment. The duration of each adequate antipsychotic treatment at an optimal dosage was 4 weeks or more. Remission was defined using the symptom-severity component of consensus remission criteria. A logistic regression model was applied to identify significant predictors of remission at discharge. Overall, 74 patients (56%) were in remission at discharge. Non-remitters were hampered from becoming remitters mainly by the presence of negative symptoms. There were no differences in first-line antipsychotics, dosage of antipsychotics at time of response and adherence rates to algorithm-based pharmacotherapy between remitters and non-remitters. Shorter duration of untreated psychosis, favourable early response and less negative symptoms at baseline were identified as independent predictors of remission at discharge. The importance of early intervention and specific and adequate treatments of negative symptoms is highlighted.

Adherence to Oral Medications During Maintenance Therapy Among Children and Adolescents With Acute Lymphoblastic Leukemia: A Medication Refill Analysis.

Adherence to oral medications during maintenance therapy is essential for pediatric patients with acute lymphoblastic leukemia. Self-reported or electronic monitoring of adherence indicate suboptimal adherence, particularly among particular sociodemographic groups. This study used medication refill records to examine adherence among a national sample of pediatric patients with acute lymphoblastic leukemia. Patients in a national claims database, aged 0 to 21 years with a diagnosis of acute lymphoblastic leukemia and in the maintenance phase of treatment, were included. Medication possession ratios were used as measures of adherence. Overall adherence and adherence by sociodemographic groups were examined. Adherence rates were 85% for 6-mercaptopurine and 81% for methotrexate. Adherence was poorer among patients 12 years and older. Oral medication adherence rates were suboptimal and similar to or lower than previously documented rates using other methods of assessing adherence. Refill records offer a promising avenue for monitoring adherence. Additional work to identify groups most at-risk for poor adherence is needed. Nurses are well positioned to routinely monitor for medication adherence and to collaborate with the multidisciplinary team to address barriers to adherence.

Minimal residual disease in adult ALL: technical aspects and implications for correct clinical interpretation.

Nowadays, minimal residual disease (MRD) is accepted as the strongest independent prognostic factor in acute lymphoblastic leukemia (ALL). It can be detected by molecular methods that use leukemia-specific or patient-specific molecular markers (fusion gene transcripts, or immunoglobulin/T-cell receptor [IG/TR] gene rearrangements), and by multi-parametric flow cytometry. The sensitivity and specificity of these methods can vary across treatment time points and therapeutic settings. Thus, knowledge of the principles and limitations of each technology is of the utmost importance for correct interpretation of MRD results. Time will tell whether new molecular and flow cytometric high-throughput technologies can overcome the limitations of current standard methods and eventually bring additional benefits. MRD during standard ALL chemotherapy is the strongest overall prognostic indicator and has therefore been used for refining initial treatment stratification. Moreover, MRD positivity after the maintenance phase of treatment may point to an impending relapse and thus enable salvage treatment to be initiated earlier, which could possibly improve treatment results. The prognostic relevance of pretransplantation MRD was shown by several studies, and MRD high-risk patients were shown to benefit from stem cell transplantation (SCT). Also, MRD positivity after SCT correlates with worse outcomes. In addition, MRD information is very instructive in current clinical trials that test novel agents to evaluate their treatment efficacy. Although conventional clinical risk factors lose their independent prognostic significance when combined with MRD information, recently identified genetic markers may further improve the treatment stratification in ALL.

Minimal residual disease in adult ALL: technical aspects and implications for correct clinical interpretation.

Nowadays, minimal residual disease (MRD) is accepted as the strongest independent prognostic factor in acute lymphoblastic leukemia (ALL). It can be detected by molecular methods that use leukemia-specific or patient-specific molecular markers (fusion gene transcripts, or immunoglobulin/T-cell receptor [IG/TR] gene rearrangements), and by multi-parametric flow cytometry. The sensitivity and specificity of these methods can vary across treatment time points and therapeutic settings. Thus, knowledge of the principles and limitations of each technology is of the utmost importance for correct interpretation of MRD results. Time will tell whether new molecular and flow cytometric high-throughput technologies can overcome the limitations of current standard methods and eventually bring additional benefits. MRD during standard ALL chemotherapy is the strongest overall prognostic indicator and has therefore been used for refining initial treatment stratification. Moreover, MRD positivity after the maintenance phase of treatment may point to an impending relapse and thus enable salvage treatment to be initiated earlier, which could possibly improve treatment results. The prognostic relevance of pretransplantation MRD was shown by several studies, and MRD high-risk patients were shown to benefit from stem cell transplantation (SCT). Also, MRD positivity after SCT correlates with worse outcomes. In addition, MRD information is very instructive in current clinical trials that test novel agents to evaluate their treatment efficacy. Although conventional clinical risk factors lose their independent prognostic significance when combined with MRD information, recently identified genetic markers may further improve the treatment stratification in ALL.

Long-term function and psychosocial outcomes with venlafaxine extended release 75–225 mg/day versus placebo in the PREVENT study

This post-hoc analysis evaluated long-term psychosocial outcomes in patients with recurrent major depressive disorder treated with venlafaxine extended release (ER) 75-225 mg/day or placebo. Patients who responded to 10-week venlafaxine ER 75-300 mg/day treatment and maintained response through a 6-month continuation treatment were assigned randomly to venlafaxine ER or placebo maintenance-phase treatment. Data from responders to acute and continuation venlafaxine ER 75-225 mg/day treatment were analyzed during 12-month maintenance treatment while receiving venlafaxine ER of up to 225 mg/day. Failure to maintain improvement in psychosocial functioning, on the basis of the Social Adjustment Scale-Self-Report, Life Enjoyment Scale, Quality of Life Enjoyment and Satisfaction Questionnaire, and Short-Form Health Survey, was defined as loss of at least 50% of the improvement from acute-phase baseline achieved during acute and continuation treatment or dose escalation of more than 225 mg/day. The probability of remaining well (no failure to maintain improvement in functioning) was significantly higher through 12-month maintenance treatment for patients treated with venlafaxine ER 75-225 mg/day versus placebo Social Adjustment Scale-Self-Report, Life Enjoyment Scale, Quality of Life Enjoyment and Satisfaction Questionnaire, and Short-Form Health Survey component summary scores (all P≤0.0351). Effects of up to 20 months of treatment with venlafaxine ER 75-225 mg/day on psychosocial functioning were consistent with the results for venlafaxine ER 75-300 mg/day.

Folate deficiency in north Indian children undergoing maintenance chemotherapy for acute lymphoblastic leukemia-Implications and outcome.

Treatment-related toxicity and mortality are not uncommon during maintenance chemotherapy for childhood acute lymphoblastic leukemia (ALL), especially in the low- and middle-income countries (LMIC). Undernutrition and micronutrient deficiencies are commonly seen in children from LMICs undergoing treatment for ALL. The present study examines the prevalence and clinical implications of folate deficiency in north Indian children with ALL during the maintenance phase of treatment in view of prolonged antifolate treatment and high population prevalence of folate deficiency. Pre-cycle folate levels/deficiency as well as weight for age z-score and serum albumin level were determined and correlated with complications of treatment and mortality encountered during the maintenance phase of treatment. Twenty-nine of 52 children enrolled in the study had folate deficiency at some point during maintenance chemotherapy. Neutropenia (18 of 29 vs. 4 of 23; P = 0.002), thrombocytopenia (17 of 29 vs. 4 of 23; P = 0.005), febrile neutropenia (17 of 29 vs. 4 of 23; P = 0.005), and need for chemotherapy dose reduction (20 of 29 vs. 7 of 21; P = 0.01) were more common in folate-deficient children. Maintenance deaths were higher (8 of 29 vs. 1 of 23; P = 0.03) and survival lower (P = 0.02) in deficient children. In multivariate analysis, hypoalbuminemia (P = 0.02) and folate deficiency (P = 0.01) were associated with febrile neutropenia, and folate deficiency with maintenance deaths (P = 0.03). Folate deficiency was associated with treatment-related complications and adverse outcome in our patients. The risks and benefits of folate supplementation in deficient children during maintenance chemotherapy need to be explored with properly designed randomized studies in similar settings.

One-Year Clinical Outcomes in an IBD Cohort Who Have Previously Had Anti-TNFa Trough and Antibody Levels Assessed.

Loss of response (LOR) is a big concern for anti-TNFa therapies in inflammatory bowel disease. Immunomonitoring may be useful to optimize response rates and overcome secondary LOR. This was an observational retrospective cohort study of a group of patients with inflammatory bowel disease on infliximab (IFX) and adalimumab (ADA) who had anti-TNFa trough and antibody levels measured, during maintenance phase of treatment. Anti-TNFa trough and antibody levels were measured using standard enzyme-linked immunosorbent assay techniques. Baseline patient characteristics were determined and patients were reviewed 1 year later. Clinical assessment took place with partial Mayo scores for ulcerative colitis and Harvey-Bradshaw index for Crohn's disease. C-reactive protein (CRP) and albumin were also measured. Poor outcomes were defined as the following: need for rescue steroids, dose intensification, surgery, or treatment discontinuation. Seventy-four patients were included in the study, 37 (50%) were female, mean age 41 years, 61 (82%) had Crohn's disease, and 42 (57%) ulcerative colitis. Forty-two (57%) patients received IFX and 32 (43%) ADA. Mean IFX trough was 3.6 μg/mL and mean ADA troughs were 3.78 μg/mL. Twenty-seven percent of patients (n = 20) overall had a poor outcome, with a similar proportion in each group 24% (n = 10) IFX and 31% (n = 10) ADA (P value 0.24). Of the cohort, 14.2% (6/42) treated with IFX had subtherapeutic trough levels, 6.2% (2/32) of ADA patients had a trough level <1 μg/mL (P value = 0.273) There was no difference in mean trough according to outcome (4.9 μg/mL poor versus 5.4 μg/mL good, P value 0.14). Low IFX trough levels did correlate with high CRP, low albumin and response rates, mean CRP 6.66 μg/mL (n = 3), mean albumin 37 g/L for patients with low trough levels and poor response versus CRP 2.0 μg/mL (n = 24), mean albumin 43 g/L for patients with high trough levels and good response (P = 0.009, 95% confidence interval, -0.78 to -0.12). LOR is still a big concern with anti-TNFa therapies. Stand-alone anti-TNFa trough and antibody levels are not useful at predicting LOR/disease progression at 1 year, but low trough levels do correlate well with elevated CRP, hypoalbuminaemia, and poor response rates.

Challenges in longitudinal exposure-response modeling of data from complex study designs: a case study of modeling CDAI score for ustekinumab in patients with Crohn's disease.

Informative exposure-response modeling of clinical endpoints is important in drug development to identify optimum dose and dosing regimens. Despite much recent progress in mechanism-based longitudinal modeling of clinical data, challenges remain in clinical trials of diseases such as Crohn's disease, where a commonly used composite endpoint Crohn's Disease Activity Index (CDAI) has considerable variation in its administration and scoring between different assessors and complex study designs typically include maintenance phases with randomized withdrawal re-randomizations and other response driven dose adjustments. This manuscript illustrates the complexities of exposure-response modeling of such composite endpoint data through a latent-variable based Indirect Response model framework for CDAI scores using data from three phase III trials of ustekinumab in patients with moderate-to-severe Crohn's Disease. Visual predictive check was used to evaluate model performance. Potential impacts of the study design on model development and evaluation of the E-R relationship in the induction and maintenance phases of treatment are discussed. Certain biases appeared difficult to overcome, and an autocorrelated residual error model was found to provide improvement.

Racial and Ethnic Differences in ADHD Treatment Quality Among Medicaid-Enrolled Youth.

We estimated racial/ethnic differences in attention-deficit/hyperactivity disorder (ADHD) care quality and treatment continuity among Medicaid-enrolled children. Using Medicaid data from 9 states (2008 to 2011), we identified 172 322 youth (age 6 to 12) initiating ADHD medication. Outcome measures included: (1) adequate follow-up care in the (a) initiation and (b) continuation and maintenance (C&M) treatment phases; (2) combined treatment with medication and psychotherapy (versus medication alone); (3) medication discontinuation; and (4) treatment disengagement (ie, discontinued medication and received no psychotherapy). Logistic regressions controlled for confounding measures. Among those initiating medication, three-fifths received adequate follow-up care in the initiation and C&M phases, and under two-fifths received combined treatment. Compared with whites, African American youth were less likely to receive adequate follow-up in either phase (P < .05), whereas Hispanic youth were more likely to receive adequate follow-up in the C&M phase (P < .001). African American and Hispanic youth were more likely than whites to receive combined treatment (P < .05). Over three-fifths discontinued medication, and over four-tenths disengaged from treatment. Compared with whites, African American and Hispanic children were 22.4% and 16.7% points more likely to discontinue medication, and 13.1% and 9.4% points more likely to disengage from treatment, respectively (P < .001). Care quality for Medicaid-enrolled youth initiating ADHD medication is poor, and racial/ethnic differences in these measures are mixed. The most important disparities occur in the higher rates of medication discontinuation among minorities, which translate into higher rates of treatment disengagement because most youth discontinuing medication receive no psychotherapy.