Predict Treatment Resistance Research Articles

Human chorionic gonadotropin (hCG) regression normograms for patients with high-risk gestational trophoblastic neoplasia treated with EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine) chemotherapy

We present normograms for human chorionic gonadotropin (hCG) regression in patients with high-risk gestational trophoblastic neoplasia (GTN) successfully treated with multiagent chemotherapy in order to predict treatment resistance. We collected data for 46 patients with high-risk GTN treated with EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine) who had hCG values available. Patients were classified as having methotrexate (MTX)-resistant disease (n = 22) or primary high-risk disease (n = 24). The 10th, 50th and 90th percentiles of the hCG before every chemotherapy course were calculated and plotted in normograms. Half of the patients treated for MTX-resistant disease and primary high-risk disease had normal hCG levels before the third and sixth course of chemotherapy, respectively. In patients with MTX-resistant disease, the 90th percentile line fell below normal before the start of the fourth course, whereas in patients with primary high-risk disease this was not the case until the eighth course of chemotherapy. Resistance to EMA/CO treatment for high-risk GTN, as illustrated by examples, could be predicted using normograms for hCG resistance. Normograms differed depending on the indication for multiagent chemotherapy due to much higher initial hCG values in patients with primary high-risk disease compared with those treated for MTX-resistant disease.

Classification of antineutrophil cytoplasmic autoantibody vasculitides: The role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis

To compare the usefulness of 3 currently used classification systems in predicting the outcomes of treatment resistance, disease relapse, end-stage renal disease (ESRD), and death in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Three classification systems were applied to 502 patients with biopsy-proven AAV: 1) the Chapel Hill Consensus Conference (CHCC) definition with categories for granulomatosis with polyangiitis (GPA) (Wegener's), microscopic polyangiitis (MPA), and kidney-limited disease; 2) the European Medicines Agency (EMA) system with categories for GPA and MPA; and 3) classification based on ANCA with specificity for myeloperoxidase (MPO ANCA) versus ANCA with specificity for proteinase 3 (PR3 ANCA). Outcomes included treatment resistance, relapse, ESRD, and death. Proportional hazards models were compared between systems using an information-theoretic approach to rank models by predictive fit. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) and P values are reported. ANCA specificity was predictive of relapse, with PR3 ANCA-positive patients almost twice as likely to relapse as those with MPO ANCA (HR 1.89 [95% CI 1.33-2.69], P = 0.0004), and ANCA specificity had the best predictive model fit (model rank 1) compared to the CHCC and EMA systems. The CHCC and EMA systems did not predict relapse. By ANCA specificity, categories of GPA, MPA, and kidney-limited disease did not distinguish differences in probability of relapse-free survival. None of the systems predicted treatment resistance, ESRD, or death. ANCA specificity independently predicts relapse among patients with AAV with renal disease. Classification and diagnostic systems that incorporate ANCA specificity, such as PR3 ANCA-positive MPA and MPO ANCA-positive MPA, provide a more useful tool than the clinical pathologic category alone for predicting relapse.

Evidence‐based options for treatment‐resistant adult bipolar disorder patients

Many patients diagnosed with bipolar disorder (BD) respond incompletely or unsatisfactorily to available treatments. Given the potentially devastating nature of this prevalent disorder, there is a pressing need to improve clinical care of such patients. We performed a literature review of the research findings related to treatment-resistant BD reported through February 2012. Therapeutic trials for treatment-resistant bipolar mania are uncommon, and provide few promising leads other than the use of clozapine. Far more pressing challenges are the depressive-dysthymic-dysphoric-mixed phases of BD and long-term prophylaxis. Therapeutic trials for treatment-resistant bipolar depression have assessed anticonvulsants, modern antipsychotics, glutamate [N-methyl-D-aspartate (NMDA)] antagonists, dopamine agonists, calcium-channel blockers, and thyroid hormones, as well as behavioral therapy, sleep deprivation, light therapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation, and deep brain stimulation-all of which are promising but limited in effectiveness. Several innovative pharmacological treatments (an anticholinesterase, a glutamine antagonist, a calcium-channel blocker, triiodothyronine, olanzapine and topiramate), ECT, and cognitive-behavior therapy have some support for long-term treatment of resistant BD patients, but most of trials of these treatments have been methodologically limited. Most studies identified were small, involved supplementation of typically complex ongoing treatments, varied in controls, randomization, and blinding, usually involved brief follow-up, and lacked replication. Clearer criteria for defining and predicting treatment resistance in BD are needed, as well as improved trial design with better controls, assessment of specific clinical subgroups, and longer follow-up.

Tumour burden predicts treatment resistance in patients with early unfavourable or advanced stage Hodgkin lymphoma treated with ABVD and radiotherapy

The purpose of the work was to investigate the factors predicting early resistance to treatment in Hodgkin lymphoma. Many staging parameters, including relative tumour burden (rTB), were analysed in 246 patients with Hodgkin lymphoma in relation to early failure, that is, less than complete remission (i.e. partial response, null response or progression) or occurrence of early relapse, as clinical expressions of resistance to treatment. Patients with early unfavourable disease were 129 and were treated with four to six cycles of ABVD + involved field radiotherapy; 117 patients with advanced stage disease received six cycles of ABVD + optional irradiation to no more than two sites. The rTB was volumetrically measured through the evaluation of staging computed tomography for all the lesions except bone marrow involvement, which was quantified by calculation. The relationship with early resistance was analysed with logistic regressions. The rTB demonstrated to be the best predictor of early failure in both patient subsets, being superior to the multiparameter International Prognostic Score. The rTB showed a significant exponential relationship with the relative risk of early failure, and with inclusion of the extranodal involvement into the model, a single equation became adequate to predict resistance in both early unfavourable and advanced stage patients. The conclusions are that the rTB is the best pretreatment factor related to the risk of resistance to combined ABVD + radiotherapy and that this relationship can be mathematically expressed in an easy way. A simplified assessment of rTB is highly desirable.

Does lack of improvement in the first two weeks predict treatment resistance in recent-onset psychosis?

Randomized controlled trials among patients with schizophrenia have shown that <20% improvement in the first two weeks of treatment predicts nonresponse after 12 weeks. The findings have been consistent for patients treated with both conventional (1) and second-generation antipsychotic (AP) drugs (2). However, despite the lack of evidence regarding the length of time that clinicians should pursue one treatment regimen, most psychiatric textbooks and practice guidelines suggest that patients should be treated for at least four to six weeks with one AP (3-5) before switching to another (6). Large pragmatic trials with chronic patients, such as the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) (7), have found no benefit from switching AP drugs (8,9). No studies have considered less chronic patients, such as patients with recent-onset schizophrenia (i.e., less than five years of illness duration). We investigated responses to APs and switching strategies in patients with recent-onset schizophrenia. We used the IPAP algorithm, which is a well-defined algorithm for treating schizophrenia (4,10).

S04-01 - Treatment Resistance in Depression

Due to the advancement of antidepressant medication, more patients receive treatment in everyday practice, and response/remission is not achieved in the majority of the patients. Several attempts to validate the definition of treatment resistance have been undertaken and the criteria usually encompased to treatment sequences are that two different classes of antidepressants given in a sufficient dosage for a sufficient time have to be administered. Clinically, it is evident that this defintion does not include the treatment refractory patients which could be defined as not responding to numerus trials including electroconvulsive therapy. The goal to improve treatment through the use of predicitve biomarkers has not as yet been obtained and will be the challenge for the future. The clinical variables predicting treatment resistance include comorbid anxiety disorders as well as melancholic features. Although there is a plethora of hints in textbooks that switching the mechanism of action should be obtained when a patient does not respond to one medication, the few controlled trials which have been undertaken to challenge this notion revealed that staying on the same antidepressant mechanism of action for a longer time is more beneficial. In previous times, the conjunctive use of agents such as lithium or thyroid augmentation have been proposed, however the new data achieved with atypical antipsychotics demonstrate a more rapid improvement. Techniques such as brain stimulation or vagus nerve stimulation have also shown promising early results. Treatment resistance continues to be a major barrier achieving remission in patients with major depressive disorder and a thorough re-evaluation of the condition and its treatment is needed.

Comparison of individual and group cognitive behavioral therapy for binge eating disorder. A randomized, three-year follow-up study

Few long-term follow-up studies evaluated the response to psychotherapeutic interventions in binge eating disorder (BED). The effectiveness of individual and group cognitive-behavioral therapy, and the possible predictors of outcome were evaluated in a randomized controlled trial. At the beginning, at the end of treatments, and three years after the end of treatments, 144 patients affected by threshold or subthreshold BED were assessed using a clinical interview and self-reported questionnaires evaluating the eating attitudes and behavior, emotional eating, and general psychopathology. The following outcome measures were considered: recovery at 3-year follow-up, weight loss, treatment resistance, relapse, and diagnostic change. Both treatments showed similar response in terms of all outcome measures in the long-term, and determined a significant reduction of binge eating frequency, and a mild reduction of weight. The absence of a history of amphetamine derivatives consumption, lower emotional eating and binge eating severity at baseline were predictors of full recovery in the long-term. A low Emotional eating was found to be the only predictor of weight reduction. Overweight during childhood, full blown BED diagnosis, and high emotional eating were predictors of treatment resistance. Treatments considering the relationships between binge eating and emotional eating could improve the outcome of BED patients.

Update on Antiplatelet Therapy in Acute Coronary Syndromes

The incidence of new coronary events in patients receiving dual antiplatelet therapy (e.g. cyclo-oxygenase inhibitors such as aspirin [acetylsalicylic acid; ASA]) and ADP receptor blockers (e.g. clopidogrel) is high. Therefore, it is critical to identify patients who require more intense treatment such as those with poor tolerance to existing drugs, those with genotypes that predict treatment resistance, diabetic patients, and smokers. The new ADP receptor blockers (prasugrel, cangrelor, Ticagrelor) can provide greater efficacy but it should not be associated with increased bleeding. Thrombin receptor antagonists (e.g. SCH530348) are another alternative that is currently being tested in randomized trials.

Human testicular (non)seminomatous germ cell tumours: the clinical implications of recent pathobiological insights

Human germ cell tumours (GCTs) comprise several types of neoplasias with different pathogeneses and clinical behaviours. A classification into five subtypes has been proposed. Here, the so-called type II testicular GCTs (TGCTs), ie the seminomas and non-seminomas, will be reviewed with emphasis on pathogenesis and clinical implications. Various risk factors have been identified that define subpopulations of men who are amenable to early diagnosis. TGCTs are omnipotent, able to generate all differentiation lineages, both embryonic and extra-embryonic, as well as the germ cell lineage itself. The precursor lesion, composed of primordial germ cells/gonocytes, is referred to as carcinoma in situ of the testis (CIS) and gonadoblastoma of the dysgenetic gonad. These pre-malignant cells retain embryonic characteristics, which probably explains the unique responsiveness of the derived tumours to DNA-damaging agents. Development of CIS and gonadoblastoma is crucially dependent on the micro-environment created by Sertoli cells in the testis, and granulosa cells in the dysgenetic gonad. OCT3/4 has high sensitivity and specificity for CIS/gonadoblastoma, seminoma, and embryonal carcinoma, and is useful for the detection of CIS cells in semen, thus a promising tool for non-invasive screening. Overdiagnosis of CIS due to germ cell maturation delay can be avoided using immunohistochemical detection of stem cell factor (SCF). Immunohistochemistry is helpful in making the distinction between seminoma and embryonal carcinoma, especially SOX17 and SOX2. The different non-seminomatous histological elements can be recognized using various markers, such as AFP and hCG, while others need confirmation. The value of micro-satellite instability as well as BRAF mutations in predicting treatment resistance needs validation in prospective trials. The availability of representative cell lines, both for seminoma and for embryonal carcinoma, allows mechanistic studies into the initiation and progression of this disease.

Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody–associated small‐vessel vasculitis: Comparison of two independent cohorts

Predictors of treatment resistance and relapse have been identified in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in the Glomerular Disease Collaborative Network (GDCN) in the southeastern US. This study was undertaken to evaluate the applicability of those predictors in an independent cohort followed up by the French Vasculitis Study Group. Predictors of treatment resistance were evaluated using logistic regression models and reported as odds ratios (ORs) with 95% confidence intervals (95% CIs). Predictors of relapse were evaluated using Cox proportional hazards models and reported as hazard ratios (HRs) with 95% CIs. Models were controlled for age, sex, race, baseline serum creatinine level, and cyclophosphamide therapy. The French cohort (n = 434) and the GDCN cohort (n = 350) had similar median followup periods (44 months versus 45 months) and initial percentages of patients taking cyclophosphamide (82% versus 78%). The French cohort included more patients with proteinase 3 (PR3) ANCA (58% versus 40%), lung involvement (58% versus 49%), and upper respiratory tract involvement (62% versus 31%). Of the predictors of treatment resistance in the GDCN cohort (female sex, African American race, presence of myeloperoxidase ANCA, elevated creatinine level, and age), only age predicted treatment resistance in the French cohort (OR 1.32 per 10 years [95% CI 1.05-1.66]). Predictors of relapse in the GDCN cohort were PR3 ANCA (HR 1.77 [95% CI 1.11-2.82]), lung involvement (HR 1.68 [95% CI 1.10-2.57), and upper respiratory tract involvement (HR 1.58 [95% CI 1.00-2.48]), while predictors in the French cohort were PR3 ANCA (HR 1.66 [95% CI 1.15-2.39]) and lung involvement (HR 1.56 [95% CI 1.11-2.20]), but not upper respiratory tract involvement (HR 0.96 [95% CI 0.67-1.38]). Our findings indicate that older age is a predictor of treatment resistance, and that PR3 ANCA and lung involvement are predictors of relapse in both cohorts. Discrepancies in predictors of treatment tract resistance may reflect differences in access to care, and differences in predictors of relapse may reflect variations in disease expression.

Incomplete remission and treatment resistance in first-episode psychosis: definition, prevalence and predictors

Background: Up to 50% of first-episode psychosis patients suffer from long-term incomplete remission or treatment resistance. Different definitions for these terms have been used in psychiatric research, making generalized statements about the prevalence and predictors of treatment resistance difficult. Objective: The aim of this study was to give an overview on state-of-the-art definitions of treatment resistance for each of the diagnoses making up the inhomogeneous diagnostic entity ‘psychosis’ and to analyze the factors leading to treatment resistance. Methods: A computerized and manual literature search for relevant articles published within recent years was undertaken. Results: In addition to symptomatic criteria, patients' functional level and quality of life have to be considered in the definition of treatment resistance. Patient-related, illness-related and treatment-related predictors of treatment resistance and incomplete remission might help to identify subjects at risk and optimize interventions.

Comorbidity and treatment issues in juvenile bipolar disorder

Juvenile bipolar disorder (BD) is reported to be more treatment-resistant than adult BD, and to show poorer outcome. Predictors of treatment non-response in early onset BD are not well defined. Many potential domains of variables may be considered. Age, gender and age at onset of BD can affect both clinical presentation and pattern of comorbidity, and both these issues may affect the pharmacological response. Some features, which in adult patients with BD are considered predictors of poor treatment response, such as severity, mixed states, psychotic symptoms, and co-morbid substance abuse are particularly frequent in youths, and they also may influence pharmacological response in children and adolescents as well. We explored this issue in a study, conducted in the last 3 years, aimed to explore the role of lifetime comorbid externalizing and internalizing disorders as possible predictors of treatment non-response, in bipolar children and adolescents with manic or mixed episodes. Nonresponders had more frequently co-morbid conduct disorder and/or ADHD. Furthermore, they were globally more severe at baseline and required more frequent addition of antipsychotic medications than treatmentresponder patients. Co-morbid anxiety disorders in our sample did not predict treatment resistance. Interestingly, anxiety disorders and CD were inversely related, with the number of anxiety disorders significantly lower in subjects without CD comorbidity. The use of antipsychotics was associated with treatment non-response, and it was probably related to the severity of the subjects who received these drugs (i.e. higher prevalence of impulsivity, psychomotor agitation, behavioral problems, psychotic symptoms). Different mechanisms can be involved in treatment-resistance of bipolar subjects with co-morbid externalizing disorders. BD plus externalizing disorders may represent a specific subtype, with earlier-onset and resistance to traditional anti-manic and mood stabilizing drugs. Poorer treatment response in BD with co-occurring externalizing disorders may be also accounted for by a more problematic compliance to treatment. Several comorbidities with negative prognostic implications (i.e. substance abuse, antisocial behaviors), which are more frequent in bipolar patients with externalizing disorders, may further affect clinical course. Follow-up studies with larger samples of subjects with BD and/or externalizing disorders appropriately treated with different options are needed to address this important issue. Additional stimulant medication after adequate coverage with mood stabilizers might represent one rational approach to this group of refractory bipolar children. from International Society on Brain and Behaviour: 3rd International Congress on Brain and Behaviour Thessaloniki, Greece. 28 November – 2 December 2007

Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis: Comparison of two independent cohorts

Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis: Comparison of two independent cohorts

Impact of cyclins E, neutrophil elastase and proteinase 3 expression levels on clinical outcome in primary breast cancer patients

Uncontrolled cell proliferation is one of the hallmarks of cancer and the transition from the G1 to S phase is the most commonly reported cell cycle abnormality in tumors. It has been shown that the oncogenic activity of G1 cyclin E (CCNE) can be amplified by generating hyperactive low molecular weight forms (LMW) through elastase-mediated proteolytic processing. Neutrophil elastase (NE) and proteinase 3 (PR3) are 2 proteases that are aberrantly expressed in breast cancer cells and seem to be involved in cell proliferation. In this study, we evaluated the effect of the expression of these 2 proteases in addition to 2 potential intracellular targets of NE (CCNE1 and CCNE2) on clinical outcome in a population of 205 primary breast cancer patients. By univariate analysis, CCNE1, CCNE2, estrogen receptor and grade significantly predicted relapse free interval (RFI). NE and PR3 did not achieve statistical significance. In a multivariate analysis, elevated CCNE2 [hazard ratio (HR) 2.10, p = 0.008] predicted shorter RFI. In subgroup analyses of the tamoxifen-only treated patients, high CCNE1 levels predicted treatment resistance, while high levels of CCNE2 were associated with poor RFI in untreated patients. Investigation of the relationship between CCNE1, CCNE2 and NE did not show any impact on RFI. To conclude, this study was the first to evaluate these markers at the mRNA level by RT-PCR in a series of primary breast cancer patients, and our results confirmed the impact of high CCNE levels on clinical outcome in systemically untreated and of CCNE1 in tamoxifen-only treated early breast cancer patients.

Impact of medical comorbid disease on antidepressant treatment of major depressive disorder.

A major factor in evaluating and treating depression is the presence of comorbid medical problems. In this paper, the authors will first evaluate studies showing that medical illness is a risk factor for depression. The authors will review a series of randomized, controlled studies of antidepressant treatment in subjects with major depressive disorder (MDD) and comorbid medical illnesses (myocardial infarction, stroke, diabetes, cancer, and rheumatoid arthritis). Most of these studies report an advantage for an active antidepressant over placebo in improvement of depressive symptoms. The authors also will review a series of studies in which the outcome of antidepressant treatment is compared between subjects with MDD with and without comorbid medical illness. In these studies, subjects with medical illness tend to have lower improvement of depressive symptoms and higher rates of depressive relapse with antidepressant treatment compared with MDD subjects with no medical comorbidity. In addition, the authors will review hypotheses on the mechanism of the interaction between medical illness and clinical response in MDD. The paper will conclude that medical comorbidity is a predictor of treatment resistance in MDD.

Combination of dopamine D2 receptor gene polymorphisms as a possible predictor of treatmentresistance to dopamine receptor antagonists in schizophrenic patients

Combination of dopamine D2 receptor gene polymorphisms as a possible predictor of treatmentresistance to dopamine receptor antagonists in schizophrenic patients

Is left stroke a risk-factor for selective serotonin reuptake inhibitor antidepressant treatment resistance?

The objective of the study was to detect changes of depression and cognitive level associated with right and left brain damage during SSRI treatment in subjects with post-stroke Major Depressive Disorder (MDD). After the baseline evaluation, the 45 patients included received a single oral dose of 20-40 mg of fluoxetine or 50-100 mg of sertraline. At day 0, 7, 14, 28, 42, and 56 a psychometric test battery comprising the Hamilton Depression Rating Scale (HDRS) and the Mini Mental State Examination (MMSE) was administered. In the whole group repeated measures ANOVAs revealed a highly significant (p < 0.0001) time effect for HDRS and MMSE scores. However, depression improved much more in right stroke subjects in comparison with left stroke subjects (p < 0.001 for the HDRS by laterality interaction). Moreover, there is a suggestion of a possible selective serotonin reuptake inhibitor (SSRI) efficacy in cognitive impairment associated to post-stroke MDD but in treatment-responders only. At the endpoint, chi-square analysis showed that there was a different prevalence rate of MDD between left (n = 10; 50 %) and right (n = 4; 16 %) stroke patients, whereas the prevalence rate of Minor Depression was identical (25 %). The SSRIs fluoxetine and sertraline could be efficacious treatments for post-stroke MDD but these findings suggest that left stroke could be a predictor of treatment resistance.

100 Expression microarrays in the prediction of treatment resistance: the CNIO Program

100 Expression microarrays in the prediction of treatment resistance: the CNIO Program

Expression microarrays in the prediction of treatment resistance: The CNIO program

Expression microarrays in the prediction of treatment resistance: The CNIO program

Do Subtle Neurological Impairments Predict Treatment Resistance to Clomipramine in Children and Adolescents with Obsessive-Compulsive Disorder?

ABSTRACT A 10-week double-blind, placebo-controlled design was employed to investigate the effectiveness of clomipramine (CMI) versus placebo in 16 outpatients (ages 10-18 years) with obsessive-compulsive disorder (OCD). While a trend favoring clomipramine was observed, the difference in efficacy between clomipramine (N=8) and placebo (N=8) did not reach statistical significance, partly due to small sample size (N = 6,8). Post-hoc exclusion of two clomipramine-resistant subjects with subtle neurological impairments did, however, yield a statistically significant improvement with drug treatment. Neurological impairments are commonly seen in children with OCD, and may be a risk factor for the disorder during childhood. Speculatively, subtle neurological impairments may also predict resistance to CMI therapy in some patients, and influence the outcome of clinical and research medication trials, depending on differences in neurological inclusion and exclusion criteria.