Progression In Subgroup Research Articles

P11.32.A GLIOBLASTOMA NOMOGRAM: PREDICTING THE LOCATION OF FIRST PROGRESSION AFTER LONG-COURSE CHEMORADIOTHERAPY BASED ON A NATIONAL COHORT

Abstract BACKGROUND Glioblastoma (GBM) is known for its high local failure rate, as well as its migration, leading to these possible locations of disease progression: 1. Local-only; lesion of progression is connected to the initial tumour location 2. Non-local; lesion of progression is not connected to the initial tumour location 3. Combined; both local-only and non-local progression lesions are present An upfront prediction of progression location could potentially be used to select patients for differential treatment strategies. The aim of this retrospective national study was therefore to predict location of first progression using clinical variables. MATERIAL AND METHODS All adults with newly diagnosed GBM between 2014-2019 who started long-course (chemo)radiotherapy were included, if they had a radiotherapy-planning MRI made. The MRI of first progression was identified by retrospective review following RANO-criteria, and used to assess the location of contrast-enhancing progression. Median time to progression (TTP) and survival beyond progression were estimated using the Kaplan-Meier method (log rank test for comparison). To predict location of progression in subgroups of patients, we used a multivariable multinomial model (age, biological sex, performance status, tumour location & focality & laterality, MGMT-methylation status, and extent of surgery). RESULTS We included 940 patients (MGMT methylated n=376, unmethylated n=483, not reported n=81), of whom 760 had radiographic progression. Of those, progression location was local-only in 69%, non-local in 16%, and combined in 15%. Median (95% CI) TTP in months was shortest in the combined group (8.4, 7.3-9.4), followed by the local-only (9.2, 8.5-9.8) and non-local (13.9, 12.3-15.6) (p-value <.001). Survival beyond progression in months was shortest in the combined group (5.0, 3.8-6.2), followed by the non-local (6.0, 4.4-7.6) and local-only (9.0, 8.3-9.7) (p-value <.001). When comparing patients with MGMT-methylated and unmethylated tumours, the probability (95%CI) of local-only progression was .67 (.62-.73) vs. .73 (.69-.78), non-local was .21 (.17-.26) vs. .11 (.08-.14), and combined was .12 (.08-.15) vs. .16 (.12-.19). In the multivariable model, the probability (95%CI) of local-only progression varied from .49 (.29-.69) to .86 (.74-.97), of non-local from .04 (.00-.09) to .34 (.15-.53), and of combined from .05 (.01-.10) to .34 (.07-.60) between respective subgroups. CONCLUSION Location of progression was associated with time to progression and survival beyond progression. In our study population it was feasible to identify subgroups of patients with a high chance of local-only progression, who may potentially benefit most from radiation dose-escalation. Both patients with MGMT-methylated and unmethylated tumours had the highest chance for first progression located at the initial tumour site only.

Clinical staging in amyotrophic lateral sclerosis: analysis of Edaravone Study 19

ObjectiveThis was a post hoc analysis of the Edaravone Phase III Study MCI186-19 (‘Study 19’) to examine the utility of clinical staging systems as end points in clinical trials in...

Author response: Migraine progression in subgroups of migraine based on comorbidities: Results of the CaMEO Study.

In our article,1 we used latent class analysis (LCA) to identify clinically homogeneous migraine subgroups. Progress in the characterization of familial hemiplegic migraine (FHM) was possible because a specific migraine phenotype was identified, facilitating the discovery of multiple causal genetic variations and biological mechanisms.2 Our approach builds on the FHM model by using LCA to identify specific migraine phenotypes based on comorbidity profiles.3 To show that these subgroups are meaningful, we sought to examine characteristics not included in LCA as external validators; these can include biological markers, treatment response, or clinical course.

Reader response: Migraine progression in subgroups of migraine based on comorbidities: Results of the CaMEO Study.

I read the article by Lipton et al.1 The sociodemographic model creating subdivisions of migraine into statistically valid subgroups based on comorbidity classes to predict progression from episodic migraine (EM) to chronic migraine (CM)1 does not have any biologic or pathophysiologic basis. The distinction between EM and CM is based on a unique, purely arbitrary symptom-based nosologic template. After the widely split primary headache classification,2—itself absolutely without any biologic or pathophysiologic substance—this statistical subdivision of migraine through comorbidities1 ensures continuous generation of data sans any overarching matrix, thereby indefinitely adding to the extant confusion.

Editors' note: Migraine progression in subgroups of migraine based on comorbidities: Results of the CaMEO Study

In their longitudinal survey of more than 8,000 patients with episodic migraine and selected comorbidities, Drs. Lipton et al. reported the results of the CaMEO Study. The investigators used 3 unique mathematical models to estimate the effect of various comorbidities on the progression of episodic migraine to chronic migraine. All comorbidity classes independently contributed to disease progression, and the effect was cumulative—with more comorbidities conferring a greater risk than fewer comorbidities. Dr. Gupta expresses concerns regarding the usefulness of classifying migraine subtypes, as there is presently unclear biologic heterogeneity of various migraine phenotypes. In response, the authors emphasize the importance of distinguishing unique migraine syndromes, as they may signify distinct biomarkers of disease or demonstrate a differential responsiveness to certain therapeutics. The authors acknowledge that the results of this study are one of several steps, which may lead to the improved care of patients with migraine. In their longitudinal survey of more than 8,000 patients with episodic migraine and selected comorbidities, Drs. Lipton et al. reported the results of the CaMEO Study. The investigators used 3 unique mathematical models to estimate the effect of various comorbidities on the progression of episodic migraine to chronic migraine. All comorbidity classes independently contributed to disease progression, and the effect was cumulative—with more comorbidities conferring a greater risk than fewer comorbidities. Dr. Gupta expresses concerns regarding the usefulness of classifying migraine subtypes, as there is presently unclear biologic heterogeneity of various migraine phenotypes. In response, the authors emphasize the importance of distinguishing unique migraine syndromes, as they may signify distinct biomarkers of disease or demonstrate a differential responsiveness to certain therapeutics. The authors acknowledge that the results of this study are one of several steps, which may lead to the improved care of patients with migraine.

Migraine progression in subgroups of migraine based on comorbidities: Results of the CaMEO Study.

ObjectiveTo test the hypothesis that statistically defined subgroups of migraine (based on constellations of comorbidities and concomitant conditions; henceforth comorbidities), previously identified using Chronic Migraine Epidemiology and Outcomes (CaMEO) Study data, differ in prognosis, as measured by rates of progression from episodic migraine (EM) to chronic migraine (CM).MethodsThe onset of CM was assessed up to 4 times over 12 months in individuals with EM and ≥1 comorbidity at baseline, based on constellations of comorbidities (comorbidity classes). The “fewest comorbidities” class served as reference. Individuals completing ≥1 follow-up survey from the web-based CaMEO Study were included. Covariates included sociodemographic variables and headache characteristics. Sex, income, cutaneous allodynia, and medication overuse were modeled as binary variables; age, body mass index, headache-related disability (Migraine Disability Assessment [MIDAS]), and Migraine Symptom Severity Scale as continuous variables. CM onset was assessed using discrete time analysis.ResultsIn the final sociodemographic model, all comorbidity classes had significantly elevated hazard ratios (HRs) for risk of progression to CM from EM, relative to fewest comorbidities. HRs for CM onset ranged from 5.34 (95% confidence interval [CI] 3.89–7.33; p ≤ 0.001) for most comorbidities to 1.53 (95% CI 1.17–2.01; p < 0.05) for the respiratory class. After adjusting for headache covariates independently, each comorbidity class significantly predicted CM onset, although HRs were attenuated.ConclusionsSubgroups of migraine identified by comorbidity classes at cross-section predicted progression from EM (with ≥1 comorbidity at baseline) to CM. The relationship of comorbidity group to CM onset remained after adjusting for indicators of migraine severity, such as MIDAS.Clinicaltrials.gov identifierNCT01648530.

Familial amyloid polyneuropathy

Transthyretin (TTR) familial amyloid polyneuropathy also called hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) is a progressive, fatal, inherited disorder first identified in Portugal, currently recognized worldwide. Over the past decade, thanks to the availability of the genetic test, various patterns and progression of the neuropathy, and of the associated cardiomyopathy, have been identified. Such refinements, along with the increased awareness of the disease, reduce the diagnostic delay and permit early treatment. Also, a better understanding of the TTR amyloid formation has allowed development of new treatments, which are less invasive than the liver transplantation initially recommended. TTR stabilizer drugs are safe and appear to delay the disease progression in subgroups of patients with mild polyneuropathy (stage 1 e.g. fully ambulatory). Recently, positive results of two phase III trials on TTR gene modifiers, namely silencing RNA and antisense oligonucleotide therapies, in a broad spectrum of hATTR patients, have been released. Both drugs are now becoming available. These major advances open a new area in the field with the expectation of long term stabilization of the disease also in severely affected patients. Furthermore, immunotherapy targeting the amyloid deposits is also being tested. Finally, appropriate management of the gene carriers, in the light of recent data on penetrance, should allow therapeutic initiation at the earliest disease manifestations.

THU0261 Continuous nsaid use reverts the effects of inflammation on radiographic progression in patients with ankylosing spondylitis

BackgroundIn a recent clinical trial it was shown that continued treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), in comparison to on-demand use of NSAIDs, reduced radiological progression in the spine in...

Continuous NSAID use reverts the effects of inflammation on radiographic progression in patients with ankylosing spondylitis

ObjectivesThe aim was to compare continuous and on-demand NSAID treatment with respect to their ability to suppress radiographic progression in subgroups of patients with high/elevated CRP-levels, ESR, ASDAS-levels or BASDAI-levels...

Regulatory T Cells Predicts Progression in Previously Untreated Myeloma Patients and Treatment by Cyclophosphamide, Thalidomide Plus Dexamethasone Reduces Regulatory T Cells

Abstract 2870 Background:Regulatory T (Treg) cells are one of the master regulators in maintaining tolerance and immune homeostasis. Several studies in hematological and non-hematological malignancies revealed that increased level of Treg cells significantly impede the anti-tumor responses. Moreover, in non-hematological malignancies Treg cells correlate inversely with patient’s survival (Beyer et al, 2006, Blood). Here in this study we evaluated the prognostic significance of Treg cells in multiple myeloma (MM) patients and influence of chemotherapies on Treg cells. Patients and Method: In this study a cohort of 74 newly diagnosed MM patients were recruited and all patients gave informed consent. Median age of the patient cohort was 67 years (range: 38–88). According to international staging system (ISS) patients were characterized as ISS1=20(27%), ISS2=27(36%), ISS3=25(34%) and undetermined=2(3%). Patients were treated with following treatment regimens: low or high dose combination of cyclophosphamide, thalidomide plus dexamethasone (CTD- 54/74), bortezomib, doxorubicin plus dexamethasone (5/74), and cyclophosphamide, doxorubicin plus dexamethasone (4/74). Eleven patients did not receive any treatment. Using multiparameter flowcytometry all the MM subjects peripheral blood (PB) samples were analyzed for total lymphocytes, CD4 T cells and Treg cells. For comparison, 10 healthy volunteers PB samples were also assessed. Results: Phenotypically, CD4 T cells were assessed based on the expression of CD4 marker and Treg cells were characterized as CD4+CD25hi+FoxP3+. The frequencies of total lymphocytes were significantly reduced in MM than healthy volunteers [median% (range %)= 16.88(2.77–45.93) vs. 36.96(29.42–53.69); P<0.0001]. CD4 T cell numbers were similar between MM patients and healthy volunteers [median% (range %)= 38.17(15.02–81.33) vs. 40.03(30.58–52.16); P=0.34]. Contrasting to lymphocyte and CD4 T cell counts, Treg cells were significantly increased in MM patients compared to healthy volunteers [median% (range %)= 5.22 (2.57–11.73) vs. 3.00 (1.96–3.59); P<0.0001]. Twenty five patients were followed and their PB samples were assessed after CTD treatment (15/25) or transplantation (10/25). Post-treatment or transplantation assessment showed significant reduction in the frequencies of CD4 T cells and Treg cells compared to pre-treatment, whereas lymphocyte numbers were similar (Table: 1). With regard to treatment responses, ≥ very good partial response (VGPR) was achieved in 12 patients (complete response-3/12 plus VGPR-9/12) and 13 patients achieved < VGPR (partial response-7/13, minimal response-1/13 and progressive disease-5/13). Patients with ≥ VGPR showed significant reduction in the frequencies of CD4 T cells and Treg cells after treatment compared to pre-treatment. However, patients with < VGPR showed only significant reduction for CD4 T cells (Table: 2). No significant association was observed between pre- and post-treatment frequencies of Treg cells with treatment responses. Time to progression (TTP) data was available for 44 patients. The median follow-up period of this patient cohort was 11 months (range: 4–18). We separated the patients into two cohorts, such as patients (23/44) with higher Treg cell count (≥ 5%) and patients (21/44) with lower Treg cell count (< 5%). Univariate analysis showed inferior TTP for patients with higher Treg cell count compared to patients with lower Treg cell count (13 months vs. median not reached; P=0.013). Other clinical variables did not hold significance for TTP in this cohort. As well, Cox regression multivariate model ensured inferior TTP for cohort with higher Treg cell count compared to cohort with lower Treg cell count (P=0.045). Conclusions: It is well known that myeloma patients suffer from various immune abnormalities and Treg cells also mediate immune dysfunctions. Unprecedentedly, our data suggest that progression in subgroup of myeloma patients was due to higher infiltration of Treg cells in the peripheral blood. This data also encourages that Treg cells could be a potential target in myeloma patients along with tumor cells. As well our finding showed that CTD efficiently depleted the Treg cells in patients who achieved ≥ VGPR. This study was supported by respective grants MSM0021622434, LC06027, IGA NS10406, IGA NS10408, and GACR P304/10/1395. [Display omitted] Disclosures:Off Label Use: cyclophosphamide, thalidomide and dexamethasone.

Aktueller Überblick über strukturelle Magnet-resonanztomographie bei Schizophrenie

Non-invasive morphologic imaging (computer tomography, magnetic resonance imaging, MRT) has contributed significantly to our understanding of schizophrenic disorders as diseases of the brain. Improved MRT techniques enable us to analyse anatomical substructures. The present overview evaluates peer-reviewed MRT studies published between 1994 and July 2000 and provides a comparison with our own results. Chronic schizophrenic patients most frequently show an enlargement in the ventricular system along with a reduction in grey matter. A more detailed subdivision into cortical and subcortical regions additionally shows the noted volume reduction to be limited to specific areas within the brain rather than being distributed equally throughout the brain. Within the area of the temporal lobes the two most frequently affected areas are the hippocampus and the gyrus temporalis superior. Alterations within these areas correlate with clinical symptoms such as hallucinations or thought disorders. Within the frontal cortex nearly 70% of all studies show a decrease in overall volume, while 63% note a reduction in size within the thalamus and 60% in the cerebellum. Morphologically speaking these structures therefore play the greatest role in the pathophysiology of schizophrenia and the onset of clinical symptoms. More recent studies also showed a specific progression in subgroups of patients pointing toward a neurodegenerative process. Additionally there are a number of differential antipsychotic effects following longterm treatment with typical neuroleptics as compared to atypical antipsychotics. Based on these findings future longitudinal studies should examine to what extent such a progressive decrease in volume might be influenced by treatment with modern antipsychotics.