Scoliosis, diabetes mellitus and total laminectomy at the 4th lumbar vertebra are independent risk factors for post-laminectomy fracture around the isthmus.

OBJECTIVE: We aimed to identify the risk factors and clinical outcomes for post-laminectomy fracture around the isthmus, which can cause back pain or radiculopathy. METHODS: We performed a retrospective cohort study involving all patients who underwent laminectomy splitting the spinous process for lumbar spinal stenosis between 2010 and 2014. The primary outcome measure was post-laminectomy fracture around the isthmus. Clinical outcomes were evaluated based on reoperation rate. To evaluate risk factors for fracture, the following parameters were collected: (1) patient characteristics and concomitant diabetes mellitus, (2) lumbar scoliosis and sagittal alignment parameters, and (3) surgical data, such as rate of total laminectomy. Logistic regression analysis was performed to identify the independent risk factors for post-laminectomy fracture. RESULTS: Twelve of the 92 patients suffered a post-laminectomy fracture around the isthmus. Logistic regression analysis revealed that diabetes mellitus (odds ratio [OR]: 15.41; 95% confidence interval [CI]: 2.93-80.98; P=0.001), L4 total laminectomy (OR: 14.68; 95% CI: 1.51-142.76; P=0.021), and lumbar scoliosis (OR: 5.72; 95% CI: 1.16-28.21; P=0.032) were independent risk factors. The fracture group included 2 patients (16.7%) who required reoperation at the decompression level for recurrent leg pain, whereas the non-fracture group included 2 (2.5%) who underwent reoperation at a level different from the index procedure. CONCLUSIONS: Post-laminectomy fractures around the isthmus were significantly associated with scoliosis, diabetes mellitus, and total laminectomy at L4. Total laminectomy at L4 is best avoided to reduce the risk of post-laminectomy fracture in patients with scoliosis or diabetes mellitus.

Principal component analysis uncovers cytomegalovirus-associated NK cell activation in Ph+ leukemia patients treated with dasatinib.

Dasatinib treatment markedly increases the number of large granular lymphocytes (LGLs) in a proportion of Ph+ leukemia patients, which associates with a better prognosis. The lymphocytosis is predominantly observed in cytomegalovirus (CMV)-seropositive patients, yet detectable CMV reactivation exists only in a small fraction of patients. Thus, etiology of the lymphocytosis still remains unclear. Here, we identified NK cells as the dominant LGLs expanding in dasatinib-treated patients, and applied principal component analysis (PCA) to an extensive panel of NK cell markers to explore underlying factors in NK cell activation. PCA displayed phenotypic divergence of NK cells that reflects CMV-associated differentiation and genetic differences, and the divergence was markedly augmented in CMV-seropositive dasatinib-treated patients. Notably, the CMV-associated highly differentiated status of NK cells was already observed at leukemia diagnosis, and was further enhanced after starting dasatinib in virtually all CMV-seropositive patients. Thus, the extensive characterization of NK cells by PCA strongly suggests that CMV is an essential factor in the NK cell activation, which progresses stepwise during leukemia and subsequent dasatinib treatment most likely by subclinical CMV reactivation. This study provides a rationale for the exploitation of CMV-associated NK cell activation for treatment of leukemias.

Local recurrence risk after previous salvage mastectomy.

INTRODUCTION: Breast-conserving surgery is a standard treatment for early breast cancer. For ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery, salvage mastectomy is the current standard surgical procedure. However, it is not rare for patients with IBTR who have received salvage mastectomy to develop local recurrence. In this study, we examined the risk factors of local recurrence after salvage mastectomy for IBTR. PATIENTS AND METHODS: A total of 118 consecutive patients who had histologically confirmed IBTR without distant metastases and underwent salvage mastectomy without irradiation for IBTR between 1989 and 2008 were included from eight institutions in Japan. The risk factors of local recurrence were assessed. RESULTS: The median follow-up period from salvage mastectomy for IBTR was 4.6 years. Patients with pN2 or higher on diagnosis of the primary tumor showed significantly poorer local recurrence-free survival than those with pN0 or pN1 at primary tumor (p < 0.001). Multivariate analysis showed that the lymph node status of the primary tumor was a significantly independent predictive factor of local recurrence-free survival (p = 0.02). CONCLUSION: The lymph node status of the primary tumor might be a predictive factor of local recurrence-free survival after salvage mastectomy for IBTR. Further research and validation studies are needed. (UMIN-CTR number UMIN000008136).

Prognosis after mastectomy versus repeat lumpectomy in patients with ipsilateral breast cancer recurrence: A propensity score analysis.

INTRODUCTION: Mastectomy is the current standard surgical procedure for ipsilateral breast tumor recurrence (IBTR). However, there is little evidence about the prognostic impact of the surgical procedure (mastectomy versus repeat lumpectomy) for IBTR. PATIENTS AND METHODS: A total of 271 consecutive patients who had histologically confirmed IBTR without distant metastases and underwent definitive surgery for IBTR between 1989 and 2008 were included from eight institutions in Japan. The impact of the surgical procedure for IBTR on distant disease-free survival (DDFS) and overall survival (OS) was evaluated using and multivariable proportional hazards regression and propensity score matching methods. RESULTS: Of the 271 patients, 149 patients (55%) underwent repeat lumpectomy and 122 patients (45%) underwent mastectomy after IBTR. The median follow-up period from definitive surgery for IBTR was 55 months. There was no difference in terms of DDFS and OS between repeat lumpectomy and mastectomy after IBTR, adjusted for various clinical and tumor characteristics. In addition, for the matched patient cohort, no difference in DDFS and OS was seen between the 2 groups. CONCLUSION: In our study, both multivariate analysis and the propensity score matching method demonstrated that there was no difference in terms of DDFS and OS between repeat lumpectomy and mastectomy after IBTR. Further studies are warranted (UMIN-CTR number UMIN000008136).

Lifting of evacuation orders and subsequent efforts in Japan.

With confirmation of the cold shutdown conditions of the nuclear reactors after the accident at Fukushima Daiichi nuclear power plant, the Japanese Government reclassified the areas under evacuation orders as follows: (1) difficult-to-return zones (>50 mSv y-1), (2) restricted residence zones (20-50 mSv y-1), and (3) zones in preparation for lifting of the evacuation order (<20 mSv y-1). The Government continued its initiatives towards reconstruction of Fukushima, and has lifted evacuation orders in Zones 2 and 3. In terms of radiological protection, the Government emphasised its policy of placing importance on individual dose, and promoted the assignment of consultants in each municipality.

Change in estrogen receptor, HER2, and Ki-67 status between primary breast cancer and ipsilateral breast cancer tumor recurrence.

INTRODUCTION: Changes in the biological marker status between primary and recurrent tumors are observed in breast cancer. However, their clinical significance is still uncertain, especially for patients with ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery. PATIENTS AND METHODS: A total of 117 patients with IBTR without distant metastases were enrolled in this study. All patients were examined for estrogen receptor (ER), HER2, and Ki-67 in both the primary tumors and paired IBTR. We evaluated the impact of changes in these biomarkers between primary tumors and IBTR on the prognosis after IBTR. RESULTS: There were no associations of changes in the ER, HER2 status with distant disease-free survival (DDFS) after surgical resection of IBTR, whereas the change in the Ki-67 status between the primary tumors and IBTR was significantly correlated with DDFS (unadjusted: p = 0.0094; adjusted: p = 0.013). Patients in the "increased or remained high" Ki-67 group had a significantly shorter DDFS than those in the "decreased or remained low" Ki-67 group (5-year DDFS: 55.5 vs. 79.3%, respectively, p = 0.0084 by log-rank test). CONCLUSION: An increased or persistently high Ki-67 status in the IBTR was significantly correlated with a poorer prognosis after IBTR.

Differences between subtotal corpectomy and laminoplasty for cervical spondylotic myelopathy.

OBJECTIVE: This study aimed to obtain guidelines for choosing between subtotal corpectomy (SC) and laminoplasty (LP) by analysing the surgical outcomes, radiological changes and problems associated with each surgical modality. STUDY DESIGN: A retrospective analysis of two interventional case series. SETTING: Department of Orthopaedic Surgery, Kagawa University, Japan. METHODS: Subjects comprised 34 patients who underwent SC and 49 patients who underwent LP. SC was performed by high-speed drilling to remove vertebral bodies. Autologous strut bone grafting was used. LP was performed as an expansive open-door LP. The level of decompression was from C3 to C7. Clinical evaluations included recovery rate (RR), frequency of C5 root palsy after surgery, re-operation and axial pain. Radiographic assessments included sagittal cervical alignment and bone union. RESULTS: Comparisons between the two groups showed no significant differences in age at surgery, preoperative factors, RR and frequency of C5 palsy. Progression of kyphotic changes, operation time and volumes of blood loss and blood transfusion were significantly greater in the SC (two- or three-level) group. Six patients in the SC group required additional surgery because of pseudoarthrosis, and four patients underwent re-operation because of adjacent level disc degeneration. In the LP group, the problem of elimination of postoperative axial symptoms remains to be solved. CONCLUSIONS: The merit of SC is the low frequency of axial symptoms. One-level SC can be considered to have similar degree of invasiveness as LP. Compared with SC, LP is more suitable for elderly patients with multilevel stenosis.

PD-1/PD-L1 expression in human T-cell leukemia virus type 1 carriers and adult T-cell leukemia/lymphoma patients.

Adult T-cell leukemia/lymphoma (ATLL) develops after infection with human T-cell leukemia virus-1 (HTLV-1) after a long latency period. The negative regulatory programmed death-1/programmed death-1 ligand 1 (PD-1/PD-L1) pathway has been implicated in the induction of cytotoxic T-lymphocyte (CTL) exhaustion during chronic viral infection along with tumor escape from host immunity. To determine whether the PD-1/PD-L1 pathway could be involved in the establishment of persistent HTLV-1 infections and immune evasion of ATLL cells in patients, we examined PD-1/PD-L1 expression on cells from 27 asymptomatic HTLV-1 carriers (ACs) and 27 ATLL patients in comparison with cells from 18 healthy donors. PD-1 expression on HTLV-1-specific CTLs from ACs and ATLL patients was dramatically elevated. In addition, PD-1 expression was significantly higher on CD8+ T cells along with cytomegalovirus (CMV)- and Epstein-Barr virus (EBV)-specific CTLs in ATLL patients compared with ACs and control individuals. Primary ATLL cells in 21.7% of ATLL patients expressed PD-L1, whereas elevated expression was not observed in cells from ACs. Finally, in functional studies, we observed that an anti-PD-L1 antagonistic antibody upregulated HTLV-1-specific CD8+T-cell response. These observations suggest that the PD-1/PD-L1 pathway plays a role in fostering persistent HTLV-1 infections, which may further ATLL development and facilitate immune evasion by ATLL cells.

A prospective randomized comparative study on the safety and tolerability of transnasal esophagogastroduodenoscopy.

BACKGROUND AND STUDY AIM: Transnasal esophagogastroduodenoscopy (EGD) with a small-caliber endoscope is well tolerated by patients. However, the effect of this procedure on cardiopulmonary function has not been fully investigated. The aim of this prospective, randomized study was to investigate the effect of transnasal EGD in comparison with transoral EGD on cardiopulmonary function. PATIENTS AND METHODS: The study involved 450 patients referred for diagnostic EGD. Patients were randomly assigned to one of three types of unsedated EGD (150 patients per group): transnasal EGD using a small-caliber endoscope (the "XP-N" group), transoral EGD using the same small-caliber endoscope ("XP-O" group), and transoral EGD using a conventional endoscope ("XQ" group). Systolic and diastolic blood pressure, pulse rate, and arterial oxygen saturation were monitored before, and 2, 4 and 6 minutes after intubation, and just after endoscope extubation. Gagging episodes were also counted, to determine tolerance. RESULTS: It was not possible to perform transnasal EGD in 12 patients (8.0%). A small amount of epistaxis was observed in eight (5.8%) of 138 patients who were examined successfully by transnasal EGD. Systolic and diastolic blood pressure, pulse rate, rate-pressure product (pulse rate x systolic blood pressure/100), and the drop in arterial oxygen saturation in the XQ group were significantly greater than in the XP-N and XP-O groups at each time point. In the XP-N group, these parameters were significantly lower than those in the XP-O group at 2 minutes after intubation. Of the tree groups the number of gagging episodes was significantly lower in the XP-N group. CONCLUSION: Transnasal EGD is safer than transoral EGD as it is associated with fewer adverse effects on cardiopulmonary function and is better tolerated by patients.

Histamine increases the expression of LOX-1 via H2 receptor in human monocytic THP-1 cells.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a member of the scavenger receptor family, and is known to be expressed in monocytes/macrophages. We investigated the effect of histamine on the expression of LOX-1 in cells of the human monocytic leukemia cell line THP-1. Histamine as well as forskolin and dibutyryl cyclic AMP (Bt2-cAMP) stimulated the THP-1 monocytes to express the LOX-1 gene at the transcription level. This histamine effect on LOX-1 gene expression, via the histamine H2 receptor-mediated cAMP signal transduction pathway, was reduced after differentiation of the cells into macrophages, even though forskolin and Bt2-cAMP still enhanced the gene expression. The alteration of the responsiveness of LOX-1 expression to histamine was related to suppressed expression of the H2 receptor in THP-1 macrophages. The switch of the predominant class of histamine receptors between H1 and H2 would modulate the effects of histamine on LOX-1 gene expression in monocytes and macrophages, and therefore, would play a certain role in the inflammatory aspects of atherogenesis.

Effects of histamine and interleukin-4 synthesized in arterial intima on phagocytosis by monocytes/macrophages in relation to atherosclerosis.

We investigated the localization of histidine decarboxylase (HDC), which is the rate-limiting enzyme that generates histamine from histidine, in human aorta/coronary artery. RT-PCR and immunohistochemical staining revealed that the HDC gene was expressed in monocytes/macrophages and T cells in the arterial intima but not in smooth muscle cells in either the arterial intima or the media. A luciferase promoter assay with U937 and Jurkat cells demonstrated that interleukin-4 (IL-4) inhibited the expression of the HDC gene. In contrast, among a scavenger receptor family, IL-4 as well as histamine up-regulated U937 cells to express the LOX-1 gene but not the SR-A gene, which genes encode receptors that scavenge oxidized lipids. These findings suggest that histamine synthesized in the arterial wall participates in the initiation and progression of atherosclerosis and that IL-4 can act as an important inhibitory and/or stimulatory factor in the function of monocytes/macrophages modulated by histamine in relation to the process of atherosclerosis.

[Complete cytogenetic response to interferon-alpha in a patient with chronic myelogenous leukemia undergoing hemodialysis].

We describe a complete cytogenetic response to interferon-alpha in a patient with chronic myelogenous leukemia undergoing chronic hemodialysis. Although IFN-alpha therapy has been applied to patients with chronic hepatitis C receiving hemodialysis, the pharmacokinetics of IFN-alpha in patients with poor renal function still remain unclear. In the present patient, the serum IFN-alpha concentration remained high even 48 hours after injection (42.9 IU/ml), and IFN-alpha was almost completely removed by hemodialysis (< 6 UI/ml). The patient was treated with IFN-alpha (3 x 10(6) IU, three times a week), and cytogenetic disappearance (0%) of the Ph-positive clone was confirmed 31 months after the start of therapy. Recombinant human erythropoietin (Epo) was used to treat anemia due to renal failure and IFN-alpha therapy. The anemia was controllable with Epo, and no adverse effect was observed.

HLA-A*26, HLA-B*4002, HLA-B*4006, and HLA-B*4801 alleles predispose to adult T cell leukemia: the limited recognition of HTLV type 1 tax peptide anchor motifs and epitopes to generate anti-HTLV type 1 tax CD8(+) cytotoxic T lymphocytes.

Genetic risk for adult T cell leukemia (ATL) has been implicated by ethnic and familial segregation of ATL patients from HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). To clarify the genetic risk for ATL, we characterized HLA class I alleles of ATL patients and analyzed the anchor motifs of HTLV-1 peptides binding to HLA class I molecules, using 291 lines of anti-HTLV-1 CD8(+) cytotoxic T lymphocytes (CTLs) generated in vitro with a total of 165 synthetic peptides for HTLV-1 Tax and Env proteins. Allele frequencies of HLA-A*26, B*4002, B*4006, and B*4801 were significantly higher in ATL patients than in HAM/TSP patients and asymptomatic HTLV-1 carriers in southern Japan. CD8(+) CTL analysis revealed the HTLV-1 Tax peptide sequence to completely lack anchor motifs of peptides binding to HLA-A*26,B*4002, and B*4006 molecules but to possess one anchor for HLA-B*4801, while the HTLV-1 Env peptide sequence had many anchor motifs for HLA-A*26, B*4002, B*4006, and B*4801 molecules. Most ATL patients featured heterozygous HLA class I alleles composed of HLA-A*26, B*4002, B*4006, and B*4801, with a lower number of HTLV-1 Tax peptide anchor motifs and epitopes generating anti-HTLV-1 Tax CD8(+) CTLs than individuals possessing other HLA alleles. The relationship between Tax epitope and ATL incidence was verified by the significantly decreased number of HTLV-1 Tax epitopes in ATL patients compared with asymptomatic HTLV-1 carriers (p < 0.01) as well as late onset ATL patients (p < 0.001). These results indicate that HLA-A*26, B*4002, B*4006, and B*4801 alleles predispose to ATL because of the limited recognition of HTLV-1 Tax peptide anchor motifs and epitopes capable of generating anti-HTLV-1 Tax CD8(+) CTLs.