Non-relapse Group Research Articles

The value of high-resolution MRI in the diagnosis, efficacy of treatment, and prognosis of central nervous system vasculitis.

To explore the high-resolution magnetic resonance imaging (HR-MRI) characteristics of central nervous system (CNS) vasculitis and to explore the value of HR-MRI in the treatment effect and prognosis evaluation of CNS vasculitis. During the follow-up of 24 patients diagnosed as CNS vasculitis by the Second Hospital of Hebei Medical University, 3.0T HR-MRI was used for imaging examination and HR-MRI characteristics were analysed. The affected vessel wall of 24 patients showed diffuse uniform centripetal thickening. The HR-MRI examination showed varying degrees of lumen stenosis, including 5 cases (20.8%) involving a single arterial segment, and 19 cases (79.2%) involving multiple arterial segments. And most cases (92.9%) showed grade 2 enhancement of the involved vessel wall. Except for one case involving the basilar artery at the same time, the remaining 23 cases involved only the anterior circulation vessels. We analysed and compared the affected vessels between the relapsed group and the non-relapsed group, and found that the average number of involved vascular segments was 6.5 ±3.4 (3-11) in the relapsed group and 3.5 ±2.1 (1-8) in the non-relapsed group, with a significant difference between the two groups (p = 0.039). The CNS vasculitis was more likely to involve the anterior circulation vessels. The number of affected vascular segments in the relapsed group of CNS vasculitis was higher than in the non-relapsed group, suggesting that the more vascular segments involved, the more prone to recurrence.

Patterns of Relapse Related to High Expression of Ki-67 After Neoadjuvant Chemotherapy in Triple Negative Breast Cancer

Introduction: Triple negative breast cancer (TNBC) has been classically considered a high-risk subtype. Early TNBC is usually managed with neoadjuvant chemotherapy (NAC). Residual disease after NAC is generally considered a surrogate marker for event free survival in these patients. The aim of this study was to explore the relationship between high Ki-67 expression in residual disease after NAC and disease relapse. Material and methods: This is a retrospective study of 121 patients diagnosed with TNBC, treated with neoadjuvant chemotherapy in our institution between 2008 and 2018. Clinical features, systemic and surgical therapy and pathological response were analyzed. Ki-67 expression was performed in the post-NAC surgical specimens when a pathological complete response (pCR) was not achieved. Results were correlated with number and type of relapse, and survival. Results: Eighty-one patients (67%) achieved a pCR with a median Ki-67 expression in the residual tumor of 22.5%. Thirteen patients (10.7%) relapsed and all of them belonged to the non-pCR group. In the non-relapse group, the median Ki-67 in the residual tumor was 10% compared to 40% found in the relapse group. (P=0.025). Median Ki-67 post NAC was 70% in those patients who developed a central nervous disease (CNS) relapse, 40% if was a nodal or bone recurrence and 28% if it was a visceral relapse. CNS recurrence was significantly associated with higher Ki-67 levels post NAC (P=0.010). Conclusions: Our results suggest that high expression levels of Ki-67 post-NAC could define different patterns of relapse in TNBC patients treated with NAC.

Cerrahi Sınır Negatif Radikal Prostatektomili Hastalarda Biyokimyasal Nüks ile İnsülin Benzeri Büyüme Faktör-1 Arasında İlişki Var mıdır?

Objective: Levels of insulin-like growth factor 1 (IGF-1) have been associated with prostate carcinoma. We have investigated whether IGF-1 level has an early predictive value for the biochemical relapse in the prostate carcinoma patients with a negative surgical margin who underwent curative surgery. Materials and Methods: We retrospectively analyzed 82 patients who were followed-up regularly and did not receive neoadjuvant or adjuvant chemotherapy. We classified patients as having Gleason scores ≥7 and <7, PSA values ≥10 ng/ml and <10, biochemical relapse positive or negative, T stages ≥T2 and <T2, tumor burden in less or more than 50% pathologic specimens, respectively. PSA cut-off value accepted was as 0.2 ng/ml. According to average values in the literature, time to PSA relapses was considered early if it was less than 18 months and late if more than 18 months. We measured PSA and IGF-1 levels at each routine control visit. Results: During 60-month follow-up, 66 (80.4%) patients had no relapse, while in 8 (9.8%) patients had early, and other 8 (9.8%) patients had a late biochemical relapse. There was no statistically significant difference between these 3 groups of patients according to their age, tPSA levels, and BMI parameters. We compared IGF-1 levels with tumor burden, tPSA levels, tumor grade, and Gleason scores without any significant difference between these parameters. When we accepted IGF-1 cut-off values as 60 ng/ml, we observed higher Gleason scores (≥ 7 and more) in these patients. There was a weak relationship between IGF-1 levels of non-relapse and early relapse patients (p:0.078). However, when we evaluated IGF-1 levels among patients with relapse, the early relapse group had significantly higher IGF-1 levels (p: 0.006). When the cut-off value of IGF-1 was accepted as 60 ng/ml, which was found to be significant for Gleason score, the early relapse group had significantly higher IGF-1 levels compared to the non-relapse group (p:0.023). Conclusions: According to our study, the IGF-1 level has a predictive value for showing biochemical recurrence after surgery. Nevertheless, considering the number of patients, we need randomized controlled trials with a large number of patients.

Decreased Circulating Transitional B-Cell to Memory B-Cell Ratio Is a Risk Factor for Relapse in Children with Steroid-Sensitive Nephrotic Syndrome

Introduction: A significant proportion of children with SSNS (steroid-sensitive nephrotic syndrome) experience recurrence. Reliable biomarkers to predict flare are currently lacking because the pathogenesis of SSNS remains obscure. Objective: Since B cells may be involved in the pathogenesis of SSNS, we aimed to identify perturbations of B-cell subsets that might predict SSNS relapse. Methods: We measured levels of circulating B-cell subsets in 69 SSNS children by flow cytometry, between 2018 and 2019. We divided them into a relapse group and a nonrelapse group according to whether a relapse occurred within 1 year of follow-up. We used Cox survival analysis to assess correlations between B-cell subsets and relapse. In addition, recurrence-free survival curves were calculated using the Kaplan-Meier method. Results: The proportion of transitional B cells was significantly lower in the relapse group (5.3 ± 5.1% vs. 8.7 ± 4.3% in nonrelapse group, p = 0.007), while the proportion of memory B cells was significantly higher (8.4 ± 3.0% vs. 5.8 ± 3.3% in nonrelapse, p = 0.002). There was a significant decrease in the transitional B-cell to memory B-cell ratio (T/M) in the relapse group (p < 0.001). Univariate analysis revealed that transitional B cells, memory B cells, and the T/M ratio were significantly correlated with relapse in SSNS patients (p < 0.05). Multivariate analysis revealed that only T/M ratio (hazard ratio 0.278, 95% confidence interval 0.085–0.908, p = 0.034) was an independent risk factor for recurrence-free survival in SSNS patients. A cutoff value for the T/M ratio of 1.16 resulted in a sensitivity of 90% and specificity of 80% (area under the curve 0.909; p < 0.001). Kaplan-Meier curves of cumulative relapse-free survival, stratified by this cutoff value, were constructed, which showed that the cumulative relapse-free rates for cutoff values of >1.16 (n = 38) and ≤1.16 (n = 31) were 76.3 and 29.0%, respectively (χ² = 18.416, p < 0.001). Conclusions: Decreased transitional B/memory B ratio is associated with SSNS recurrence in the reported cohort. Thus, it may prove to be a useful marker to predict SSNS relapse in children.

Mucosal microbiota and gene expression are associated with long-term remission after discontinuation of adalimumab in ulcerative colitis

Given that sustained remission is the ultimate treatment goal in the management of patients with ulcerative colitis (UC), the decision to stop anti-tumor necrosis factor (anti-TNF) treatment in UC patients is difficult. The aim of this study was to evaluate mucosal microbiota and gene expression profiles associated with long-term remission after discontinuation of anti-TNF therapy. In nine UC patients who received anti-TNF therapy for 6 months, microbiota isolated from uninflamed mucosae and gene expression in inflamed and uninflamed mucosae were investigated at week 0 and at week 24. At treatment initiation, Fusobacterium sp. and Veillonella dispar were over-represented in the relapse group compared with the non-relapse group. After treatment, Dorea sp. and Lachnospira sp. were over-represented in the non-relapse group. In the relapse group only, a significant shift in gut bacterial community composition was found between week 0 and week 24. Gene expression of ALIX (PDCD6IP) and SLC9A3 was significantly higher in the non-relapse group than in the relapse group. Lastly, we used machine learning methods to identify relevant gene signatures associated with sustained remission. Statistical analyses of microbiota and expression profiles revealed differences between UC patients who did or did not keep remission after the discontinuation of TNF inhibitors.Trial registration: UMIN000020785: Evaluation of adalimumab therapy in mesalazine-resistant or -intolerant ulcerative colitis; an observational study (EARLY study).

Whole-Exome Sequencing Identifies a Somatic Cell Mutation Signature That Predicts Relapse Risk and Survival Probability in Multiple Myeloma

Introduction: Multiple myeloma (MM) is a plasma cell neoplasm associated with heterogeneous somatic alterations. Despite the development of novel anti-myeloma agents that have significantly prolonged patient survival, disease relapse remains a daunting problem. Our goal was to employ whole-exome sequencing (WES) to better describe the mutational landscape in MM beyond the tumor cell and identify genomic factors that might predict relapse. WES was performed using autograft samples obtained from MM patients that were then treated with high dose melphalan and autologous hematopoietic cell transplant (HCT). We identified a panel of genes that were most frequently mutated in all patients and then identified those genes mutated with greater frequency in patients that relapsed. A relapse burden signature was generated based upon the genes that were most frequently mutated genes in relapsed patients. Finally, the relapse burden signature was correlated with patient progression-free survival (PFS) and overall survival (OS) following autologous HCT. Methods. DNA was extracted from one ml of cryopreserved, mobilized hematopoietic cell product obtained from patients (N=93) that underwent HCT and was provided by the Case Comprehensive Cancer Center Hematopoietic Biorepository Core. Targeted sequencing was performed using the Tempus xE whole exome platform (Tempus, Chicago, IL). Variants were identified using a variant allele frequency (VAF) ≥0.1 for each sample. Variants were tabulated for each gene in each patient. Patients were grouped according to their relapse status; "No Relapse" (N=39) and "Relapse" (N=54) which corresponded to their post-HCT outcome. Relapse time was defined as time from transplant to event. Variants identified in each gene and patient group were counted and ranked. A relapse burden signature was defined and included twenty-two genes over-represented in the relapse group compared to the non-relapse group by &amp;gt; 10%. Genes in the relapse burden signature were subjected to gene set enrichment analysis (GSEA) and cross referenced against Gene Ontology (GO) categories. PFS and OS were defined as the time from transplant until the event of interest, with censoring at time of last follow up. Patients were regrouped according to their mutation burden in the relapse signature genes ("High burden" defined as &amp;gt;=six signature genes with variants) and their OS and PFS were analyzed with an R package (survival) to generate Kaplan-Meier curves and statistical significance based on a Chi-square test between low and high burden patients. Results: In total, 3,523 genes were identified as containing variants. Table 1 lists the top thirty genes that were identified and ranked based upon total number of mutations (mutational count) and most frequently mutated in relapsed and non-relapsed patients (sample count). We then identified those genes that were more frequently mutated by at least 10% in relapsed patients compared to non-relapsed patients (Fig. 1A). GSEA revealed that the relapse burden gene signature was associated with protein O-linked glycosylation, glycan processing, Golgi lumen and innate immune response activating cell surface receptor signaling pathways (Table 2). Interestingly, multiple mucin family members (Muc2, Muc3A, Muc12 and Muc19) were represented in the relapse burden signature. GO analysis indicated that the individual mucin genes were associated with the same signaling pathways that had been associated with the relapse burden signature by GSEA (Table 3). Importantly, a high relapse burden signature was correlated with a statistically significant reduction in both PFS and OS (Fig. 1B, C). Conclusion: Taken together, our results support the feasibility of WES to generate a relapse burden signature that predicts the risk of MM patients for relapse following HCT. Moreover, the mutational landscape associated with relapse, i.e. the specific genes mutated, has provided insights on the mechanisms of relapse. It is noteworthy that the relapse burden signature genes identified here were mutated at a much greater frequency than genes associated with clonal hematopoiesis of indeterminate potential (CHIP). The identification of patient subgroups at heightened risk of relapse can better guide treatment decisions. Future studies will be conducted to evaluate the effect of pathways identified here on myeloma cell survival and to validate actionable therapeutic targets. Disclosures Malek: Bluespark: Research Funding; Takeda: Other: Advisory board , Speakers Bureau; Medpacto: Research Funding; Janssen: Other: Advisory board, Speakers Bureau; Sanofi: Other: Advisory board; Clegene: Other: Advisory board , Speakers Bureau; Amgen: Honoraria; Cumberland: Research Funding. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Kite pharmaceuticals: Other: Advisory Board; Celgene: Speakers Bureau; ADC therapeutics: Other: Advisory Board, Research Funding. de Lima:Celgene: Research Funding; BMS: Other: Personal Fees, advisory board; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board; Pfizer: Other: Personal fees, advisory board, Research Funding.

Nonsurgical correction of congenital auricular deformities in children older than early neonates

Objective:To report the nonsurgical correction of congenital auricular deformities in children older than 3 months, analysis the effect and the recurrence and the influencing factors. Method:Patients with auricular deformities who came to our department from July 2017 to August 2019 were collected. EarWell correction was performed for non-invasive correction. Follow-up was performed for at least 3 months after treatment. Data was collected to analysis the effect and the recurrence and the influencing factors. Result:At the end of follow-up, 76 cases of 88 ears were collected, at the end of treatment in this group, the efficiency was 87.5%, and the recurrence rate was 19.48%, 3 months after the end of treatment. There was a statistically significant difference in the distribution of auricle deformities（P=0.018） and the age of first treatment（P=0.028） between children in the effective group and those in the ineffective group. Of all the auricle deformities, the treatment of cryptotia was the most effective, and the effectiveness of prominent ears was the lowest. The family history（P=0.314）, gender（P=0.421）, and feeding method（P=0.557） of the effective and ineffective groups. There was no significant difference in the gestational weeks at birth（P=0.641）, the mode of production（P=0.849）, and birth weight（P=0.08）. There was no significant difference in age between the relapsed group and the non-relapsed group at the age of first treatment（P=0.833）.There was significant difference in the distribution of auricle deformities between the relapsed group and the non-relapsed group（P=0.013）. There was no statistically significant difference between the effective group and the ineffective group at the age of first diagnosis and treatment time if we exclude cryptotia. Conclusion:For children who are treated beyond the treatment time window, the main factor affecting the treatment effect is the type of deformity. Nonsurgical correction can still be tried for older than 3 months with auricular deformities, especially for cryptotia, ear wheel deformities, and auricular cavity deformities. We do not recommend to try nonsurgical correction for children older than 3 months with prominent ears and cup ears.

Restoration of psychosocial functioning in remitted major depressive disorder patients: A 1-year longitudinal study

BackgroundThe recovery of psychosocial functioning is an important treatment goal for patients with depression. The aim of the present study is to investigate psychosocial functioning restoration 1 year after major depressive disorder (MDD) remission. MethodsDepression symptoms and psychosocial functioning were assessed in 167 remitted MDD patients at baseline, as well as 1, 2, 6, 9, and 12 months following remission, according to the Hamilton Depression Scale (HAMD-17) and Generic Quality of Life Inventory (GQOLI-74). ResultsOf the 167 MDD patients, 85 completed the final evaluation at 1 year, 32 relapsed, and 50 dropped out. The total relapse rate over 1 year was 27%. A rapid increase in psychosocial functioning was found in the first 2 months after remission in the non-relapse group. In the non-relapse group, psychosocial functioning was higher at 2 months than at baseline. At baseline and 2 months, psychosocial functioning was lower in the relapse group patients compared to those in the non-relapse group. ConclusionsPatients with MDD showed continuous improvement in psychosocial functioning during the first year after remission, though psychosocial functioning in the relapse group remained the same during the first two months, suggesting possible further relapse.

Development of an immune-related prognostic model for pediatric acute lymphoblastic leukemia patients.

BackgroundAcute lymphoblastic leukemia (ALL) is the most common hematological malignancy in pediatrics, and immune‐related genes (IRGs) play crucial role in its development. Our study aimed to identify prognostic immune biomarkers of pediatric ALL and construct a risk assessment model.MethodsPediatric ALL patients’ gene expression data were downloaded from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. We screened differentially expressed IRGs (DEIRGs) between the relapse and non‐relapse groups. Cox regression analysis was used to identify optimal prognostic genes, then, a risk model was constructed, and its accuracy was verified in different cohorts.ResultsWe screened 130 DEIRGs from 251 pediatric ALL samples. The top three pathways that DEIRGs may influence tumor progression are NABA matrisome‐associated, chemotaxis, and antimicrobial humoral response. A set of 84 prognostic DEIRGs was identified by using univariate Cox analysis. Then, Lasso regression and multivariate Cox regression analysis screened four optimal genes (PRDX2, S100A10, RORB, and SDC1), which were used to construct the prognostic risk model. The risk score was calculated and the survival analysis results showed that high‐risk score was associated with poor overall survival (OS) (p = 3.195 × 10−7). The time‐dependent survival receiver operating characteristic curves showed good prediction accuracy (Area Under Curves for 3‐year, 5‐year OS were 0.892 and 0.89, respectively). And the predictive performance of our risk model was successfully verified in testing cohort and entire cohort.ConclusionsOur prognostic risk model can effectively divide pediatric ALL patients into high‐risk and low‐risk groups, which may help predict clinical prognosis and optimize individualized treatment.

Risk Factors for Relapse of Childhood B Cell Acute Lymphoblastic Leukemia.

BackgroundB cell acute lymphoblastic leukemia (B-ALL) is the most common type of ALL. This study aimed to explore risk factors for relapse of childhood B-ALL.Material/MethodsTotal of 102 pediatric B-ALL patients were included in this study. B-ALL patients were divided into a relapse group and a non-relapse group. Chemotherapy-induced agranulocytosis time, fusion gene, and minimal residual disease (MRD) were assessed. White blood cell (WBC) count in peripheral blood and risk stratification were evaluated in newly-diagnosed patients. Kaplan-Meier plots were used to evaluate the correlation between risk factors and relapse rates. Multivariate analysis was performed with Cox proportional hazard model to estimate relative risk (RR), 95% confidence interval (95% CI), and hazard ratio (HR). Finally, 99 cases of B-ALL were included in this study.ResultsThere were significant differences between the relapse group and the non-relapse group in age (p=0.004), chemotherapy-induced agranulocytopenia (p=0.001), WBC count in peripheral blood of newly diagnosed patients (p=0.016), risk stratification (p=0.000), and MRD at 12th week (p=0.007). Age over 10 years, high-risk stratification, long period of agranulocytopenia, higher WBC counts, and MRD more than 10−4 were correlated with higher B-ALL relapse rate (p<0.05). Multivariate analysis showed significantly higher relapse rates for age ≥10 years, high-risk stratification, and MRD at 12th week >10−4, with RR (95% CI) of 4.001 (1.005–15.930), 4.964 (1.050–23.456), and 4.646 (1.383–15.614), respectively.ConclusionsAgranulocytopenia ≤7 days, peripheral blood WBC >100×109/L, and MRD at 33rd day >10−4 were associated with B-ALL relapse. Age ≥10 years, high-risk stratification, and MRD at 12th week >10−4 were independent risk factors for relapse.

Ten-year disease progression in multiple sclerosis: walking declines more rapidly than arm and hand function

Background and aimsFrom a clinical perspective there is a difference in the decline of arm and hand function and leg function in patients with multiple sclerosis (PwMS). Therefore, this study investigated the course of walking and arm and hand functions in PwMS over the first 10 years after diagnosis, including whether any function declined earlier or faster. MethodsA long-term prospective follow-up study of an incidence cohort of 156 patients with a definite diagnosis of MS, either non-relapse onset (n=28) or relapse onset (n=128) type. Participants were systematically examined immediately after definite diagnosis, at 6 months, and at 1, 2, 3, 6 and 10 years. Walking was determined with the fast 10-meter timed walk test (10mTWT), arm and hand function with the Action Research Arm test (ARAT) and the nine-hole peg test (9HPT). The 10-year trajectories of walking and arm and hand functions were compared using standardized z-scores. ResultsFrom 3 years onwards the z-scores of the arm and leg function were visually diverging, with a trend towards significance at 6 years, and at 10 years the 10mTWT z-score is significantly higher than the 9HPT. This difference is more pronounced in non-relapse onset patients than in patients with relapse onset type MS, but present in both groups over the first 10 years. In the non-relapse onset group a difference in z-scores at 10 years post-diagnosis between the 10m TWT and 9HPT was found of -12.94 (95% confidence interval (CI) -20.2 to -5.73) for the right and -10.14 (95% CI -17.3 to -2.93) for the left hand. In the relapse onset group there was a difference at 10 years post-diagnosis of -2.17 (95% CI -3.75 to -0.59) for the right and a difference of -2.29 (95% CI -3.87 to -0.71) for the left hand. ConclusionThis is the first longitudinal study that shows that walking declines earlier and more rapidly than arm and hand function in patients with MS. These results give important insights that can be linked to the pathophysiological disease process regarding the ascending order of deterioration in patients with MS.

OUTCOMES OF TALC PLEURODESIS IN MALIGNANT PLEURAL EFFUSION

TYPE: Abstract Publication TOPIC: Procedures PURPOSE: Malignant pleural effusion (MPE) is a common condition, representing an advanced state of disease with poor survival. Slurry talc pleurodesis (TP) is one of the most effective treatment in patients without trapped lung that significantly improves symptoms. This study aims to determine the success rate of TP in MPE, predictive factors associated and the survival outcome. METHODS: Retrospective study of all patients with MPE submitted to slurry TP, performed between January 2016 and August 2019. Effective pleurodesis was defined by lack of recurrence of pleural effusion in the studied period. RESULTS: 49 patients were identified, 61.2% male, mean age 74±12 years. Most of MPE were originated by lung tumors (63.3%). Other malignancies included were 14.3% gastro-intestinal tumors, 8.2% breast tumors, 8.2% urologic tumors, 4% hematologic tumors and 2% laryngeal tumors. 42.9% had a positive cytology for malignant disease. The procedure was effective in 79.6% of cases. We found 75.5% of 30-day survival post-pleurodesis. In post-pleurodesis relapse group, the average survival estimated was 186 days and for non-relapse group was 405 days. Pleural fluid biochemical, bacteriological and cytological findings and type of tumor had no significant statistical relation with recurrence. Relapse group was significantly older compared to non-relapse group (p=0.025). CONCLUSIONS: In this study, TP had high success rate, prolonging survival. Pleural fluid laboratorial findings and type of tumor may not be enough to predict recurrence post-procedure. CLINICAL IMPLICATIONS: Slurry TP in selected patients is an effective treatment in MPE. The older patients may be at higher risk of post-pleurodesis relapse. DISCLOSURE: No significant relationships. KEYWORDS: pleurodesis, pleural effusion

Association between Endoglin and nm23-H1 Expression and the Recurrence in Elderly Patients with Laryngeal Squamous Cell Carcinoma

To explore the association between endoglin and nm23-H1 expression and the recurrence in elderly patients with laryngeal squamous cell carcinoma. Patients diagnosed with laryngeal squamous cell carcinoma in The First Affiliated Hospital of Soochow University Suzhou from January 2012 to April 2015 were selected as the subjects, all patients underwent surgical resection and followed up for 5 y, and disease recurrence was chosen as the experimental endpoint. The basic clinical data of all patients were collected, immunohistochemical methods was used to evaluate the expression of endoglin and nm23-H1. According to disease recurrence patients were divided into relapse group and non-relapse group, the differences between the two groups were compared. The independent related factors affecting the relapse of patients were investigated by Logistic regression analysis. 32 patients relapsed with a recurrence rate of 31.37 %. There were significant differences in T stage, clinical stage, and pathological grade between the two groups. The positive expression rate of endoglin in the relapse group was significantly higher than that in the non-relapse group ((6.51±0.64) % vs. (5.63±0.57) %, p<0.001); the positive expression rate of nm23-H1 was significantly lower than that in the non-relapse group ((9.71±0.84) % vs. (10.52±0.78) %). Multivariate logistic regression analysis showed that nm23-H1 and endoglin were independent related factors that affected the recurrence of the disease. Endoglin expression ≥5.91%, nm23-H1 expression <10.27 % are independent risk factors that affect patients’ relapse.

Pioglitazone Did Not Affect PPAR-Γ, STAT5, HIF2α and CITED2 Gene Expression in Chronic Myeloid Leukemia Patients with Deep Molecular Response

Preliminary reports demonstrated that pioglitazone, an antidiabetic drug that is agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ) was able to reduce expression of STAT5 and its downstream targets HIF2α and CITED2, which are key guardians of the quiescence and stemness of chronic myeloid leukemia (CML) leukemia stem cells (LSCs). Leaving quiescence would turn the LSCs more sensitive to imatinib (IM) and cause an erosion of the LSCs. This was demonstrated in vitro and in vivo in CML patients that achieved complete molecular response after pioglitazone use. This was the rational for the design of EDI-PIO trial (Pilot Study of Imatinib Discontinuation in Patients with Chronic Myeloid Leukemia with Deep Molecular Response - Evaluation of Pioglitazone in Treatment-Free Remission) (NCT02852486). In this trial, pioglitazone was given in association with IM, with the aim to pull out the LSCs from the quiescence and sensitizing them to IM effect, increasing treatment-free remission (TFR) rates after treatment interruption. Aims: to evaluate PPAR-γ, STAT5, HIF2α and CITED2 gene expression before and after pioglitazone use in CML patients with criteria for IM discontinuation Patients and methods: EDI-PIO is a prospective, phase II trial. Inclusion criteria: CML in chronic phase, treated with IM for at least 3 years, with stable deep molecular response (MR4.5) for at least 2 years. Patients received pioglitazone 30 mg/day, orally, for 3 months before IM discontinuation. BCR-ABL levels were measured by real-time quantitative PCR monthly in the first year after discontinuation, every two months in the second year, and then every 3 months during the subsequent follow-up. Imatinib was reinitiated at molecular relapse (loss of major molecular response or confirmed loss of MR4.0). Total RNA was extracted from peripheral blood leukocytes, pre and post pioglitazone, and at 3 and 6 months after IM discontinuation. After cDNA synthesis, an aliquot was used for gene expression analysis by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR), using specific primers for PPAR-γ, STAT5, HIF2α and CITED2. The relative gene expression was calculated using the equation, 2-ΔΔCT. GAPDH was used as control gene. Statistical analysis was performed using ANOVA. Treatment-free remission (TFR) was calculated from IM discontinuation until molecular relapse, reintroduction of IM by any cause, progression to advanced phases or death to any cause. Results: The study is closed for enrollment. Between June 2016 and January 2019, 32 chronic phase CML patients were recruited, of which 30 patients were included in gene expression analysis. Median age was 55 years at trial initiation; 56.7% were men, 50% low risk Sokal and the median time of IM treatment was 117 months (41-191). The median follow-up time was 20 months. TFR was 60% at 24 months. Eleven patients relapsed and IM was reintroduced, but none presented hematologic relapse or progression to advanced phases. There was no significant difference in STAT5, PPAR-γ, HIF2α and CITED2 expression pre and post pioglitazone, at 3 and 6 months after IM discontinuation. No difference was found in the comparison of the relapsed vs. non-relapsed group. Conclusions: pioglitazone did not affect STAT5, PPAR-γ, HIF2α and CITED2 gene expression in this group of pts with deep molecular response. The ACTIM trial demonstrated a reduction in STAT5 expression in bone marrow cells 6 months after pioglitazone exposure, but pioglitazone was given to pts with MMR, without MR4.0. There was no difference in gene expression in the groups with or without molecular relapse. TFR rates remains similar to those reported in other discontinuation trials. Disclosures Delamain: Novartis: Honoraria. Pagnano:Sandoz: Consultancy; Pint Pharma: Consultancy; Abbvie: Consultancy.

Quantitative Analysis of Thymus-Independent Donor-Derived T Cell Expansion in Transplant Patients.

Although thymus-independent donor-derived T cell expansion may determine the occurrence of graft-versus-host disease (GVHD) and relapse after transplantation, the characteristics and dynamics of the expansion process remain unclear. To address this issue, we monitored T cell receptor β repertoire at day 0, day 28, and day 61 after transplantation in 30 patients with hematologic malignancies by next-generation sequencing. The clonality index showed an increasing clonality over time (P = .001). The top 200 clonotypes accounted for more than half of the total clonotypes (median frequency, 63.55%) at day 61, and there was a remarkable overlapping between the top 200 clonotypes of each repertoire and its former repertoire (>50%). A normalized index, called the T Cell Response Index (TCRI), was designed on the basis of rank-shift analysis to quantify antigen-driven expansion. The TCRI during the first month was not related to relapse or GVHD (P> .05), whereas the TCRI during the second month was related to relapse (P=.006). Recipients with a TCRI below 1.0 during the second month had a higher cumulative relapse rate (31.25% versus 0%, P=.0323) and had a lower 1-year survival rate (56.25% versus 78.57%, P=.281). The clonotypes with strong competitiveness in the second month in the nonrelapse group preferentially used TRBV2, TRBV12-3, TRBJ1-1 and TRBJ1-5 segments (P< .01). In conclusion, homeostatic expansion predominates in the first month due to nonspecific T cell proliferation, whereas antigen-driven expansion predominates in the second month and results in a graft-versus-tumor (GvT) effect. Moreover, TCRI could serve as a quantitative indicator of GvT against relapse within the first year. The difference in V and J segment usage reveals that T cells responsible for potent GvT effect are similar among patients.

Effect of clinical characteristics on relapse of alcohol dependence: a prospective cohort study

To investigate whether craving and demographic factors to predict relapse in alcohol dependence. This study was a prospective cohort study. From August 2017 to August 2018, 158 Han male inpatients who met the diagnositic and statistical manual disorders-fourth version(DSM-IV) alcohol dependence diagnostic criteria were recruited from three mental hospitals in China. The participants were interviewed at baseline and followed up by telephone after 3 months for assessment. The baseline assessment after the acute withdrawal period included demographic data and alcohol-related data, clinical institute withdrawal assessment-advanced revised (CIWA-Ar), withdrawal and cue-induced craving on visual analog scale (VAS), Michigan alcoholism screening test (MAST), self-rating anxiety scale (SAS), self-rating depression scale (SDS) and alcohol urge questionnaire (AUQ). According to the follow-up results, "relapse" was defined as the consumption of beverages containing ethanol at any time during the follow-up study, and "time to relapse" was defined as the number of days from the first drinking to the baseline. Whether relapse occurred and the time to relapse were the primary endpoints. Cox proportional hazard regression model was used to analyze the factors affecting the relapse of alcohol dependence. In the study, 158 alcohol dependence patients were finally included, age from 21 to 60 years, with the mean age of (40.31±9.14) years. The relapse rate was 63.7% three months after baseline assessment. According to Cox univariate analysis and multivariate analysis, the age (OR=0.975, P=0.030) and CIWA-Ar scores (OR=1.126, P=0.010) significantly predicted relapse. And there was no significant difference in education level, marital status, withdrawal and cue-induced craving on VAS, SAS and SDS between the relapse group and the non-relapse group (P>0.05). Age and severity of alcohol-dependent withdrawal symptoms during hospitalization are significantly related to relapse for alcohol in alcohol-dependent patients. To be exact, the older age is a protective factor, that is to say, the younger patients are prone to relapse, while the risk of relapse is raised by the higher severity of withdrawal symptoms. However, neither cue-induced nor withdrawal craving can predict relapse of alcohol-dependent patients.

Scalp EEG high frequency oscillations as a biomarker of treatment response in epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS)

PurposeWe investigated whether the presence of interictal scalp EEG high frequency oscillations (HFOs) in children with epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS) can predict seizure and cognitive outcome after steroid therapy. MethodsTwenty-two children with CSWS were prospectively enrolled and received methylprednisolone therapy. Interictal scalp HFOs, spike wave index (SWI) and intelligence quotient (IQ) were assessed before and after the treatment. The children were divided into two groups based on the early seizure reduction ratio at 2 weeks (≥50%, “response group”; otherwise “non-response group”). The “response group” was further divided into two subgroups (“relapse” and “non-relapse” subgroups) according to the late seizure outcome (after 3 months). ResultsInterictal HFOs and electrical status epilepticus in sleep (ESES) (defined as SWI ≥ 85%) were detected in all children at the baseline. In the response with relapse group (n = 11), the detection ratio of HFOs was significantly higher than that of ESES at 2 weeks (81.2 vs. 27.3%), 3 months (90.9 vs. 36.4%), and 6 months (100 vs. 54.5%) post-therapy. In the non-response group (n = 4), both HFOs and ESES persisted in all children. The average IQ improved significantly only in the response with non-relapse group. The persistence of HFOs negatively correlated with both the average IQ, yet the persistence of ESES did not. ConclusionInterictal scalp HFOs may be a favorable non-invasive biomarker of predicting seizure and cognitive outcome in CSWS.

Usefulness of an Initial Single Intravenous Immunoglobulin Infusion with Delayed Use of Aspirin against Kawasaki Disease Relapse: A Single-Center Retrospective Study

Background: Kawasaki Disease (KD) relapse is a risk factor for Coronary Artery Lesion (CAL) development. However, the frequency and outcomes of patients with relapse remain unclear. Objective: To determine the frequency and outcomes of patients with KD relapse and to ascertain the usefulness of treatment with initial single intravenous immunoglobulin (IVIG) therapy (2g/kg) with delayed use of aspirin (DUA). Materials and Methods: The outcomes of 207 patients who underwent initial single IVIG therapy at 2 g/ kg/ dose with DUA for KD were analyzed retrospectively. The patient data were divided according to whether the patients had relapses (relapse group, n=5) or not (non-relapse group, n=202). KD presentations were considered as relapses when a second episode appeared within 2 months of the first one. Stat Flex version 6 for Windows was used for all statistical analyses. Chi-square, Fisher’s exact, and Mann-Whitney U tests were used as appropriate, with sample size considerations. Results: The frequency of patients with disease relapse was 2.4%. The five patients who experienced relapses (two boys and three girls; median age, 10 months; range, 3 months to 3 years 11 months) received initial IVIG therapy at 5 days of illness. The median day of illness for the relapse was 16 (range, 12-29). No patients with disease relapse developed CAL. The rate of incomplete type, IVIG resistance and CAL, and timing of initial IVIG therapy with regard to the days of illness were similar between the relapse group and the non-relapse group. Three parameters, including serum C-reactive protein, albumin values, and Neutrophil-to-Lymphocyte ratio (NLR) before and after initial IVIG, were similar between the two groups. Although not statistically significant (P=0.055), the median NLR after initial IVIG therapy of the relapse group was higher than that of the non-relapse group (2.48 vs. 0.84). Conclusion: An initial single IVIG therapy (2g/ kg/ dose) with DUA for KD may lead to a low KD relapse frequency and to favorable patient outcomes.

Relationship between recurrent benign paroxysmal positional vertigo and serum 25-hydroxyvitamin D in middle-aged and elderly patients

Objective To investigate the correlation between serum 25-hydroxyvitamin D (25-OHD) and benign paroxysmal positional vertigo(BPPV) in middle-aged and elderly patients. Methods From October 2015 to October 2016, 250 middle-aged and elderly patients with idiopathic BPPV in Quhua Hospital of Zhejiang Province were selected in the research.According to whether the patients relapsed, the patients were divided into recurrence group(120 cases) and non-recurrent group(130 cases). And 100 healthy subjects who were examined in our hospital during the same period were selected as the healthy control group(control group). The serum 25-OHD levels and bone mineral density(BMD) were compared.The DHI scores of the three groups were scored and compared.Then, the correlation between 25-OHD, osteoporosis and DHI score and BPPV was analyzed. Results The levels of serum 25-OHD in the control group, non-relapse group and recurrence group were (35.12±3.95)μg/L, (21.62±4.32)μg/L and (16.25±3.86)μg/L, respectively, there were statistically significant differences among the three groups (F=4.567, P<0.05). The BMD in thecontrol group, non-relapsed group and recurrence group were (0.97±0.61), (-1.24±0.19), (-2.62±0.37), respectively, and the difference was statistically significant (F=6.478, P<0.05). The DHI scores in the control group, non-relapsed group and relapsed group were (4.62±3.15)points, (35.26±12.54)points, (53.28±11.68)points, respectively, there were statistically significant differences among the three groups (F=6.231, P<0.05). Regression analysis showed that the severity of BPPV in middle-aged and elderly patients was negatively correlated with 25-OHD level(r=-0.367, P<0.05). Conclusion The level of 25-OHD is negatively correlated with the severity of BPPV in middle-aged and elderly patients. Key words: Vertigo; 25-Hydroxyvitamin D; Bone density; Middle aged; Aged

Predictive factors for relapse of cryptogenic organizing pneumonia

BackgroundRelapse of cryptogenic organizing pneumonia (COP) may lead to poor long-term prognosis and necessitates multiple rounds of steroid treatment with potential adverse effects. The objective of this study is to identify predictive factors of COP relapse by comparing demographic and clinical variables between relapse and non-relapse groups.MethodsDuring 2008–2013, 33 COP patients were treated, of which 23 (69.7%) and 10 patients (30.3%) were assigned to the non-relapse and relapse group, respectively. From medical records, we compared the following variables at initial episode: clinical characteristics, serum parameters, chest CT scan findings, and steroid treatment.ResultsClinical characteristics, cumulative prednisone dose, and steroid treatment duration were similar between groups. In univariate analysis, alternatively, the proportion of patients with bilateral shadow pattern, traction bronchiectasis, and partial remission after steroid treatment was significantly higher in the relapse group. These differences were not significant by multivariate Cox regression analysis.ConclusionsWe identified radiographic findings, such as bilateral shadow pattern, traction bronchiectasis, and partial remission, may have possibility of predictive factors for COP relapse. Larger-scale studies are required to confirm if any are independent predictors of COP relapse.