Significance of Single-cell Level Dual Expression of BCL2 and MYC Determined With Multiplex Immunohistochemistry in Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a fatal heterogenous neoplasm. Recent clinical trials have failed partly due to nebulous criteria for defining high-risk patients. Patients with double-expresser lymphoma (DEL) have a poor prognosis and are resistant to conventional treatment. However, many diagnostic and clinical controversies still surround DEL partly due to the arbitrariness of criteria for the diagnosis of DEL. In this study, we suggest a refined method for diagnosing DEL by evaluating the concurrent expression of BCL2 and MYC at the single-cell level (dual-protein-expressing lymphoma [DUEL]). For the proof of concept, a multiplex immunofluorescence assay for CD20, BCL2, and MYC was performed and quantitatively analyzed using spectral image analysis in patients. The analysis results and clinical applicability were verified by using dual-color immunohistochemistry performed on 353 independent multicenter patients who had been uniformly treated with standard therapy. DUEL showed significantly worse overall survival (OS) and event-free survival (EFS) (P=0.00011 and 0.00035, respectively). DUEL status remained an independent adverse prognostic variable with respect to the International Prognostic Index risk and the cell of origin. Moreover, the advantage of determining DUEL status by dual-color immunohistochemistry was shown by more robust classification and more homogeneous high-risk subgroup patient identification in both training (n=271) (OS: P<0.0001; EFS: P<0.0001) and validation sets (n=82) (OS: P=0.0087; EFS: P<0.0001). This concept of DUEL is more consistent with carcinogenesis and has greater practical utility, hence it may provide a better basis for both basic and clinical research for the development of new therapeutics.

Subjective Needs and Thoughts for the Treatment of Patients with Inflammatory Bowel Disease: Applying Q Methodology.

Backgrounds/Aims: Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract that requires lifetime management. Many studies have attempted to establish questionnaires and/or parameters to assess the quality of care for IBD patients. However, no study to date has investigated patients using the Q-methodology, which is subjective and has been studied systematically, to identify and categorize their opinions and subjective thinking about their disease and treatment. We have therefore aimed here to conduct a preliminary study of the Q-methodology to investigate the subjective thinking of IBD patients in Korea. Methods: Q-methodology, a method of analyzing the subjectivity of questionnaire items, was examined in this study. Inputs from 50 IBD patients were classified into 34 normalized statements using a 9-point scale with a normal distribution. The collected data were analyzed using the QUANL PC program. Results: Using the Q-methodology, IBD patients were classified into type I, II, III, and IV treatment needs: medical staff-dependent, relationship-oriented, information-driven, and social awareness, respectively. Conclusions: The subjective needs of IBD patients and their thoughts about the treatment can be classified into four types. Our findings suggest that we can establish a systematic strategy for personalized care according to patient type.

Human Plasmablast Migration Toward CXCL12 Requires Glucose Oxidation by Enhanced Pyruvate Dehydrogenase Activity via AKT.

Migration of human plasmablast to the bone marrow is essential for the final differentiation of plasma cells and maintenance of effective humoral immunity. This migration is controlled by CXCL12/CXCR4-mediated activation of the protein kinase AKT. Herein, we show that the CXCL12-induced migration of human plasmablasts is dependent on glucose oxidation. Glucose depletion markedly inhibited plasmablast migration by 67%, and the glucose analog 2-deoxyglucose (2-DG) reduced the migration by 53%; conversely, glutamine depletion did not reduce the migration. CXCL12 boosted the oxygen consumption rate (OCR), and 2-DG treatment significantly reduced the levels of all measured tricarboxylic acid (TCA) cycle intermediates. AKT inhibitors blocked the CXCL12-mediated increase of OCR. CXCL12 enhanced the pyruvate dehydrogenase (PDH) activity by 13.5-fold in an AKT-dependent manner to promote mitochondrial oxidative phosphorylation. The knockdown and inhibition of PDH confirmed its indispensable role in CXCL12-induced migration. Cellular ATP levels fell by 91% upon exposure to 2-DG, and the mitochondrial ATP synthase inhibitor oligomycin inhibited CXCL12-induced migration by 85%. Low ATP levels inhibited the CXCL12-induced activation of AKT and phosphorylation of myosin light chains by 42%, which are required for cell migration. Thus, we have identified a mechanism that controls glucose oxidation via AKT signaling and PDH activation, which supports the migration of plasmablasts. This mechanism can provide insights into the proper development of long-lived plasma cells and is, therefore, essential for optimal humoral immunity. To our knowledge, this study is the first to investigate metabolic mechanisms underlying human plasmablast migration toward CXCL12.

Late-onset noninfectious interstitial lung disease following autologous haematopoietic stem cell transplantation in paediatric patients.

BACKGROUND AND OBJECTIVE: High-dose chemotherapy (HDCT) followed by autologous haematopoietic stem cell transplantation (HSCT) is widely used in paediatric cancer patients, but few data about noninfectious interstitial lung disease (ILD) following this treatment are available. Therefore, we aimed to evaluate the incidence, clinical features and risk factors of noninfectious ILD after HDCT in paediatric patients. METHODS: This was a retrospective cohort study of paediatric solid tumour patients who underwent HDCT and autologous HSCT between 1997 and 2012. ILD was diagnosed using clinical symptoms and radiography after excluding cardiac, renal and infectious causes. Risk factors were analysed using a Cox proportional hazard regression model. RESULTS: Three hundred and forty patients were enrolled, and the median age was 3 years (interquartile range 1-7). Eight patients (2.4%) were diagnosed with noninfectious ILD. The median duration of symptom onset was 30 months (range 7-74). Six (75%) of eight ILD patients died during the study period, even though steroids were administered for treatment. High-dose cyclophosphamide use (hazard ratio = 11.37, 95% confidence interval = 1.38-93.32, P = 0.023) and sex (hazard ratio = 0.10, 95% confidence interval = 0.01-0.84, P = 0.034) were associated with late-onset, noninfectious ILD upon multivariate analysis. CONCLUSION: The incidence of noninfectious ILD after HDCT and autologous HSCT was not negligible, and the clinical features of ILD showed late onset and a poor prognosis. Female gender and high-dose cyclophosphamide treatment may be risk factors for noninfectious ILD, but further studies with a larger number of ILD patients are suggested.

Torsion of a parasitic myoma that developed after abdominal myomectomy.

Iatrogenic parasitic myomas are rare. The condition is defined by the presence of multiple smooth-muscle tumorous nodules in the peritoneal cavity. This may be attributable to seeding of myoma particles during uterine surgery. The clinical course is usually indolent. The disease is often asymptomatic and is usually discovered only incidentally. A 38-year-old woman who had undergone abdominal myomectomy 7 months prior presented with acute abdominal pain and a huge pelvic mass. We performed exploratory laparotomy. A parasitic mass 17 cm in diameter with a twisted omental pedicle was identified. En bloc excision of the mass and omentum was performed, followed by total abdominal hysterectomy. Histopathological examination of multiple sections revealed features compatible with an infarcted leiomyoma. Thus, we present a very rare case of an iatrogenic, rapidly growing parasitic myoma complicated by omental torsion (which caused the acute abdominal pain). We also offer a literature review.

Long-term follow-up radiologic and clinical evaluation of cylindrical cage for anterior interbody fusion in degenerative cervical disc disease.

OBJECTIVE: Various procedures have been introduced for anterior interbody fusion in degenerative cervical disc disease including plate systems with autologous iliac bone, carbon cages, and cylindrical cages. However, except for plate systems, the long-term results of other methods have not been established. In the present study, we evaluated radiologic findings for cylindrical cervical cages over long-term follow up periods. METHODS: During 4 year period, radiologic findings of 138 patients who underwent anterior cervical fusion with cylindrical cage were evaluated at 6, 12, 24, and 36 postoperative months using plain radiographs. We investigated subsidence, osteophyte formation (anterior and posterior margin), cage direction change, kyphotic angle, and bone fusion on each radiograph. RESULTS: Among the 138 patients, a minimum of 36 month follow-up was achieved in 99 patients (mean follow-up : 38.61 months) with 115 levels. Mean disc height was 7.32 mm for preoperative evaluations, 9.00 for immediate postoperative evaluations, and 4.87 more than 36 months after surgery. Osteophytes were observed in 107 levels (93%) of the anterior portion and 48 levels (41%) of the posterior margin. The mean kyphotic angle was 9.87° in 35 levels showing cage directional change. There were several significant findings : 1) related subsidence [T-score (p=0.039) and anterior osteophyte (p=0.009)], 2) accompanying posterior osteophyte and outcome (p=0.05). CONCLUSION: Cage subsidence and osteophyte formation were radiologically observed in most cases. Low T-scores may have led to subsidence and kyphosis during bone fusion although severe neurologic aggravation was not found, and therefore cylindrical cages should be used in selected cases.

Perioperative risk factors related to lumbar spine fusion surgery in korean geriatric patients.

OBJECTIVE: Life expectancy for humans has increased dramatically and with this there has been a considerable increase in the number of patients suffering from lumbar spine disease. Symptomatic lumbar spinal disease should be treated, even in the elderly, and surgical procedures such as fusion surgery are needed for moderate to severe lumbar spinal disease. However, various perioperative complications are associated with fusion surgery. The aim of this study was to examine perioperative complications and assess risk factors associated with lumbar spinal fusion, focusing on geriatric patients at least 70 years of age in the Republic of Korea. METHODS: We retrospectively investigated 489 patients with various lumbar spinal diseases who underwent lumbar spinal fusion surgery between 2003 and 2007 at our institution. Three fusion procedures and the number of fused segments were analyzed in this study. Chronic diseases were also evaluated. Risk factors for complications and their association with age were analyzed. RESULTS: In this study, 74 patients experienced complications (15%). The rate of perioperative complications was significantly higher in patients 70 years of age or older than in other age groups (univariate analysis, p=0.001; multivariate analysis, p=0.004). However, perioperative complications were not significantly associated with the other factors tested (sex, comorbidities, operation procedures, fusion segments involved). CONCLUSION: Increasing age was an important risk factor for perioperative complications in patients undergoing lumbar spinal fusion surgery whereas other factors were not significant. We recommend good clinical judgment and careful selection of geriatric patients undergoing lumbar spinal fusion surgery.

Transplantation of human adipose-derived stem cells in a rabbit model of traumatic degeneration of lumbar discs.

OBJECTIVE: The purpose of the present study is to assess the possibility of disc regeneration by treatment with adipose-derived stem cells (ADSCs) in a rabbit model of degenerative disc disease, and to evaluate the efficacy of a percutaneous technique for constructing a model of degenerative disc disease in rabbits. METHODS: The study sample consisted of 20 mature male New Zealand white rabbits. Intervertebral discs were injured in each rabbit by a percutaneous technique at L2-3, L3-4, and L4-5 under C-arm guidance with a 19-gauge spinal needle. Magnetic resonance images (MRI) were checked at 6, 9, 12, and 15 weeks after injury to evaluate disc degeneration. Nineteen weeks after injury, ADSCs were injected into the L4-5 disc space, with saline injected into the L3-4 disc as a control, using a 21-gauge spinal needle. Histologic confirmations of degenerated discs were performed at 10 and 18 weeks after injury with safranin O and trichrome stains. RESULTS: MRI revealed intervertebral disc degeneration from 9 weeks after injury, and full degeneration at 15 weeks after injury, when compared with uninjured control discs. We confirmed the proliferation of ADSCs at the L4-5 level in 10-week rabbits after cell injection. Histologically, the ADSC-injected discs exhibited elevated extracellular matrix secretion and little ossification of damaged cartilage in the nucleus pulposus compared with degenerative control discs. CONCLUSIONS: These results suggest that the injection of ADSCs into injured lumbar discs could be an effective treatment for degenerative disc disease by promoting the cartilage regeneration.

[Comorbidity and health habits of Seoul city elders with dementia].

PURPOSE: The aim of this study was to clarify the actual condition of elders with dementia who were registered in the Seoul Dementia Management Project. METHODS: Data were collected from 5,312 elderly patients with dementia. Demographic included characteristics, comorbidity, and healthy lifestyle habits; data from the Seoul Dementia Management Project. RESULTS: First, demographic characteristics were as follows; mean age at the time of definite diagnosis was 78.0 yr. There were slightly more women (69.3%), and 4.55 yr was the average length of education with 41.4% being illiterate or uneducated patients. Second, there were several comorbidities including hypertension (61.7%), diabetes mellitus (31.8%), hypercholesterolemia (10.2%), heart disease (11.1%), obesity (4.2%), and stroke (21.4%). Third, alcoholic history was found in 11.8% of the patients, and smoking in 9.8%. Regular exercise was done by only 29.1% of the patients with dementia. Finally, significant differences between men and women were found for the following; age, education, medical security, hypertension, diabetes mellitus, stroke, alcoholic consumption, smoking, and regular exercise. CONCLUSION: Authors expect that the present data will be used for establishment of dementia associated projects and policies.