Poor Outcome Subgroups Research Articles

High-throughput screening as a drug repurposing strategy for poor outcome subgroups of pediatric B-cell precursor Acute Lymphoblastic Leukemia

Although a great cure rate has been achieved for pediatric BCP-ALL, approximately 15% of patients do not respond to conventional chemotherapy and experience disease relapse. A major effort to improve the cure rates by treatment intensification would result in an undesirable increase in treatment-related toxicity and mortality, raising the need to identify novel therapeutic approaches. High-throughput (HTP) drug screening enables the profiling of patients’ responses in vitro and allows the repurposing of compounds currently used for other diseases, which can be immediately available for clinical application.The aim of this study was to apply HTP drug screening to identify potentially effective compounds for the treatment of pediatric BCP-ALL patients with poor prognosis, such as patients with Down Syndrome (DS) or carrying rearrangements involving PAX5 or KMT2A/MLL genes.Patient-derived Xenografts (PDX) samples from 34 BCP-ALL patients (9 DS CRLF2r, 15 PAX5r, 10 MLLr), 7 human BCP-ALL cell lines and 14 hematopoietic healthy donor samples were screened on a semi-automated HTP drug screening platform using a 174 compound library (FDA/EMA-approved or in preclinical studies). We identified 9 compounds active against BCP-ALL (ABT-199/venetoclax, AUY922/luminespib, dexamethasone, EC144, JQ1, NVP-HSP990, paclitaxel, PF-04929113 and vincristine), but sparing normal cells. Ex vivo validations confirmed that the BCL2 inhibitor venetoclax exerts an anti-leukemic effect against all three ALL subgroups at nanomolar concentrations.Overall, this study points out the benefit of HTP screening application for drug repurposing to allow the identification of effective and clinically translatable therapeutic agents for difficult-to-treat childhood BCP-ALL subgroups.

Morphological alterations of the corpus callosum in antipsychotic-naive first-episode schizophrenia before and 1-year after treatment

ObjectiveThe corpus callosum (CC) is known to be altered in patients with schizophrenia. However, its morphologic characteristics are less well studied in treatment-naive first-episode schizophrenia patients, as is the effect of antipsychotic treatment on this structure. MethodsT-1 weighted MRI scans were obtained from 160 antipsychotic-naïve first-episode schizophrenia patients (AN-FES) and 155 healthy controls (HCs) before treatment initiation. Among the patients, forty-four were available for follow-up studies after one year of antipsychotic treatment, and were divided into good-outcome (n = 31) and poor-outcome subgroups (n = 13) based on whether there was a 50% reduction in Positive and Negative Symptom Scale (PANSS) total scores from baseline. A computer algorithm was applied to automatically identify the mid-sagittal plane (MSP) and obtain morphological measurement parameters of the CC. ResultsCompared with HCs, AN-FES patients showed a significant reduction of thickness in the posterior midbody of the CC. This deficit was correlated with severity of negative symptoms. After one year of antipsychotic treatment, there was no significant change in CC morphological measurements in schizophrenia patients, nor was there a significant difference of CC morphological measurements between good-outcome and poor-outcome subgroups at baseline or at 1-year follow-up. ConclusionThickness of the posterior midbody of the CC is reduced in the early course of schizophrenia before treatment. This alteration was not affected by antipsychotic treatment and was unrelated to treatment outcome at 1-year.

Physical Therapy Use, Costs, and Value for Latent Classes of Good vs Poor Outcome in Patients Who Catastrophize About Their Pain Prior to Knee Arthroplasty

ObjectiveTo examine use, costs, and value of physical therapy (PT) among subgroups. DesignWe conducted an observational study of data from a randomized trial of a pain coping skills intervention. Good and poor outcome subgroups were determined based on Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) Pain and Physical Function scores. The use and costs of PT care as well as changes in WOMAC Pain and Physical Function scores over 4 time periods during a 1-year follow-up were reported. We compared the number of PT visits, total PT costs, and cost per 1-unit improvement in WOMAC scores for the 2 latent subgroups. SettingFive academic medical centers. ParticipantsPatients who catastrophized about their pain prior to knee arthroplasty (N=384). InterventionsPain coping skills training, arthritis education, and usual care. Main Outcome MeasuresThe WOMAC Pain Scale was the primary outcome. ResultsThe value of PT was lower and the cost of PT was higher for poor vs good outcome subgroups beginning 2 months after knee arthroplasty. For example, during the 2- to 6-month period, participants in the poor outcome subgroup incurred a PT cost of $5181.22 per 1-unit improvement in WOMAC Pain compared with $437.87 per 1-unit improvement in WOMAC Pain for the good outcome subgroup (P<.001). From the 6- to 12-month period, WOMAC scores worsened for the poor outcome subgroup, indicating no benefit from PT. ConclusionsPatients in 2 latent classes demonstrated clinically important differences in value of PT. Future research should identify rehabilitation-based interventions that reduce utilization and enhance effectiveness for patients at high risk for poor outcome.

Proteogenomic Subtyping of Chronic Lymphocytic Leukemia Identifies a Novel Poor Outcome Subgroup with a Distinct Drug Response Profile

Proteogenomic Subtyping of Chronic Lymphocytic Leukemia Identifies a Novel Poor Outcome Subgroup with a Distinct Drug Response Profile

Development of therapeutic alliance in mentalization-based treatment—Goals, Bonds, and Tasks in a specialized treatment for borderline personality disorder

Objective: Mentalization-based treatment (MBT) is an evidence-based long-term treatment for borderline personality disorder (BPD). Alliance is central for effective psychotherapies. Few studies have addressed aspects of working alliance in BPD evidence-based treatments. This study aimed to investigate alliance development in MBT therapies with different clinical outcomes. Method: The sample included 155 patients in an MBT programme. Clinical outcomes were based on Global Assessment of Functioning (GAF). The sample was divided in two subgroups according to GAF levels at the end of treatment (cut-off = 60). Working alliance was assessed by patient report (Working Alliance Inventory, subscales, Goals, Bonds and Tasks) and assessed repeatedly over 36 months. The method for statistical analyses was linear mixed models. Results: Initial levels of Goals, Bonds, and Tasks did not differ by subgroup, but change over time differed significantly by subgroup. In the good outcome subgroup, ratings of Goals, Bonds, and especially Tasks increased significantly over time. In the poor outcome subgroup, paranoid PD was associated with poorer alliance development over time. Conclusions: Good outcome therapies were characterized by a process where the working alliance grew over time. Results encourage an explicit focus on tasks in therapy particularly for patients with high levels of mistrust.

Intratumoural (IT) evolutionary landscape of high-risk prostate cancer and outcome: The PROGENY (PROstate cancer GENomic heterogeneitY) study of genomic and immune parameters.

e17500 Background: IT heterogeneity (ITH) is well recognised in prostate cancer (PC), but its role in high-risk disease and patient outcomes are uncertain. Methods: This was a prospective, single-arm, translational study using targeted multi-region prostate biopsies to study genomic and T-cell ITH in clinically high-risk PC aiming to identify drivers and potential therapeutic strategies. A pre-defined exploratory objective was to evaluate the association of ITH, median inflammatory infiltrate (MII), total, clonal and neoantigens, with overall survival (OS) and time-to-next-line of therapy (TTNL). Results: 49 men with elevated prostate-specific antigen (PSA) and multiparametric-magnetic resonance imaging (MRI) detected PC underwent image-guided multiregion transperineal biopsy. 79 tumour regions from 25 patients (pts) with PC underwent sequencing, analysis of mutations, copy number and neoepitopes combined with tumour infiltrating T-cell subset quantification. The median follow-up was 60 months (m) with 10 death events. For %ITH, MII, total, clonal and subclonal neoantigens, patients were split by the median. Conclusions: The PROGENY study provides a diagnostic platform suitable for studying tumour ITH and has the potential to identify poor outcome subgroups in PC. Larger sample numbers in prospective trials are warranted to further investigate this hypothesis. [Table: see text]

NUP98 \u2013 a novel predictor of response to anthracycline-based chemotherapy in triple negative breast cancer

BackgroundTriple Negative breast cancer (TNBC) is a poor outcome subgroup of breast cancer defined based on the absence of expression of ERα and PR and HER2 amplification. These hard to treat cancers lack targeted treatment options and are therefore treated with a standard of care (SoC) generic cocktail of DNA damaging chemotherapy, with a wide range of clinical responses. While a subset of TNBC patients respond very well to this treatment, others receive no clinical benefit and die from their disease within a short time period. We currently lack biomarkers to prospectively identify patients likely to relapse and we lack alternate treatment options.MethodsNUP98 protein expression was investigated in patient samples using two independent tissue microarrays (TMAs), as well as a normal breast TMA. Correlation with pathological response to various chemotherapy regimens was investigated.ResultsWe have shown that high NUP98 is significantly associated with poor outcome in TNBC patient samples both by gene expression and IHC-based protein analysis. While trends linking NUP98 expression with poorer outcomes were observed in breast cancer overall (and more specifically in the LuminalB Her2- subgroup), significant correlations were observed in TNBC. This appeared to be specific to anthracycline based regimens as the association between NUP98 and response was not observed in patients treated with taxane-based chemotherapy.ConclusionsWe have identified a novel biomarker, NUP98, that can predict response to anthracycline based chemotherapy in TNBC. The ability to prospectively identify patients who are less likely to respond to SoC chemotherapy is a vital step in improving the overall survival of these patients.

Clinical and radiological features of Marchiafava-Bignami disease.

Marchiafava-Bignami disease (MBD) is a rare neurological disease usually associated with chronic alcoholism and characterized by demyelination and necrosis. Our aims were to describe the clinicoradiological features and identify factors that may affect the prognosis of patients with MBD.We examined clinical manifestations, laboratory results, and neuroradiological features of 9 patients with MBD. The patients were classified into 2 subgroups (favorable and poor outcome subgroups) based on the Modified Oxford Handicap Scale (MOSH). In addition, we compared the clinical and neuroimaging features between the 2 subgroups.Nine adult male patients (age of onset range 37-62 years, with a mean age of 47.00 ± 14.50 years) were included in this study. According to MOSH, 4 patients were placed in the poor outcome subgroup (MOHS ≥ 3), 5 patients were placed in the favorable outcome subgroup (MOHS ≤ 2). Relatively high score of MAST-C (≥6) (P = .008), extracallosal lesions (P = .048), GCS (P = .026), cerebral lobe impairment (P = .048) was significantly more common in the poor outcome subgroup.Clinical manifestations of MBD are variable and lack specificity. Early diagnosis by relatively specific performance of bisymmetric lesions in corpus callosum of diffusion-weighted imaging (DWI) may affect the prognosis. The prognosis of patients with severe disturbance of consciousness, heavy alcohol consumption, extracallosal lesions, cerebral lobe impairment is probably unfavorable.

A two kinase-gene signature model using CDK2 and PAK4 expression predicts poor outcome in non-small cell lung cancers.

Risk classification on the basis of specific genomic features can lead to more precise tailoring of treatment for cancer patients. Kinases are potential therapeutic targets and survival factors, but the predictive prognostic potentials of multi-kinase genes have seldom been investigated. In this study, with publicly available microarray data of non-small cell lung cancers (NSCLC), we identified two kinase genes cyclin-dependent kinase 2 (CDK2) and p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) significantly associated with poor outcome. Then we present acombined gene signature model using CDK2 and PAK4 that can stratify disease poor outcome independently of standard clinical prognostic factors. Next, the predictive robustness of this 2-gene classifier was in silico confirmed in an independent microarray dataset, and experimentally validated in alung cancer cohort by immunohistochemistry. Therefore, in this study, we demonstrated that the CDK2-PAK4 kinase signature may be auseful prognostic indicator and potential target for NSCLC. We also propose that poor outcome subgroup stratified by this classifier may benefit from the recently developed CDK2 and PAK4 inhibitors.

Clinicoradiological spectrum of reversible splenial lesion syndrome (RESLES) in adults: a retrospective study of a rare entity.

The presence of reversible lesions that involve the splenium of the corpus callosum (SCC) has been reported in patients with a broad spectrum of diseases and conditions and is referred to as reversible splenial lesion syndrome (RESLES).To describe the clinicoradiological features and establish a clinical position for this disease, we retrospectively examined the clinicoradiological features of adult RESLES patients, as well as discuss the potential pathophysiological mechanisms of this disease.The clinical and MRI findings of patients who presented with RESLES accompanied by symptoms of neurological disorders were retrospectively reviewed. The patients were classified into 2 subgroups (favorable and poor outcome subgroups), which corresponded to the severity of the disability using the Modified Oxford Handicap Scale. In addition, we compared the clinical and neuroimaging features between the 2 outcome subgroups.Eight patients with RESLES associated with various diseases and conditions were included. The clinical presentation was nonspecific; however, MRI exhibited consistent lesions in the SCC with a hypointensity on apparent diffusion coefficient maps and a hyperintensity via diffusion-weighted imaging, which disappeared after a variable lapse. The number of patients with a severe disturbance of consciousness, extracallosal lesions, or diffuse slow waves in the poor outcome subgroup was significantly increased compared with the favorable outcome subgroup (P < 0.05). Thus, the clinicoradiological spectrum of RESLES could be classified into 2 principal categories according to differential outcomes.RESLES is a rare entity with a broad clinicoradiological spectrum because of the various diseases and conditions. Although the overall symptoms of RESLES patients tend to be alleviated, the prognosis of patients with a severe disturbance of consciousness, extracallosal lesions, or diffuse slow waves is likely unfavorable.

Characteristics and outcome of patients with ganglioneuroblastoma, nodular subtype: A report from the INRG project

AimDescribe characteristics and outcome of INRG patients with ganglioneuroblastoma, nodular subtype (GNBn). Patients and methodsAmongst 4071 patients in the INRG database with known INPC histological category, 232 patients with GNBn were identified. Patients were categorised by clinical, pathological and genetic characteristic. For event-free survival (EFS) and overall survival (OS), Kaplan–Meier curves and lifetables were generated, and the outcome of subgroups was compared using log rank test. ResultsPatients with GNBn were older (83% >18 months), a higher proportion had unfavourable INPC pathology (83%), and rarely had MYCN gene amplified tumours (2%). Otherwise, the distribution of clinical and biological risk factors including stage, ferritin, initial treatment, grade of NB differentiation, MKI, 11q, 1p, and 17q were similar between patients with GNBn and the overall INRG cohort. EFS and OS were 54%±5% and 68%±5%, respectively. A cohort with superior outcome was identified: OS for GNBn patients younger than 18 months was 95%±5% (n=39) and for GNBn patients with stage 1, 2, 3, 4s was 95%±3% (n=125). Conversely, a poor outcome sub-group could also be identified: OS for stage 4 was 35%±7% (n=107). ConclusionsPatients with GNBn tumours are rare and have a very heterogeneous outcome. Except for LDH and MKI, the factors prognostic in the overall NB cohort are also prognostic in patients with GNBn. Similar to the overall NB cohort, patients with GNBn older than 18 months of age, with stage 4 disease represent a high-risk sub-group and should be considered for aggressive treatment upfront.

Association of primary mediastinal B-cell lymphoma (PMBL) in children (C) and adolescents (A) with a significantly inferior prognosis: Final results of the FAB/LMB 96 trial

10001 Background: Single pediatric cooperative group studies have demonstrated an EFS ranging from 65 - 75% in C &amp; A with large cell lymphomas arising in the mediastinum (Lones/Cairo et al, J Clin Oncol, 2000; Burkhardt/Reiter et al, Br J Haematol, 2005; Seidman/Reiter et al, J Clin Oncol, 2003). Recently, Staudt and Shipp have independently demonstrated that following gene expression profiling by oligonucleotide microarray that PMBL resembles more like classical Hodgkin lymphoma than diffuse large B-cell lymphoma with enhanced NF-κB pathway gene expression (Rosenwald et al, J Exp Med, 2003; Abramson et al, Blood, 2005). It remains to be determined what the optimal therapy for C &amp; A with PMBL is and if poor outcome subgroups can be identified. Methods: We analyzed the results of C &amp; A with PMBL treated with group B therapy on FAB/LMB 96 (Patte/Cairo et al, Blood, 2007). Results: There were 528 patients with stage III/IV disease treated on group B therapy on FAB/LMB 96 resulting in a 2 yr EFS of 84% (CI95: 82–86%). Forty-two of these patients had PMBL; M/F: 26/16; 10 - 14 vs 15 -19 yrs: 28/14; and LDH &lt; 2 vs ≥ 2 upper normal: 20/22. Response to COP reduction: 1 CR (100%), 33 IR (20–99%) and 7 NR (&lt; 20%). There was no significant difference in EFS with respect to age, gender, COP response and initial LDH. 5 yr EFS and OS were 54% (CI95: 38–68%) and 73% (CI95: 56–84%), respectively. 5 yr EFS was significantly inferior compared to the remainder of the other patients with stage III disease treated on group B therapy (54%: CI95 38–68% vs 85%: CI95 81–88%) (p &lt; 0.001). Conclusions: PMBL in C &amp; A is associated with a significantly inferior EFS compared to other histological forms of stage III/IV mature B-NHL. Alternate treatment strategies including consideration of underlying biological differences need to be developed to improve EFS in C &amp; A with this poor-risk sub-group of mature B-NHL. No significant financial relationships to disclose.

The density ratio of grey to white matter on computed tomography as an early predictor of vegetative state or death after cardiac arrest

Objectives:To evaluate whether the ratio (in Hounsfield units; HU) of grey matter (GM) to white matter (WM) on computed tomography (CT) scans taken within 24 h of resuscitation can be...

Recent advances in the molecular biology and immunobiology of chronic lymphocytic leukemia

B-cell chronic lymphocytic leukemia (B-CLL) has long been viewed as a relatively homogeneous disease caused by the accumulation of monoclonal immature, immunoincompetent B cells with faulty apoptotic capacities. However, recent evidence, reviewed here, demonstrates that at least two different B-CLL subgroups exist with different clinical courses and outcomes. The malignant cells from both B-CLL subgroups are antigen-experienced cells that have a normal apoptotic apparatus and turnover continually. The leukemic cells of the two B-CLL subgroups have engaged antigen before transformation, although primarily the cells of patients in the poor outcome subgroup can respond to antigens following transformation. The difference in the ability to respond to antigen as a full-fledged B-CLL probably accounts for the different biological features and clinical outcomes of the patients in these subgroups.

Volume of the cingulate and outcome in schizophrenia

Background: Previous studies indicated that schizophrenia patients have reduced frontal volumes in comparison with normal, but among schizophrenics, reduced volumes of the posterior (temporal, parietal and occipital) cortex were associated with poor outcome. We examined whether this pattern is seen within the anteroposterior arch of the cingulate gyrus. Methods: MR images were acquired in 37 schizophrenia patients (Kraepelinian, n=13; non-Kraepelinian, n=24) and 37 controls, and CSF, gray and white matter volumes in individual Brodmann's areas (BA) of the cingulate arch (areas 25, 24, 23, 31, 30, 29) were assessed and examined in relation to outcome. Results: Schizophrenia patients had significant gray matter reductions in the absolute (mm 3) volume of Brodmann's area 24 in anterior cingulate and, when corrected for brain size, in the whole cingulate and retrosplenial (areas 29–30) cortex. White matter volumes were increased in right posterior cingulate (area 31). Schizophrenia patients also showed abnormal lateralization of white matter volumes in retrosplenial cortex (area 30) and had lower correlations between frontal and anterior cingulate regions than controls. Poor-outcome subgroup exhibited significant bilateral gray matter deficits in posterior cingulate and retrosplenial cortices compared to good-outcome patients, while no white matter increases in these areas were seen. Conclusions: Poor outcome was associated with gray matter deficits in posterior cingulate while compensatory white matter increases in dorsal posterior regions may be related to better outcome. Possible consequences of this may include thought disorder, disturbance of consciousness, treatment resistance, and cognitive decline indicative of a dementing process as a superimposed or inherent part of this schizophrenia subtype.

ACUTE BLEEDING AFTER ALLOGENEIC BONE MARROW TRANSPLANTATION: ASSOCIATION WITH GRAFT VERSUS HOST DISEASE AND EFFECT ON SURVIVAL1

Hemorrhagic complications are frequently implicated clinically for the high morbidity and mortality of acute graft versus host disease (GVHD), however, only few reports characterize the incidence and timing of bleeding in relation to GVHD, and essentially no study has quantified the effect of bleeding on survival of allogeneic patients with GVHD. This study examines the association of bleeding with acute GVHD and the effect of both complications on survival. A total of 463 allogeneic patients transplanted at the Johns Hopkins Hospital, were included in the study. Bleeding evaluation was based on daily scores of intensity and blood transfusions. All bleeding sites were recorded. GVHD staging was defined by the extent of rash, serum bilirubin, diarrhea, and confirmatory histology. The incidence of GVHD was 27.4%, bleeding occurred in 40.2%. The incidence of bleeding was higher in patients with GVHD as compared with non-GVHD, and correlated with GVHD severity. The higher bleeding incidence in GVHD was due to gastrointestinal hemorrhage, hemorrhagic cystitis, and pulmonary hemorrhage. While the majority of bleeding (51/75) in non-GVHD patients initiated within 30 days after bone marrow transplantation (BMT), only 32.3% (21/65) of the bleeding in the GVHD group initiated within 30 days, and the risk for bleeding continued until day 100. Bleeding was a late event compared to GVHD, however, most bleeding episodes were associated with active GVHD. Both GVHD and bleeding were individually associated with reduced survival, with profound additive adverse effect: median survival in 221 nonbleeding non-GVHD was >83.2 months, GVHD nonbleeding (39 patients) had median of 10.6 months, bleeding non-GVHD (99 patients) had median of 4.3 months, and median survival of the GVHD bleeding group (85 patients) was 3.2 months. Our results support an association of bleeding with acute GVHD, suggesting that GVHD is a risk factor for bleeding after BMT. The occurrence of bleeding clearly identified poor outcome subgroup within GVHD, suggesting further evaluation for clinical application of bleeding in the assessment of GVHD severity.

The significance of the pathology margins of the tumor excision on the outcome of patients treated with definitive irradiation for early stage breast cancer

To evaluate the significance of the pathology margins of the tumor excision on the outcome of treatment, an analysis was performed of 697 consecutive women with clinical Stage I or II invasive carcinoma of the breast treated with breast-conserving surgery and definitive irradiation. Complete gross excision of the primary tumor was performed in all cases, and an axillary staging procedure was performed to determine pathologic axillary lymph node status. The 697 patients were divided into four groups based on the final pathology margin from the primary tumor excision or from the re-excision if performed. These four groups were: (a) 257 patients with a negative margin (>2 mm), (b) 57 patients with a positive margin, (c) 37 patients with a close margin (⪯2 mm), and (d) 346 patients with an unknown margin. The patients with positive final pathology margins were focally positive on microscopic examination. Patients with grossly positive margins or with diffusely positive microscopic margins were treated with conversion to mastectomy. There was a significant difference in the total radiation dose for the four groups (median dose of 6000 vs 6500 vs 6400 vs 6240 cGy, respectively; p < .0001). There was no significant difference among the four groups for 5-year actuarial overall survival (p = .19), no evidence of disease (NED) survival (p = .95), or relapsefree survival (p = .80). There was no significant difference among the four grous for five year actuarial local or regional control (all p ≥ .29). Subset analyses did not identify any poor outcome subgroups. These results have demonstrated that selected patients with focally positive or close microscopic pathology margins can be adequately treated with definitive breast irradiation. Patient selection and the technical delivery of radiation treatment including a boost may have been important contributing factors to the good outcome in these patients.