Important Predictor Of Relapse Research Articles

A Novel and Cost-Efficient Measurable Residual Disease (MRD) Detection Assay Using a Single Molecule Molecular Inversion Probe-Based Next Generation Sequencing (NGS) Assay Predicts Overall Survival in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation

Introduction Relapse remains the main reason for poor outcomes of patients (pts) with acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (HSCT) is the preferred post-remission treatment in pts at high risk of relapse. The presence of measurable residual disease (MRD) after intensive frontline treatment or before or after HSCT has emerged as an important predictor of relapse. Various methods are used for MRD detection, including flow cytometry and molecular assays detecting individual gene mutations (mut) such as NPM1mut. Next generation sequencing (NGS)-based assays covering multiple genes commonly mutated in AML may allow sensitive MRD detection in a broad range of pts with diverse genetic characteristics. Methods We established a targeted, error corrected NGS MRD assay utilizing single-molecule molecular inversion probes (smMIPs). The smMIP protocol uses a hybridization-capture approach to selectively enrich and amplify both DNA strands of 92 regions in 32 genes in a single reaction. Unique molecular identifiers (UMIs) facilitate computational correction of sequencing errors to enable reliable detection of variants ≥0.5% variant allele frequency (VAF), with the additional advantage of relatively low reagent and sequencing costs of < $100 per sample. The smMIP assay was used to evaluate MRD status on pre-HSCT bone marrow samples from 98 AML pts who received an HSCT in first (n=83) or second (n=15) complete remission with or without count recovery. Median age at HSCT was 59 (range 20-75) years, 42% were female; 70% had de novo AML, 19% had an antecedent myeloid neoplasm and 11% had AML post cytotoxic therapy. European LeukemiaNet (ELN)-2022 risk groups at diagnosis were favorable in 11%, intermediate in 33%, adverse in 20% and unknown in 22%. All pts had received intensive induction chemotherapy. Twenty-nine percent received a myeloablative conditioning regimen (MAC), while 23% received reduced intensity conditioning (RIC) and 48% a non-myeloablative (NMA) conditioning regimen. Donors were matched related (18%), haploidentical (6%), or matched (55%) or mismatched (21%) unrelated. The median follow-up for pts alive was 34.8 months. Results Overall, we detected 190 variants in 71 (72%) of 98 pre-HSCT remission samples. The most commonly affected genes were DNMT3A (in 37% of pts), TET2 (21%), PPM1D (12%), IDH2 (10%) and TP53 (5%). Twenty-nine percent of pts had only variants affecting the clonal hematopoiesis-related genes DNMT3A, TET2 or ASXL1 (‘DTA‘), while 44% of patients had ≥1 variant involving a non-DTA gene. MRD-positive pts, defined as those with ≥1 non-DTA variant, had similar baseline and HSCT-related characteristics (includingage, sex, ELN risk group, de novo vs. secondary AML) compared to pts without non-DTA variants. Overall survival (OS) was significantly inferior in NGS MRD-positive pts compared to those with no non-DTA variant (Figure A, 5-year OS, 49% vs. 85%, P=.011). MRD-positive pts also had a non-significant higher cumulative incidence of relapse at 5 years (46% vs. 24%, P=.14), while non-relapse mortality was similar in both groups (P=.72). We next performed multivariable analyses, considering variables associated with OS at an univariable P<.10 (MRD status, patient sex, therapy-related AML, conditioning intensity), and using stepwise backward variable selection to identify factors significantly associated with OS (Figure B). In the final multivariable model, pre-HSCT MRD detection remained associated with inferior OS (hazard ratio 2.51; 95% confidence interval, 1.07 - 5.91; P=.035). Female sex associated with favorable OS, while myeloablative conditioning (MAC) showed a borderline significant association with superior OS. Of note, we did not detect an interaction between conditioning intensity and detection of MRD with regard to OS, i.e. the prognostic association of MRD detection was not different between pts receiving myeloablative or less-intensive conditioning. However, this analysis was limited by the small patient number. Conclusion Detection of MRD by targeted NGS using the smMIPs approach provides prognostic information in pts undergoing allogeneic HSCT, including those without established molecular markers such as NPM1mut. This method is applicable to a large proportion of AML pts and is cost-efficient for broad clinical use. S.M.K. and T.H., and M.J. and K.H.M. contributed equally to this abstract.

KIT exon 17 mutations are predictive of inferior outcome in pediatric acute myeloid leukemia with RUNX1::RUNX1T1.

Pediatric core binding factor acute myeloid leukemia (CBF-AML), although considered a favorable risk subtype, exhibits variable outcomes primarily driven by additional genetic abnormalities, such as KIT mutations. In this study, we examined the prognostic impact of KIT mutations in 130 pediatric patients with CBF-AML, treated uniformly at a single center over 4years (2017-2021). KIT mutations were detected via next-generation sequencing using a myeloid panel comprising 52 genes for most patients. Our findings revealed that KIT mutations were present in 31% of CBF-AML cases. Exon 17 KIT mutation was most commonly (72%) seen with notable occurrences at the D816 and N822 residue in 48% and 39% of cases, respectively. The 3-year cumulative incidence of relapse (CIR) and overall survival (OS) for patients with exon 17 KIT mutation were 36% and 40%, respectively, and was significantly worse in comparison to other site KIT mutations (3-year CIR: 11%; OS: 64%) and without KIT mutation (3-year CIR: 13%; OS:71%). Notably, the prognostic impact of KIT mutations was prominent in patients with RUNX1::RUNX1T1, but not in those with CBFB::MYH11 fusion. Additionally, a high KIT variant-allele frequency (VAF) (>33%) predicted for a higher disease relapse; 3-year CIR of 40% for VAF greater than 33% versus 7% for VAF less than 33%. When adjusted for site of KIT mutation and end-of-induction measurable residual disease, VAF greater than 33% correlated with poor OS (hazard ratio [HR]: 4.4 [95% CI: 1.2-17.2], p=.034). Exon 17 KIT mutations serve as an important predictor of relapse in RUNX1::RUNX1T1 pediatric AML. In addition, a high KIT VAF may predict poor outcomes in these patients. These results emphasize the need to incorporate KIT mutational analysis into risk stratification for pediatric CBF-AML.

MRD Monitoring of Non-DTA Genes By Digital Droplet PCR in the Early Period after Allogeneic Hematopoietic Stem Cell Transplantation Can Effectively Predict Patients at High Risk of Relapse

Background: Hematological malignancies relapse is the major cause of death after allogeneic hematopoietic stem cell transplantation (HSCT). The detection of measurable residual disease (MRD) after HSCT is the effective and important predictor of relapse. Digital droplet polymerase chain reaction (ddPCR), as the third generation PCR, is a novel technology for absolute quantification of nucleic acids developed in recent years. Compared with real-time quantitative PCR (qPCR, first generation) and next-generation sequencing (NGS), ddPCR has better sensitivity, specificity and repeatability, which provide a new platform for the detection of MRD. The purpose of this study was to evaluate whether early MRD monitoring by ddPCR after HSCT can effectively predict the recurrence of primary disease. Methods: We retrospectively analyzed patients with hematological malignancies who underwent allogeneic HSCT and monitored post-transplant MRD by ddPCR at the BMT Center of the First Affiliated Hospital of Zhejiang University School of Medicine from August 2018 to February 2021. Patients who met the following criteria were included in our study: (1) at least one hematological tumor-associated mutations or fusion genes for MRD monitoring at the time of diagnosis; (2) underwent allogeneic HSCT and the stem cell engraftment was successful; (3) received bone marrow MRD detection by ddPCR at least once in the early period (+30 days to +120 days) after HSCT; (4) bone marrow morphology was in remission status within +30 days to +120 days. Results: 100 patients were included in our study. The median follow-up time of patients was 20 months (range 5-46), and the median age was 41 years (range 14-67). Among them, 59 (59.0%) were male, and the most frequent primary diseases were AML (N=59, 59.0%), ALL (N=21, 21.0%), MDS (N=16, 16.0%), respectively. A total of 43 (43.0%) patients were found to be MRD+ after HSCT by early ddPCR detection. The difference in the 2-year cumulative incidence of relapse (2y CIR, 32.5% vs. 19.6%, P= 0.103), 2-year relapse-free survival (2y RFS, 67.0% vs. 79.8%, P=0.110), and overall survival (OS, 63.0% vs. 84.1%, P=0.566) between the MRD+ and MRD- groups were not statistically significant. 30 patients had at least one mutation related to clonal hematopoiesis gene: DNMT3A, TET2, and ASXL1 (DTA), whereas 97 patients had at least one non-DTA gene. When DTA group and non-DTA group were considered separately, MRD+ were 33.3% in DTA gene group and MRD+ were 36.1% in non-DTA gene group. The 2y CIR (0% vs. 21.5%, P=0.160), 2y RFS (100% vs. 78.5%, P=0.170) and OS (90.0% vs. 85.0%, P=0.737) after HSCT was not statistically different between DTA MRD+ group and DTA MRD- group, suggesting that DTA was not suitable as monitoring genes for relapse after transplantation. However, in the non-DTA group, patients with MRD+ had higher 2y CIR (39.8% vs. 18.4%, P=0.014) and inferior 2y RFS (60.2% vs. 80.8%, P=0.017) compared with MRD- patients. To explore whether ddPCR and multiparameter flow cytometry (MFC) can complement each other and further improve the prediction accuracy of relapse, we conducted a joint analysis on the bone marrow MRD detected simultaneously by non-DTA ddPCR and MFC, and divided into four parts: ①MFC MRD+ and non-DTA MRD+ (F+/M+, n=7); ②MFC MRD- and non-DTA MRD+ (F-/M+, n=26); ③MFC MRD+ and non-DTA MRD- (F+/M-, n=8); ④MFC MRD- and non-DTA MRD- (F-/M-, n=56). The sensitivity of ddPCR was higher than that of MFC. The 2y CIR of the four groups was (F+/M+ 71.4% vs. F-/M+ 34.5% vs. F+/M- 53.1% vs. F-/M- 12.2%, P<0.001), and the 2y RFS was (F+/M+ 28.6% vs. F-/M+ 65.5% vs. F+/M- 46.9% vs. F-/M- 87.3%, P<0.001) and OS was (F+/M+ 31.3% vs. F-/ M+ 61.8% vs. F+/M- 87.5% vs. F-/M- 83.8%, P=0.219). Through multivariate analysis, F+/M+ is an independent risk factor for relapse after HSCT (hazard ratio, 9.531, 95%CI, 2.884 to 31.496). It suggested that F+/M+ detected in the early stage after transplantation had higher CIR and inferior RFS. Conclusion: MRD monitoring for non-DTA gene in the early period after HSCT based on ddPCR has a prognostic effect on the recurrence of primary disease and overall survival after transplantation. When ddPCR is combined with MFC to monitor MRD, it is more accurate in predicting relapse and may help instruct preemptive treatment and then reduce the risk of relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cell-Free DNA (cfDNA)-Based Measurable Residual Disease (MRD) Detection As a Predictor of Relapse Post-Allogeneic Blood or Marrow Transplant (alloBMT) in Patients with Myeloid Malignancies

Background: AlloBMT is the only curative therapy for many patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). With the significant improvement in non-relapse mortality, disease relapse remains the main cause of therapeutic failure. The presence of leukemia-specific somatic mutations provides an attractive strategy for molecular assessment of measurable residual disease (MRD). The level of MRD at the time of complete remission (CR) has been an important predictor of relapse in patients undergoing alloBMT. Widely utilized molecular MRD assays require invasive bone marrow (BM) aspiration to ensure an adequate amount of residual leukemia cells. Circulating tumor DNA (ctDNA) released from malignant cells can be reliably detected in patients' plasma and has been widely used in diagnosis, early detection, and disease burden monitoring in solid tumors. This assay is not widely used in myeloid malignancies as the proper assessment of its technical and clinical utility as an MRD monitoring strategy has not been performed. In the current study, we aimed to determine the differential sensitivity between bone marrow and ctDNA-based MRD and its utility as a minimally invasive diagnostic and disease monitoring tool. Additionally, we evaluated the clinical utility of dynamic ctDNA-based MRD monitoring and its effect on post-alloBMT relapse by using plasma samples from 2 large prospective clinical trials (BMT CTN 0201 and 0402). Methods: The technical validation cohort included 20 consecutive patients with myeloid malignancies undergoing alloBMT at Johns Hopkins. A minimum of 10mL of plasma and bone marrow DNA was collected at the time of remission and at multiple time points after alloBMT. The clinical validation cohort included 90 patients participating in two prospective alloBMT trials (BMT CTN-0201 and 0402). The eligibility criteria included the diagnosis of myeloid malignancy (72 AML, 18 MDS) and the minimum of 2mL of plasma available from day 0 and/or day 90 after alloBMT. Ultra-deep error-corrected targeted sequencing was performed on plasma and bone marrow-derived DNA. The variant allele frequency (VAF) per patient was represented by the maximum VAF of all detected mutations. Results: To measure the exact contribution of hematopoietic tissue to plasma cell-free DNA (cfDNA) we analyzed cfDNA in alloBMT recipients. Using donor and recipient-specific polymorphisms we demonstrated that after full donor hematopoietic reconstitution by standard chimerism assays (day +180), 94.6% (range 93.9-95.3%) of cfDNA was of hematopoietic origin. To determine the differential sensitivity of the cfDNA vs. BM-based MRD we focused only on leukemia-specific mutations found in the diagnostic specimens. The minimum level of detection was 0.03%. Forty leukemia-specific mutations were detected in the technical validation cohort. Out of 31 mutations seen in the BM, only 3 were not detected in cfDNA (3/31, 9.7%). On the contrary, out of 37 mutations in cfDNA, 9 were not seen in BM (9/37, 25%). While we observed a strong positive correlation (rho = 0.8, p<0.0001) at any level of MRD between BM and cfDNA, cfDNA was superior at the lower MRD level (VAF cut-off < 0.26%). The clinical utility of cfDNA MRD was utilized in a separate validation cohort of 90 patients enrolled on 2 BMT CTN trials. The median (Q1, Q3) follow-up was 26 months (25 - 27 months). cfDNA-MRD positivity (VAF cutoff >0.25%) at day +90 was associated with significantly worse relapse-free survival (RFS) (46.2% vs 84.0%, p<0.001) and overall survival (OS) at two years (53.8% vs 87.2%, p=0.0013) after alloBMT. Conclusions: cfDNA-based MRD assessment appears to be a promising, minimally invasive test that provides important prognostic information in patients with myeloid malignancies undergoing alloBMT. The presence of cfDNA MRD at day 90 post alloBMT was associated with significantly worse RFS and OS in patients with myeloid malignancies. The dynamic assessment of MRD by cfDNA may not only provide important prognostic information but may also guide the therapeutic decision-making and timely implementation of post-alloBMT maintenance therapies to improve outcomes of patients with myeloid malignancies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Histologic Remission (NANCY Index) is Superior to Endoscopic Mucosal Healing in Predicting Relapse Free Survival in Patients With Ulcerative Colitis in Clinical and Endoscopic Remission.

Histologic activity is recognized as an important predictor of relapse in ulcerative colitis (UC) patients. Current treatment targets aim at mucosal healing; however, many patients continue to have histologic activity. The aim was to assess histologic activity using the validated Nancy histologic index (NHI) score as a predictor of future relapse amongst UC patients in endoscopic and clinical remission. In this retrospective cohort study, UC patients in clinical and endoscopic remission at a single tertiary center between 2015 and 2018, who underwent a surveillance colonoscopy were included. Clinical remission was defined by partial Mayo score (MSp) <2, and endoscopic remission was defined by Mayo endoscopic subscore (MES) ≤1. Histologic remission was defined by NHI <2. Predictive factors associated with the primary endpoint of clinical relapse were analyzed. A total of 74 of 184 UC patients were included in the study. Amongst this cohort, 33 patients (45%) demonstrated histologic activity (NHI >1) at enrollment. The median follow-up time was 42 months (interquartile range: 26 to 63 mo) with median relapse free period of 30 months (interquartile range: 18 to 48 mo). Kaplan-Meier analysis demonstrated patients with MES 0 ( P =0.02) and histologic remission ( P <0.0001) had significantly longer relapse free survival. On multivariate analysis only histologic activity remained an independent risk factor of future clinical relapse (hazard ratio: 4.36, confidence interval: 1.68-11.27, P =0.002). Histologic remission using the NHI independently predicts significantly longer relapse free survival and may be a superior therapeutic target than endoscopic remission.

Relationship of alcohol use pattern with locus of control and impulsivity: A cross-sectional study in hospitalized alcohol use disorder patients in Western India.

Background:Alcohol use disorders (AUDs) are increasing in developing countries like India and it has high relapse rates. Locus of control (LOC) and impulsivity can be important predictors of relapse and knowledge about them can help in management of AUD.Method:Cross-sectional analytical study of 116 indoor patients in tertiary care hospital, between ages 18 and 65 years diagnosed as AUD according to DSM-5, after acute detoxification was done. For interview, a sociodemographic sheet, Alcohol Use Disorder Identification Test, Drinking-Related Locus of Control Scale, and Barrett’s Impulsiveness Scale 11 scale (Gujarati versions) were used. Patients with complicated withdrawal and any other comorbid organic brain conditions were excluded. The data were analyzed using SPSS version 25.Result:Total participants consisted of 65% middle-aged (35–50 years) rural inhabitants. Eighty-six-percent of patients were employed and around 80% were educated >5th standard. No association was found between sociodemographic variables and severity of alcohol use. Severity of alcohol use increased with more duration of alcohol consumption (P = 0.001). Patients being earlier aged for first intake of alcohol had a high external LOC (r = 0.209, P = 0.050). Patients with high external LOC (P = 0.003) and more impulsivity (P = 0.001) had more relapses (more numbers of attempts to quit alcohol). With increased external LOC (r = 0.315) and increased impulsivity (r = 0.716), severity of alcohol use also increased. As impulsivity increased, patients’ LOC was found more toward external side (P = 0.007) (r = 0.345).Conclusion:External LOC and impulsivity have a strong association with alcohol use. Patients with high external LOC and more impulsivity had early age of first intake, severe alcohol use, and more duration of alcohol consumption.

Disrupting the path to craving: Acting without awareness mediates the link between negative affect and craving.

Low treatment utilization, relapse, and chronicity are characteristic of substance use disorders (SUDs). Craving is an important predictor of relapse. Individuals with an SUD report using various coping strategies in response to negative affect, two of which are investigated in the current study: suppression and acting with awareness. Suppression is typically understood to be avoidance of unwanted experience through turning attention away from unwanted stimuli. Acting with awareness (AWA) is a facet of mindfulness, which includes turning toward experience with kindness and curiosity, even when the experience is unwanted. Evidence suggests mindfulness may reduce craving, while suppression has been associated with increased craving. In the current study, participants (N = 210) had recently completed inpatient or intensive outpatient SUD treatment followed by a randomized controlled trial of aftercare. Participants completed measures within 2 weeks following the completion of the aftercare intervention. Negative affect and severity of dependence were both positively associated with craving. Structural equation modeling evaluated AWA and suppression as partial mediators of the link between negative affect and craving. Suppression was positively associated and AWA was negatively associated with craving. Mediation analyses revealed the indirect effect of negative affect on craving through AWA was significant, but the path through suppression was not. These findings suggest that AWA may inhibit the development of craving from negative affect, but further research is needed. Future research should investigate the path from negative affect to craving with greater temporal resolution to evaluate how these phenomena function with increased ecological validity. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Intractable hepatic encephalopathy in cirrhotic patients: mid-term efficacy of balloon-occluded retrograde portosystemic shunt obliteration.

To evaluate the efficacy and intermediate-term outcome of balloon-occluded retrograde transvenous obliteration (BRTO) for the treatment of hepatic encephalopathy (HE) secondary to portosystemic shunt (PSS) in cirrhotic patients. Institutional review board (IRB) approval was obtained for this study and hospital records of patients who underwent BRTO, from August 2011 to August 2015, were analyzed. Based on the inclusion and exclusion criteria, 39 patients (age, 54.07 ± 9.1years (37-67years); 33 males and 6 females) with cirrhosis and spontaneous PSS were included. Clinical and laboratory parameters and HE grade were evaluated in all patients before and after the procedure. Forty sessions of BRTO were attempted in 39 patients. Follow-up imaging revealed complete obliteration of the treated PSS in all patients with clinical success in 37 patients (94.9%). The 1-, 2-, 3-, 4-, 5-, 6-, and 7-year HE-free survival rates among responders were 91.7%, 91.7%, 88.8%, 85.5%, 80.8%, 80.8%, and 80.8% respectively and overall survival rates were 89.7%, 82.1%, 76.9%, 74.4%, 74.4%, 64.8%, and 64.8% respectively. Logistic regression highlighted Child-Turcotte-Pugh (CTP) score at 6months as a positive predictive factor of HE recurrence with a cutoff of ≥ 9. Five patients (12.8%) had fever and leukocytosis and 1 (2.6%) patient developed spontaneous bacterial peritonitis after the procedure. BRTO is an effective treatment for refractory HE in cirrhotics secondary to large PSS with a few possible complications. • BRTO is an effective and safe treatment for refractory HE, arising from PSS in cirrhotic patients. • Patients with preserved liver function show better outcome and CTP score is the most important predictor of relapse during follow-up.

IKZF1 Deletions with COBL Breakpoints Are Not Driven by RAG-Mediated Recombination Events in Acute Lymphoblastic Leukemia

IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBL is a hotspot for breakpoints in leukemia and could promote IKZF1 deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of B-ALL with COBL rearrangements (COBL-r). Patients with B-ALL and IKZF1 deletion (n = 133) were included. IKZF1 ∆1-8 were associated with large alterations within chromosome 7: monosomy 7 (18%), isochromosome 7q (10%), 7p loss (19%), and interstitial deletions (53%). The latter included COBL-r, which were found in 12% of the IKZF1 ∆1-8 cohort. Patients with COBL-r are mostly classified as intermediate cytogenetic risk and frequently harbor ETV6, PAX5, CDKN2A/B deletions. Overall, 56% of breakpoints were located within COBL intron 5. Cryptic recombination signal sequence motifs were broadly distributed within the sequence of COBL, and no enrichment for the breakpoint cluster region was found. In summary, a diverse spectrum of alterations characterizes ΔIKZF1 and they also include deletion breakpoints within COBL. We confirmed that COBL is a hotspot associated with ΔIKZF1, but these rearrangements are not driven by RAG-mediated recombination.

Risk Factors for Early Relapse after Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia

Risk Factors for Early Relapse after Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia

Facial emotion recognition, socio-occupational functioning and expressed emotions in schizophrenia versus bipolar disorder

Facial emotion recognition deficits have been consistently demonstrated in patients with severe mental disorders. Expressed emotion is found to be an important predictor of relapse. However, the relationship between facial emotion recognition abilities and expressed emotions and its influence on socio-occupational functioning in schizophrenia versus bipolar disorder has not been studied. In this study we examined 91 patients with schizophrenia and 71 with bipolar disorder for psychopathology, socio occupational functioning and emotion recognition abilities. Primary caregivers of 62 patients with schizophrenia and 49 with bipolar disorder were assessed on Family Attitude Questionnaire to assess their expressed emotions. Patients of schizophrenia and bipolar disorder performed similarly on the emotion recognition task. Patients with schizophrenia group experienced higher critical comments and had a poorer socio-occupational functioning as compared to patients with bipolar disorder. Poorer socio-occupational functioning in patients with schizophrenia was significantly associated with greater dissatisfaction in their caregivers. In patients with bipolar disorder, poorer emotion recognition scores significantly correlated with poorer adaptive living skills and greater hostility and dissatisfaction in their caregivers. The findings of our study suggest that emotion recognition abilities in patients with bipolar disorder are associated with negative expressed emotions leading to problems in adaptive living skills.

Triggers of Substance Abuse Slip and Relapse During Outpatient Treatment in Methadone/Buprenorphine Maintenance Therapy Clinics: A Predictive Model with Emphasis on Treatment-Related Factors

Background: Most addicts relapse in the first year of treatment especially in the first 3 - 6 months, which is the most vulnerable period. Objectives: The present study aimed to assess the predictors of substance abuse slip and relapse among addicts in the first 6 months of treatment with an emphasis on treatment related factors. Methods: The data of this cross-sectional study collected through assessment of 148 patients who were referred to the Methadone/Buprenorphine maintenance therapy clinics of Kermanshah city during April to September of 2015. Demographic, history, treatment checklist, comorbidity index, and medical records were used for collecting data. Data was analyzed through chi-square, t-test, and Binary logistic regression analysis. Results: The mean age of total participants was 42.4 ± 11.3 years and 98% of them were male. 27% and 35.1% of the patients, respectively, had a slip and relapse during the first 6 months of treatment. After adjustment for all demographic data, it was indicated that self-employment (P = 0.037), more treatment costs (P = 0.049), previous treatment history (P = 0.027), not satisfied dose of medication (P = 0.012), and lack of medical therapy history under physicians supervision (P = 0.046) can increase the possibility of a slip significantly. Conclusions: Despite the fact that prevention of re-abuse and relapse of disease includes multi-factorial approach, it seems that the treatment-related factors are as the most major factors in relapse and slip during the first 6 months of treatment. Health practitioners’ special attention to treatment related factors in addiction, especially previous treatment history as the most important predictor of relapse, are probably effective in the control and decrease of a slip and relapse.

Immunophenotypic Characterization of Cytogenetic Subgroups in Egyptian Pediatric Patients With B-Cell Acute Lymphoblastic Leukemia.

Identification of prognostic factors in acute lymphoblastic leukemia (ALL) patients is important for stratifying patients into risk groups and tailoring treatment accordingly. Molecular and cytogenetic abnormalities are the most important prognostic factors. Minimal residual disease (MRD) is also an important predictor of relapse in ALL. However, the correlation of both prognostic variables has not been thoroughly studied. We investigated the correlation between defined cytogenetic abnormalities and selected new MRD markers (CD79b, CD123, and CD200) in 56 newly diagnosed Egyptian pediatric B-cell ALL patients. CD123 found to be expressed in 45% of patients, CD200 in 80.3%, and CD79b in 67.9%. MRD analysis during treatment showed stable expression patterns of CD200. There was significant association of CD123 expression with the hyperdiploid ALL group (P= .017). Another association (P= .029) was found between CD79b negativity and the t(12;21) group. CD200 was widely expressed in all groups. There is a significant correlation between some markers, and certain ALL recurrent cytogenetic subgroups (CD123 and hyperdiploidy, CD79b negativity, and ETV-RUNX1 group) have good prognostic value. CD200 can be used as MRD markers in ALL patients and can also can serve as therapy targets.

COBL is a novel hotspot for IKZF1 deletions in childhood acute lymphoblastic leukemia.

IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in childhood B-cell precursor acute lymphoblastic leukemia. Because of its clinical importance, we previously mapped breakpoints of intragenic deletions and developed a multiplex PCR assay to detect recurrent intragenic ΔIKZF1. Since the multiplex PCR was not able to detect complete deletions (IKZF1 Δ1-8), which account for ~30% of all ΔIKZF1, we aimed at investigating the genomic scenery of IKZF1 Δ1-8. Six samples of cases with IKZF1 Δ1-8 were analyzed by microarray assay, which identified monosomy 7, isochromosome 7q, and large interstitial deletions presenting breakpoints within COBL gene. Then, we established a multiplex ligation-probe amplification (MLPA) assay and screened copy number alterations within chromosome 7 in 43 diagnostic samples with IKZF1 Δ1-8. Our results revealed that monosomy and large interstitial deletions within chromosome 7 are the main causes of IKZF1 Δ1-8. Detailed analysis using long distance inverse PCR showed that six patients (16%) had large interstitial deletions starting within intronic regions of COBL at diagnosis, which is ~611 Kb downstream of IKZF1, suggesting that COBL is a hotspot for ΔIKZF1. We also investigated a series of 25 intragenic deletions (Δ2–8, Δ3–8 or Δ4–8) and 24 relapsed samples, and found one IKZF1-COBL tail-to-tail fusion, thus supporting that COBL is a novel hotspot for ΔIKZF1. Finally, using RIC score methodology, we show that breakpoint sequences of IKZF1 Δ1-8 are not analog to RAG-recognition sites, suggesting a different mechanism of error promotion than that suggested for intragenic ΔIKZF1.

Type 1 autoimmune pancreatitis and IgG4-related sclerosing cholangitis is associated with extrapancreatic organ failure, malignancy, and mortality in a prospective UK cohort.

OBJECTIVESType I autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-related SC) are now recognized as components of a multisystem IgG4-related disease (IgG4-RD). We aimed to define the clinical course and long-term outcomes in patients with AIP/IgG4-SC recruited from two large UK tertiary referral centers.METHODSData were collected from 115 patients identified between 2004 and 2013, and all were followed up prospectively from diagnosis for a median of 33 months (range 1–107), and evaluated for response to therapy, the development of multiorgan involvement, and malignancy. Comparisons were made with national UK statistics.RESULTSAlthough there was an initial response to steroids in 97%, relapse occurred in 50% of patients. IgG4-SC was an important predictor of relapse (P < 0.01). Malignancy occurred in 11% shortly before or after the diagnosis of IgG4-RD, including three hepatopancreaticobiliary cancers. The risk of any cancer at diagnosis or during follow-up when compared with matched national statistics was increased (odds ratio = 2.25, CI = 1.12–3.94, P = 0.02). Organ dysfunction occurred within the pancreas, liver, kidney, lung, and brain. Mortality occurred in 10% of patients during follow-up. The risk of death was increased compared with matched national statistics (odds ratio = 2.07, CI = 1.07–3.55, P = 0.02).CONCLUSIONSOur findings suggest that AIP and IgG4-SC are associated with significant morbidity and mortality owing to extrapancreatic organ failure and malignancy. Detailed clinical evaluation for evidence of organ dysfunction and associated malignancy is required both at first presentation and during long-term follow-up.

Outcomes of Human Leukocyte Antigen–Matched Sibling Donor Hematopoietic Cell Transplantation in Chronic Lymphocytic Leukemia: Myeloablative Versus Reduced-Intensity Conditioning Regimens

Allogeneic hematopoietic cell transplantation (HCT) can cure some chronic lymphocytic leukemia (CLL) subjects. This study compared outcomes of myeloablative (MA) and reduced-intensity conditioning (RIC) transplants from HLA-matched sibling donors (MSD) for CLL. From 1995 to 2007, information regarding 297 CLL subjects was reported to the Center of International Blood and Marrow Transplant Research; of these, 163 underwent MA and 134 underwent RIC MSD HCT. The MA subjects underwent transplantation less often after 2000 and less commonly received antithymocyte globulin (4% versus 13%, P = .004) or prior antibody therapy (14% versus 53%; P < .001). RIC was associated with a greater likelihood of platelet recovery and less grade 2 to 4 acute graft-versus-host disease compared with MA conditioning. One- and 5-year treatment-related mortality (TRM) were 24% (95% confidence intervals [CI], 16% to 33%) versus 37% (95% CI, 30% to 45%; P = .023), and 40% (95% CI, 29% to 51%) versus 54% (95% CI, 46% to 62%; P = .036), respectively, and the relapse/progression rates at 1 and 5 years were 21% (95% CI, 14% to 29%) versus 10% (95% CI, 6% to 15%; P = .020), and 35% (95% CI, 26% to 46%) versus 17% (95% CI, 12% to 24%; P = .003), respectively. MA conditioning was associated with better progression-free (PFS) (relative risk, .60; 95% CI, .37 to .97; P = .038) and 3-year survival in transplantations before 2001, but for subsequent years, RIC was associated with better PFS and survival (relative risk, 1.49 [95% CI, .92 to 2.42]; P = .10; and relative risk, 1.86 [95% CI, 1.11 to 3.13]; P = .019). Pretransplantation disease status was the most important predictor of relapse (P = .003) and PFS (P = .0007) for both forms of transplantation conditioning. MA and RIC MSD transplantations are effective for CLL. Future strategies to decrease TRM and reduce relapses are warranted.

Risky Decision-Making but Not Delay Discounting Improves during Inpatient Treatment of Polysubstance Dependent Alcoholics

Background: High levels of impulsivity, characteristics of addicted patients, are known to be important predictors of relapse. However, so far, little is known about the stability or variability of two main components of impulsivity (delay discounting and decision-making). The present study examined the changes in impulsivity during the first week of an abstinence based, behavioral orientated inpatient treatment program.Method: Thirty-seven polysubstance dependent alcoholics completed the Delay Discounting Task (DDT), and the Iowa Gambling Task (IGT) using the original version with decks A′B′C′D′, and an alternative version with decks K′L′M′N′, for measuring decision-making, after 2 and 6 weeks of active treatment.Results: It was found that performances on the IGT changed during treatment while performances on the DDT did not (test-retest period: 4 weeks).Conclusion: The results provide preliminary evidence that improvements in decision-making might be related to treatment effects. All patients followed a highly structured cognitive-behavioral treatment program, which might have enhanced their executive functioning (coping skills training).

Early chemosensitivity of normal hematopoietic cells and malignant lymphoblasts predicts relapse in childhood acute lymphoblastic leukemia

For the last 30 years, numerous clinical and biological pretreatment risk factors have been utilized for risk-based treatment assignment in childhood acute lymphoblastic leukemia (ALL). However, with improved chemotherapy regimens, many of these traditional prognostic factors have lost clinical significance. We aimed to improve relapse prediction in children with ALL through evaluation of the early chemosensitivity of normal and malignant cells and to determine the relationship between such chemosensitivity and risk of relapse. We retrospectively analyzed a cohort of 60 children with newly diagnosed ALL of whom 40 patients were in complete remission for at least 4 years and 20 patients relapsed during or following treatment. Time to peripheral blood blast clearance (PBBC) was used as a measure of chemosensitivity of malignant lymphoblasts while end-of-induction complete blood count (CBC) parameters were used as a measure of chemosensitivity of normal hematopoietic cells. Our results showed that longer time to PBBC and lower end-of-induction total leukocyte count (TLC) and absolute neutrophil count (ANC) were significantly associated with increased risk of relapse. In conclusion, time to PBBC and end-of-induction TLC and ANC are important predictors of relapse and should be used to modify the intensity of chemotherapy at earlier time points during the course of treatment. A wider prospective, randomized, controlled trial is required to confirm our results.

Optimizing treatment of schizophrenia to minimize relapse

One of the most important predictors of relapse in schizophrenia is medication status. Continuous prophylactic antipsychotic treatment reduces the risk of relapse by approximately 70% [1]. Therefor...

Daily ratings measures of alcohol craving during an inpatient stay define subtypes of alcohol addiction that predict subsequent risk for resumption of drinking

Background Both depressive symptoms and alcohol craving have been postulated as important predictors of relapse in patients with addictive disorders. The purpose of this study was to examine the course of affective symptoms and cravings for alcohol use during the initial 25 days of residential treatment for middle aged and older adults addicted to alcohol and the relationship between these symptoms and recovery outcomes. Methods 95 alcohol-dependent subjects were enrolled in this observational study. Participants completed a daily diary of alcohol craving, positive affect, and negative affect during residential treatment. Participants were interviewed 1 and 6 months after discharge to assess clinical symptoms of relapse and functioning. Results Latent class analysis identified three groups of individuals for each of the three daily measures. For alcohol craving, 17 subjects reported elevated cravings during the entire treatment stay, 37 subjects reported initially elevated but then a slight improvement in craving, and 41 subjects reported relatively low craving from the time of admission to the end of residential treatment. Alcohol craving class was associated with negative affect but not positive affect. Alcohol craving class but not affective class was predictive of time to relapse to any drinking in the 6 months after residential treatment ( p < 0.05). Conclusion Results suggest that non-cue induced alcohol craving may define a subtype of alcohol dependence that is less responsive to treatment and may explain heterogeneity in treatment outcomes. These results also may suggest a role for differential treatment programming to address high states of craving for alcohol.