Patients In Chronic Phase Research Articles

Structural magnetic resonance imaging and detailed motor assessment for chronic-phase patients after stroke

Structural magnetic resonance imaging and detailed motor assessment for chronic-phase patients after stroke

Final Evaluation of Randomized CML-Study IV: 10-Year Survival and Evolution of Terminal Phase

▪BackgroundChronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400mg/day (n=400) could be optimized by doubling the dose (n=420), adding IFN (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128).MethodsFrom July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. The impact of patients' and disease factors on survival was prospectively analyzed. At the time of evaluation, at least 62% of patients still received imatinib, 26.2% were switched to 2nd generation tyrosine kinase inhibitors.ResultsAfter a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival 80% and 10-year relative survival 92%. In spite of a faster response with IM800mg, the survival difference between IM400mg and IM800mg was only 3% at 5 years. In a multivariate analysis, the influence on survival of risk-group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs. other) was significant in contrast to any form of initial treatment optimization. Patients that reached the response milestones 3, 6 and 12 months, had a significant survival advantage of about 6% after 10 years regardless of therapy. The progression probability to blast crisis was 5.8%. Blast crisis was proceeded by high-risk additional chromosomal aberrations.ConclusionsFor responders, monotherapy with IM400mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease and blast crisis, more life-time can currently be gained by carefully addressing non-CML determinants of survival. DisclosuresHehlmann:Novartis: Research Funding; BMS: Consultancy. Saussele:Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Pfirrmann:BMS: Honoraria; Novartis: Honoraria. Krause:Novartis: Honoraria. Baerlocher:Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Bruemmendorf:Novartis: Research Funding. Müller:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Jeromin:MLL Munich Leukemia Laboratory: Employment. Hänel:Roche: Honoraria; Novartis: Honoraria. Burchert:BMS: Honoraria. Waller:Mylan: Consultancy, Honoraria. Mayer:Eisai: Research Funding; Novartis: Research Funding. Link:Novartis: Honoraria. Scheid:Novartis: Honoraria. Schafhausen:Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Hochhaus:Incyte: Research Funding; MSD: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; ARIAD: Research Funding.

Factors Leading to Improved Gait Function in Patients with Subacute or Chronic Central Nervous System Impairments Who Receive Functional Training with the Robot Suit Hybrid Assistive Limb.

The factors that lead to the improvement of gait function in patients with diseases of the central nervous system (CNS) who use a hybrid assistive limb (HAL) are not yet fully understood. The purpose of the present study was to analyze these factors to determine the prognosis of the patients’ gait function. Patients whose CNS disease was within 180 days since onset were designated as the subacute-phase patients, and patients whose disease onset had occurred more than 180 days previously were designated as chronic-phase patients. Fifteen subacute-phase patients and 15 chronic-phase patients were given HAL training. The study analyzed how post-training walking independence in these patients was affected by the following factors: age, disease, lesion area, lower limb function, balance, period until the start of training, number of training sessions, additional rehabilitation, higher-order cognitive dysfunction, HAL model, and the use of a non-weight-bearing walking-aid. In subacute-phase patients, walking independence was related to lower limb function (rs = 0.35). In chronic-phase patients, there was a statistically significant correlation between post-training walking independence and balance (rs = 0.78). In addition, in patients with a severe motor dysfunction that was accompanied by inattention and global cognitive dysfunction, little improvement occurred, even with double-leg model training, because they had difficulty wearing the device. The results demonstrated that the factors that improved walking independence post HAL training differed between patients with subacute- and chronic-stage CNS diseases. The findings may serve as valuable information for future HAL training of patients with CNS diseases.

Quantification of large and middle proteins of hepatitis B virus surface antigen (HBsAg) as a novel tool for the identification of inactive HBV carriers

ObjectiveAmong individuals with chronic hepatitis B, those with hepatitis B e-antigen (HBeAg)-negative chronic hepatitis (CHB) can be difficult to distinguish from those with HBeAg-negative chronic HBV infection, also referred to...

Expression differences of genes in the PI3K/AKT, WNT/b-catenin, SHH, NOTCH and MAPK signaling pathways in CD34+ hematopoietic cells obtained from chronic phase patients with chronic myeloid leukemia and from healthy controls.

The fusion gene BCR-ABL has an important role to the progression of chronic myeloid leukemia (CML) and several signaling pathways have been characterized as responsible for the terminal blastic phase (BP). However, the initial phase, the chronic phase (CP), is long lasting and there is much yet to be understood about the critical role of BCR-ABL in this phase. This study aims to evaluate transcriptional deregulation in CD34+ hematopoietic cells (CD34+ cells) from patients with untreated newly diagnosed CML compared with CD34+HC from healthy controls. Gene expression profiling in CML-CD34 cells and CD34 cells from healthy controls were used for this purpose with emphasis on five main pathways important for enhanced proliferation/survival, enhanced self-renewal and block of myeloid differentiation. We found 835 genes with changed expression levels (fold change ≥±2) in CML-CD34 cells compared with CD34 cells. These include genes belonging to PI3K/AKT, WNT/b-catenin, SHH, NOTCH and MAPK signaling pathways. Four of these pathways converge to MYC activation. We also identified five transcripts upregulated in CD34-CML patients named OSBPL9, MEK2, p90RSK, TCF4 and FZD7 that can be potential biomarkers in CD34-CML-CP. We show several mRNAs up- or downregulated in CD34-CML during the chronic phase.

Treatment outcome in a population-based, 'real-world' cohort of patients with chronic myeloid leukemia.

Evaluations of the ‘real-world’ efficacy and safety of tyrosine kinase inhibitors in patients with chronic myeloid leukemia are scarce. A nationwide, population-based, chronic myeloid leukemia registry was analyzed to evaluate (deep) response rates to first and subsequent treatment lines and eligibility for a treatment cessation attempt in adults diagnosed between January 2008 and April 2013 in the Netherlands. The registry covered 457 patients; 434 in chronic phase (95%) and 15 (3%) in advanced disease phase. Seventy-five percent of the patients in chronic phase were treated with imatinib and 25% with a second-generation tyrosine kinase inhibitor. At 3 years 44% of patients had discontinued their first-line treatment, mainly due to intolerance (21%) or treatment failure (19%). At 18 months 73% of patients had achieved a complete cytogenetic response and 63% a major molecular response. Deep molecular responses (MR4.0 and MR4.5) were achieved in 69% and 56% of patients, respectively, at 48 months. All response milestones were achieved faster in patients treated upfront with a second-generation tyrosine kinase inhibitor, but ultimately patients initially treated with imatinib also reached similar levels of responses. The 6-year cumulative incidence of eligibility for a tyrosine kinase cessation attempt, according to EURO-SKI criteria, was 31%. Our findings show that in a ‘real-world’ setting the long-term outcome of patients treated with tyrosine kinase inhibitors is excellent and the conditions for an attempt to stop tyrosine kinase inhibitor therapy are met by a third of the patients.

Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants

Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients’ and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.

PTCH1 is a reliable marker for predicting imatinib response in chronic myeloid leukemia patients in chronic phase.

Patched homolog 1 gene (PTCH1) expression and the ratio of PTCH1 to Smoothened (SMO) expression have been proposed as prognostic markers of the response of chronic myeloid leukemia (CML) patients to imatinib. We compared these measurements in a realistic cohort of 101 patients with CML in chronic phase (CP) using a simplified qPCR method, and confirmed the prognostic power of each in a competing risk analysis. Gene expression levels were measured in peripheral blood samples at diagnosis. The PTCH1/SMO ratio did not improve PTCH1 prognostic power (area under the receiver operating characteristic curve 0.71 vs. 0.72). In order to reduce the number of genes to be analyzed, PTCH1 was the selected measurement. High and low PTCH1 expression groups had significantly different cumulative incidences of imatinib failure (IF), which was defined as discontinuation of imatinib due to lack of efficacy (5% vs. 25% at 4 years, P = 0.013), probabilities of achieving a major molecular response (81% vs. 53% at first year, P = 0.02), and proportions of early molecular failure (14% vs. 43%, P = 0.015). Every progression to an advanced phase (n = 3) and CML-related death (n = 2) occurred in the low PTCH1 group (P<0.001 for both comparisons). PTCH1 was an independent prognostic factor for the prediction of IF. We also validated previously published thresholds for PTCH1 expression. Therefore, we confirmed that PTCH1 expression can predict the imatinib response in CML patients in CP by applying a more rigorous statistical analysis. Thus, PTCH1 expression is a promising molecular marker for predicting the imatinib response in CML patients in CP.

Analysis of clinical characteristics and efficacy of chronic myeloid leukemia onset with extreme thrombocytosis in the era of tyrosine kinase inhibitors

The aim of this study was to investigate the clinical characteristics and efficacy of chronic myeloid leukemia (CML) onset with extreme thrombocytosis. A total of 121 newly diagnosed and untreated CML patients in chronic phase with complete clinical information from the First Hospital of Jilin University, from January 2010 to December 2014 were retrospectively recruited. Based on the platelet (PLT) count, 22 patients were assigned into CML with thrombocytosis (CML-T) group (PLT >1,000×109/L) and 65 patients were classified into CML without extreme thrombocytosis (CML-N) group (PLT ≤1,000×109/L). Fifty-four point five percent of patients in the CML-T group were female, which was higher than that in the CML-N group (27.7%) (P=0.022). Except for gender, there was no significant difference for clinical information of patients between the two groups. For Sokal and Hasford scoring systems, the percentage of patients at high risk in the CML-T group were higher than those in the CML-N group, 95.5% vs 52.3% (P=0.000) and 68.2% vs 41.5% (P=0.031), respectively; however, there was no significant difference for European Treatment and Outcome Study (EUTOS) score system between the two groups (P=0.213). In terms of major molecular response (MMR) rate, the percent of patients with MMR in CML-T group was lower than that in CML-N group at 36 months after tyrosine kinase inhibitor therapy (P=0.037). Up until December 2016, the median of event-free survival was 21 months in the CML-T group, however, that was not reached in the CML-N group (P=0.027). The majority of CML patients with extreme thrombocytosis were females, and compared to patients in the CML-N group, the percentage of high risk patients based on the Sokal and Hasford scoring systems was higher in the CML-T group, and the median event-free survival of patients was shorter.

Influence of BCR-ABL Transcript Type on Outcome in Patients With Chronic-Phase Chronic Myeloid Leukemia Treated WithImatinib.

The prognostic significance of breakpoint cluster region gene-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) transcripts in chronic myeloid leukemia (CML) is still controversial. All consecutive CML patients in chronic phase treated with imatinib in a single center were analyzed (n= 170). BCR-ABL1 transcript was evaluated using multiplex reverse transcription polymerase chain reaction. Exclusively patients with BCR-ABL transcripts e13a2 and/or e14a2 were included in this analysis. Patients with e14a2 transcripts presented higher rates of optimal molecular responses at 3 months and higher rates of complete cytogenetic response (CCR) at 6 months. E13a2, e14a2, and e14a2 with e13a2 (e14a2+e13a2) groups presented similar rates of 5-year event-free, progression-free, and overall survival. There was a superior 10-year overall survival in patients with transcripts e13a2 compared with e14a2 (alone or coexpressed with e13a2; 93% vs. 73%; P= .03), although the 5-year overall survival was 96% vs. 88%, respectively (P= not significant). In a multivariate analysis, high/intermediate Sokal score and e14a3/e14a3+e14a2 were independent factors for poor overall survival (hazard risk [HR], 4.63; P= .023 for Sokal score and HR, 10.6; P= .041 for BCR-ABL transcript). Patients with BCR-ABL transcripts e14a2 transcripts have higher rates of CCR at 6 months and higher rates of optimal molecular response at 3 months compared with e13a2 or with both transcripts, but no difference in 5-year overall, progression-free, and event-free survival. There was a superior 10-year overall survival among patients with transcripts e13a2 compared with e14a2 (alone or coexpressed with e13a2).

Impact of the BCR-ABL1 fusion transcripts on different responses to Imatinib and disease recurrence in Iranian patients with Chronic Myeloid Leukemia

BackgroundOne genomic breakpoint can result in variable BCR-ABL1 transcript types due to alternative splicing. The influence of different BCR-ABL1 transcript types on clinical outcome is still controversial. Aim of the studyThe objective of this analysis was to determine the impact of transcript type on response, clinical outcome, recurrence risk after treatment with Imatinib mesylate in Chronic Myeloid Leukemia (CML) patients. MethodsSixty CML patients in chronic phase were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and banding standard protocols. ResultsThere was a significant difference in collective incidence of complete cytogenetic response (CCR) between the e14a2 and e13a2 groups (P=0.04). The median time to achieve CCR was shorter in e14a2 patients than to e13a2 (P=0.01). This finding is paralleled by the molecular response where the median of the BCR-ABL1/ABL1 expression levels were significantly lower in e14a2 transcript compared to e13a2 type at 3, 6, 9 and 12months from the start of therapy (P<0.01). The probability of recurrence after treatment discontinuation was 9.33 fold higher in e13a2 transcript, that is reported here for the first time (χ2=5.49; P=0.01; OR: 9.33; 95% CI: 1.59, 54.67). No significant difference was observed regarding overall survival (OS), although Patients with e14a2 transcript displayed a significant tendency toward a higher event free survival (EFS) ratio (P=0.03). ConclusionWe found that patients with the e14a2 transcript achieved better and faster responses to Imatinib mesylate. In this study, parallel data regarding molecular and cytogenetic responses, impact of transcript type on the probability of recurrence might suggest a general outcome that the type of transcript can be used as a prognostic marker at diagnosis.

An analysis of the kinetics of molecular response during the first trimester of treatment with nilotinib in newly diagnosed chronic myeloid leukemia patients in chronic phase

PurposeThis study was aimed to analyze the association of very early molecular response to nilotinib with the achievement of deep molecular response (MR4) at 18 months. We hypothesized that the BCR-ABL1 levels during the first 3 months of therapy, and the kinetics of their descent in this period, could be predictive of deep molecular response thereafter.MethodsThis substudy of the ENEST1st trial included 60 patients with chronic myeloid leukemia in chronic phase treated with front-line nilotinib, and BCR-ABL1IS levels were measured using GUS as the control gene. The analysis included seven time points during the first trimester of treatment (baseline and fortnightly thereafter).ResultsThe rates of MMR at 12 months, and of MR4 at 18 months (primary variable of the study), were 70 and 41%, respectively, similar to those obtained in the core study. BCR-ABL1IS ≤10% was achieved at 1, 1.5, 2 and 3 months in 50, 70, 83 and 93% of the patients, respectively. The observed shape of the BCR-ABL1IS descent was biphasic, with a faster slope during the first trimester and a median halving time (HT) of 11 days, the shortest reported in the literature. An HT ≤13 days was predictive of MMR at 12 months and MR4 at 18 months.ConclusionsThe association of a shorter HT with response provides a rationale for exploring very early kinetics patterns in all patients treated with potent TKIs such as nilotinib.

Ten-year survival after randomized comparison of imatinib (IM) 400 mg vs. IM 800 mg vs. IM + IFN vs. IM + Ara C vs. IM after IFN in chronic myeloid leukemia (CML).

7049 Background: It is unclear whether IM 400 mg is the optimum choice for the successful treatment of CML. Treatment optimization was therefore attempted. Methods: From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase (CP) were randomized into a 5-arm study to analyze 2 IM doses and 3 combinations. 1536 patients were evaluable, 400 for IM 400 mg, 420 for IM 800 mg, 430 for IM + Interferon (IFN), 158 for IM + Ara C and 128 for IM after IFN. Recruitment to the latter two arms was stopped after a pilot phase. Results: 10-year overall survival (OS) of all patients was 82%, 10-year progression free survival (PFS) 80%. 10-year OS was 80% with IM 400 mg, 79% with IM 800 mg, 84% with IM + IFN, 84% with IM + Ara C and 79% with IM after IFN. The differences were not significant. 10-year PFS was 80% with IM 400mg, 77% with IM 800mg, 83% with IM + IFN, 82% with IM + Ara C and 75% with IM after IFN. The differences were not significant either. Survival with any treatment was not significantly different from IM 400mg at any risk level by any risk score (Euro Sokal, EUTOS, ELTS). 87 patients progressed to blast crisis (BC). The 10-year cumulative incidence of BC was 5.8% (95% CI: 4.7%; 7.1%) equally distributed across treatment arms. Most BC occurred in the first 2 years. Median survival after BC was 7.9 months across treatment arms. 275 patients have died, 23 after stem cell transplantation in first CP. Two thirds of deaths were unrelated to CML. Incidence of death due to CML by competing risk analysis with death unrelated to CML as competing risk was not different between the 5-treatment arms. 10-year relative survival probability was 92% when compared to matched general population data. Patients reaching the cytogenetic or molecular response landmarks according to European LeukemiaNet criteria ( &lt; 10% BCR-ABL IS at 3 months, &lt; 1% BCR-ABL IS or complete cytogenetic remission at 6 months, &lt; 0.1% BCR-ABL IS (MMR) at 12 months) had a significantly better survival than those not reaching the landmarks regardless of therapy. Conclusions: In conclusion, outcome of CML is currently more determined by prognostic markers than by choice of therapy. IM400 mg remains an excellent choice for initial therapy of CP-CML. Clinical trial information: NCT00055874.

Plasma exchange for the patients with dilated cardiomyopathy in children is safe and effective in improving both cardiac function and daily activities.

Autoantibodies against cardiac proteins play an important role in the development of dilated cardiomyopathy (DCM). The efficacy and safety of apheresis such as immunoadsorption (IA) or plasma exchange (PE) to remove such antibodies have been reported in adult DCM patients. However, apheresis for pediatric DCM has not been performed because of technical difficulty due to relatively low blood volume and instability of hemodynamics. As we have experiences of preforming apheresis on hemodynamically unstable children, we have preformed ten courses of PE on seven child DCM patients including both patients in chronic and acute phase to assess the safety and efficacy to PE. Under general anesthesia, the patients were administered PE three times during 3 days as 1 course. Simultaneously, continuous hemodiafiltration (CHDF) was performed in series with the PE circuit to stabilize hemodynamic status and to minimize the adverse effects of PE. The changes in LVEF, CTR, mBP, the dosage of furosemide and NYHA were assessed before and after the procedure of PE. There were no severe adverse effects such as systemic bleeding or refractory hypotension due to apheresis. Echocardiography showed that mean baseline LVEF was 24.3 ± 7.8%. Mean LVEF significantly increased 1 week after PE to 30.5 ± 12.5%. CTR significantly decreased after PE. Mean BP significantly increased 1 month after PE (54.5 ± 10.7 to 60.7 ± 9.8mmHg). NYHA improved after PE significantly (NYHA; 3.4 ± 1.1 to 2.5 ± 1.1). PE is safe and effective in improving both cardiac function and daily activities.

Effect of Glutathione S-transferase mu 1 (GSTM1) gene polymorphism on chronic myeloid leukemia risk and Imatinib treatment response

Glutathione S-transferases (GSTs) gene polymorphisms were demonstrated to be associated with inter-individual variability of Imatinib mesylate (IM) response for chronic myeloid leukemia (CML) patients in a few studies; however, the results have been inconclusive. The aim of this study was to assess the role of such GSTs gene polymorphisms (GSTT1 and GSTM1) in relation to IM treatment outcome in 96 Syrian CML in chronic phase (CP) patients. Screening of GSTM1 and GSTT1 genotypes (null or present of these genes) was determined by multiplex polymerase chain reaction. Our results revealed that a GSTM1 null genotype frequency was significantly higher in CML patients than control (reference group) (OR=2.12, 95% CI: 1.24–3.7; p=0.007) while the GSTT1 null had no significant effect on CML development (OR=1.54, 95% CI: 0.83–2.9; p=0.19). Dual GSTM1 and GSTT1 null were associated with the risk of CML development (OR=3.6, 95% CI: 1.37–9.3; p=0.01). The GSTM1 null significantly increased the risk of minimal cytogenetic response (p=0.001). The similar trend was observed in patients with GSTT1 present/GSTM1 null genotypes (p=0.009). The highest number of patients with minimal cytogenetic response was in the group treated with 400mg of IM, while 600 and 800mg of IM significantly decreased this frequency. Our results highlight the significance of GSTM1 null alone, or in combination with the GSTT1 gene null, significantly increased the likelihood of IM failure in the CML patients studied. Especially patients with minimal cytogenetic response and GSTM1 null suffered from IM treatment failure in case of low dosage IM.

Cytogenetic and molecular response of EUTOS risk groups in children with chronic myeloid leukemia chronic phase on imatinib treatment

Introduction Recently (2011), the European Treatment and Outcome Study (EUTOS) scoring system was formulated to risk-stratify chronic myeloid leukemia (CML) chronic phase patients on imatinib treatment. CML during childhood is rare, making prognostication and management difficult. This study was conducted to investigate the cytogenetic and molecular response rates among EUTOS risk groups in pediatric CML patients on treatment with imatinib. Patients and methods Hospital records of pediatric CML chronic phase patients (age18 years) from 2009 to 2012 were analyzed retrospectively for demographic data, imatinib dose, date of initiation of treatment, EUTOS risk score, follow-up details, and cytogenetic and molecular response. Results A total of 57 children were included in this study, with a median age of 14.5 years (range: 5–18 years) and male preponderance (M:F, 1.19:1). The majority (67%) of them were in the low-risk group as per the EUTOS score and the remaining were in the high-risk group. Complete hematological response at 3 months was 100% in the low-risk and 94% in the high-risk group. Complete cytogenetic response at 12 months was 76 and 73% in the low-risk and high-risk groups, respectively. Major molecular response at 18 months was 85 and 79% in the low-risk and high-risk groups, respectively. Two-year event-free survival was 89 and 80% in the low-risk and high-risk groups, respectively. Conclusion The EUTOS low-risk cohort responded better than the high-risk cohort, but the difference was not statistically significant. Both groups had similar outcome at the end of 2 years. The EUTOS score did not predict the response and outcome in pediatric CML.

Post-concussion symptoms and chronic pain after mild traumatic brain injury are modulated by multiple locus effect in the BDNF gene through the expression of antisense: A pilot prospective control study

ABSTRACTBackground: Mild traumatic brain injury (mTBI) often results in post-concussion symptoms, chronic pain, and sleepiness. Genetic factors are thought to play an important role in poor prognosis.Aims: The aims of this study are to (1) document the prevalence of pain and post-concussion symptoms in mTBI patients in acute and chronic phases (2) determine whether candidate genes predispose to post-concussive symptoms and pain.Methods: Posttraumatic symptoms, evaluated using the Rivermead Post-Concussion Symptoms Questionnaire, and pain were assessed in 94 mTBI patients in the acute phase as well as in 22 healthy controls. Assessment was repeated in 36 patients after one year who agreed to participate in the follow-up visit. Gene polymorphisms and expression were assessed in mTBI patients and healthy controls.Results: In the acute phase, mTBI patients with pain (69%) presented more psychological symptoms and sleepiness and were less able to return to work than those without pain. At one year, 19% of mTBI patients had persistent pain and psychological distress. Two haplotypes (H2 and H3) in the brain-derived neurotrophic factor (BDNF) gene were shown to be respectively deleterious and protective against post-concussion symptoms and pain in both acute and chronic phases. Protective haplotype H3 was associated with a decreased expression of the anti-sense of BDNF (BDNF-AS). Deleterious haplotype H2 predicted the development of chronic pain at one year, whereas H3 was protective.Conclusions: This pilot study suggests a protective mechanism of a multilocus effect in BDNF, through BDNF-AS, against post-concussion symptoms and pain in the acute phase and possibly chronic pain at one year post-mTBI. The role of antisense RNA should be validated in larger cohorts.

Morphological Changes in Bone Marrow Post Imatinib Therapy in Chronic Phase CML: A Follow up Study on Sequential Bone Marrow Aspirates and Biopsies.

Imatinib mesylate is used extensively for first line treatment of Chronic Myeloid Leukemia (CML). However, not many studies have documented morphological changes in bone marrow biopsies produced during Imatinib therapy with reference to myelofibrosis. To document the morphological changes produced in the bone marrow during Imatinib therapy. This longitudinal study followed up 75 Philadelphia Chromosome Positive Chronic Myeloid Leukemia with chronic phase(Ph+ CML- CP) patients sequentially, receiving 400-600mg Imatinib over a period of 12 or more months. Haematologic parameters were measured at admission, 2 weeks, 1 month, 3 months, 6 months and 12 or more months. Morphologic changes in bone marrow aspirate and biopsy were evaluated at admission, 6 months and ≥12 months of treatment in accordance with National Comprehensive Cancer Network(NCCN) guidelines. Complete Haematologic Response (CHR) was seen in 47.1%, 80%, 85.4%, 90.4% at ≥1 month, 3 months, 6 months and 12 months respectively after therapy. It was noted that patients not showing CHR by 3 months were less likely to show CHR at 6 months and beyond. Bone marrow aspirates and biopsies showed reduction in cellularity and myeloid precursors with regeneration of erythroid precursors in 70-83% at ≥12 months. A significant decrease in myelofibrosis (p-value< 0.04) was noted as early as 6 months. Mild to moderate hypoplasia was noted in 31.8% of biopsies within 6 months. Pseudo gaucher cells and benign lymphoid nodules were also seen. Sequential analysis showed that Imatinib reduced the grade of myelofibrosis significantly (p-value< 0.04). It also prevented development of myelofibrosis in patients who did not have it at presentation. Hence Imatinib is effective when used early in the course of CML-CP.

Implementation of rehabilitation Service in the Outpatient Facility

This facility is the only one which is the institution introduced the Takizawa method rehabilitation service in Japan as the integrative one now1). A functional sustentation is the most important problem for the chronic phase patients living at home who are using the nursing-care-insurance 2) when continuing a home life. According to aging and house environment of a person requiring care or a care giver, a pejoration of the degree of care of the insurance will be a shift factor to institution use service irrespective of their intention. It would appear that the program 3) easily implements would be indispensable in order to maintain activity and home life and to prevent a pejoration of the degree of care.

HES-1 and CEBPA mRNA in Chronic and Late Phase (accelerated and blast crisis) of Chronic Myeloid Leukemia (CML) Patients

Chronic Myeloid Leukemia (CML) is a myeloproliferative disorder of hematopoietic , characterized by Philadelphia chromosome containing BCR-ABL fusion gene. The gene encodes protein with constitutive tyrosine kinase activity result in myeloid proliferation and leads to form an early phase of CML called chronic phase. Unsuccessful treatment will lead to progression of the disease into late phase (accelerated and blast crisis). The mechanisms involving disease progression are still poorly understood. It is assumed that additional genetic event involves in differentiation blocking of myeloid progenitor cells, such as Hes-1 overexpression and CEBPA down regulation. However, study on the expression of these genes in CML patient’s samples is still limited. This study aims to measure Hes-1 and CEBPA mRNA in chronic and late phase of CML patients. The peripheral blood mRNA level of Hes-1 was measured in CML patient’s sample with BCR-ABL positive both in chronic phase (n=61) and late phase (n=17) using qRT-PCR with GAPDH as internal control. Hes-1 mRNA was statistically higher (p value=0.0) in the chronic phase (mean ± SD=97.8 ± 236.6) compared to those in late phase (mean ± SD=8.5 ± 30.7). In addition, even though CEBPA expression in chronic and late phase were not statistically different (p value=0.1), those in chronic phase (mean ± SD=5.2 ± 16.0) were generally higher compared to those in late phase (mean ± SD=1.7 ± 2.4). Hes-1 expression upregulated in 70.5% of chronic phase patients and in 17.6% of late phase patients, whereas CEBPA expression down regulated in 42.6% of chronic phase patients and in 47.1% in late phase patients. High standard deviation, particularly in mRNA Hes-1 gene expression measurement of the chronic phase, indicated the presence of individual variations in the sample that might be influenced by other genetic factors. This study found that Hes-1 mRNA is significantly higher in peripheral blood of chronic phase than blast crisis CML, whereas CEBPA mRNA is not different.