Influence of concurrent and staggered dosing of semi-solid nutrients on the pharmacokinetics of orally administered carbamazepine in rats.

In the present study, we examined the effects of concurrent and staggered dosing of PG-soft ace-MP TM (PG), novel semi-solid enteral nutrients, on the pharmacokinetics of orally administered carbamazepine (CBZ) in rats due to the high possibility of drug interaction during the absorption process. The pharmacokinetic behavior of CBZ was considerably altered when administered concurrently with PG. The maximum serum CBZ concentration (Cmax) significantly decreased and the mean residence time (MRT) significantly increased. The elimination constant (ke) also significantly increased, but there were no significant changes in the area under the serum CBZ concentration versus time curve (AUC) and the time to reach Cmax (Tmax). However, these changes in the pharmacokinetic parameters were eliminated by waiting 20 min, the time interval equivalent to the Tmax described above, between CBZ administration and PG dosing. This study suggested that PG interferes with CBZ absorption from the digestive tract, although staggered administration of CBZ and PG prevented their interaction.

Tumor microenvironment in triple-negative breast cancer: the correlation of tumor-associated macrophages and tumor-infiltrating lymphocytes

Purpose Immune cells such as cytotoxic T cells, helper T cells, B cells or tumor-associated macrophages (TAMs) contribute to the anti-tumor response or pro-tumorigenic effect in triple negative breast cancer (TNBC). The interrelation of TAMs, T and B tumor-infiltrating lymphocytes (TILs) in TNBC has not been fully elucidated. Methods We evaluated the association of tumor-associated macrophages, T and B TILs in TNBC. Results TNBCs with a high CD68+, CD163+ TAMs and low CD4+, CD8+, CD20+ TILs had a significantly shorter relapse-free survival (RFS) and overall survival (OS) than those with low CD68+, CD163+ TAMs and high CD4+, CD8+, CD20+ TILs. TNBCs with high CD68+ TAMs/low CD8+ TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD68+ TAMs/high CD8+ TILs, low CD68+ TAMs/high CD8+ TILs, and low CD68+/low CD8+. TNBCs with high CD163+ TAMs/low CD8+, low CD20 + TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD163+ TAMs/high CD8+ TILs and high CD163+ TAMs /high CD20+ TILs. Conclusions Our study suggests that TAMs further create an optimal tumor microenvironment (TME) for growth and invasion of cancer cells when evasion of immunoreactions due to T and B TILs occurs. In TNBCs, all these events combine to affect prognosis. The process of TME is highly complex in TNBCs and for an improved understanding, larger validation studies are necessary to confirm these findings (AU)

Tumor microenvironment in triple-negative breast cancer: the correlation of tumor-associated macrophages and tumor-infiltrating lymphocytes.

PURPOSE: Immune cells such as cytotoxic T cells, helper T cells, B cells or tumor-associated macrophages (TAMs) contribute to the anti-tumor response or pro-tumorigenic effect in triple negative breast cancer (TNBC). The interrelation of TAMs, T and B tumor-infiltrating lymphocytes (TILs) in TNBC has not been fully elucidated. METHODS: We evaluated the association of tumor-associated macrophages, T and B TILs in TNBC. RESULTS: TNBCs with a high CD68+, CD163+ TAMs and low CD4+, CD8+, CD20+ TILs had a significantly shorter relapse-free survival (RFS) and overall survival (OS) than those with low CD68+, CD163+ TAMs and high CD4+, CD8+, CD20+ TILs. TNBCs with high CD68+ TAMs/low CD8+ TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD68+ TAMs/high CD8+ TILs, low CD68+ TAMs/high CD8+ TILs, and low CD68+/low CD8+. TNBCs with high CD163+ TAMs/low CD8+, low CD20 + TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD163+ TAMs/high CD8+ TILs and high CD163+ TAMs /high CD20+ TILs. CONCLUSIONS: Our study suggests that TAMs further create an optimal tumor microenvironment (TME) for growth and invasion of cancer cells when evasion of immunoreactions due to T and B TILs occurs. In TNBCs, all these events combine to affect prognosis. The process of TME is highly complex in TNBCs and for an improved understanding, larger validation studies are necessary to confirm these findings.

SAPPHIRE: a randomised phase II study of planned discontinuation or continuous treatment of oxaliplatin after six cycles of modified FOLFOX6 plus panitumumab in patients with colorectal cancer.

BACKGROUND: Fluorouracil (5-FU), leucovorin (LV) and oxaliplatin (FOLFOX) plus panitumumab therapy is a commonly used first-line chemotherapy for metastatic colorectal cancer (mCRC). However, the long-term administration of oxaliplatin is associated with peripheral neuropathy (PN). We investigated whether the planned discontinuation of oxaliplatin after FOLFOX plus panitumumab therapy can maintain efficacy and reduce PN incidence. PATIENTS AND METHODS: Chemotherapy-naive patients with RAS wild-type mCRC, aged ≥20 years, were enrolled and received six cycles of modified FOLFOX6 (mFOLFOX6) plus panitumumab as induction therapy. Patients who completed induction therapy without progression were randomised to mFOLFOX6 plus panitumumab (group A) or to 5-FU/LV plus panitumumab (group B). The primary end-point was the progression-free survival (PFS) rate at 9 months after randomisation. The secondary end-points were PFS, overall survival (OS), time to treatment failure (TTF), response rate (RR) and safety. RESULTS: In total, 164 patients were enrolled; of whom, 113 patients were then randomised (group A, n = 56; group B, n = 57). The median follow-up after randomisation was 19.6 months. The PFS rates at 9 months and median PFS were 46.4% (80% confidence interval [CI], 38.1-54.9) and 9.1 months (95% CI, 8.6-11.1) in group A, compared with 47.4% (80% CI, 39.1-55.8) and 9.3 months (95% CI, 6.0-13.0) in group B, respectively. RR, OS and TTF were also similar in both groups. Grade ≥2 PN incidence was lower in group B (9.3%) than in group A (35.7%). CONCLUSION: Planned discontinuation of oxaliplatin after six cycles of mFOLFOX6 plus panitumumab is a potential treatment option in patients with mCRC, achieving similar efficacy while reducing oxaliplatin-associated PN compared with mFOLFOX6 plus panitumumab. TRIAL REGISTRATION NUMBER: NCT02337946.

A nationwide, cross-sectional survey on unusual sleep postures and sleep-disordered breathing-related symptoms in people with Down syndrome.

BACKGROUND: People with Down syndrome (DS) often have sleep-disordered breathing (SDB). Unusual sleep postures, such as leaning forward and sitting, are observed in people with DS. This study aimed to clarify the prevalence of unusual sleep postures and their relationships with SDB-related symptoms (SDB-RSs), such as snoring, witnessed apnoea, nocturnal awakening and excessive daytime sleepiness. METHODS: A questionnaire, including demographic characteristics and the presence of unusual sleep postures, as well as SDB-RSs, was completed by 1149 parents of people with DS from Japan. RESULTS: Unusual sleep postures were recorded in 483 (42.0%) people with DS. These participants were significantly younger and had a history of low muscle tone more frequently than people without unusual sleep postures. In all ages, the leaning forward posture was more frequent than sitting. People with DS with unusual sleep postures suffered from SDB-RSs. Those who slept in the sitting posture had more frequent SDB-RSs than did those who slept with the leaning forward posture. Snoring, witnessed apnoea and nocturnal awakening were observed in 73.6, 27.2 and 58.2% of participants, respectively. Snoring increased with aging. Witnessed apnoea was more common in males and in those with hypothyroidism than in females and in those without hypothyroidism. CONCLUSIONS: Our study shows that there is a close relationship between unusual sleep postures and SDB-RSs. We recommend that all people with DS with unusual sleep postures should be checked for the presence of SDB.

Time-of-Flight MR Angiography for Detection of Cerebral Hyperperfusion Syndrome after Superficial Temporal Artery-Middle Cerebral Artery Anastomosis in Moyamoya Disease.

BACKGROUND AND PURPOSE: Cerebral hyperperfusion syndrome is a potential complication of superficial temporal artery-MCA anastomosis for Moyamoya disease. In this study, we evaluated whether TOF-MRA could assess cerebral hyperperfusion syndrome after superficial temporal artery-MCA anastomosis for this disease. MATERIALS AND METHODS: This retrospective study included patients with Moyamoya disease who underwent superficial temporal artery-MCA single anastomosis. TOF-MRA and SPECT were performed before and 1-6 days after anastomosis. Bilateral ROIs on the source image of TOF-MRA were manually placed directly on the parietal branch of the superficial temporal artery just after branching the frontal branch of the superficial temporal artery and on the contralateral superficial temporal artery on the same axial image, respectively. The change ratio of the maximum signal intensity of the superficial temporal artery on TOF-MRA was calculated by using the following formula: (Postoperative Ipsilateral/Postoperative Contralateral)/(Preoperative Ipsilateral/Preoperative Contralateral). RESULTS: Of 23 patients (26 sides) who underwent the operation, 5 sides showed cerebral hyperperfusion syndrome postoperatively. There was a significant difference in the change ratio of signal intensity on TOF-MRA observed between the cerebral hyperperfusion syndrome and non-cerebral hyperperfusion syndrome groups (cerebral hyperperfusion syndrome group: 1.88 ± 0.32; non-cerebral hyperperfusion syndrome group: 1.03 ± 0.20; P = .0009). The minimum ratio value for the cerebral hyperperfusion syndrome group was 1.63, and the maximum ratio value for the non-cerebral hyperperfusion syndrome group was 1.30. Thus, no overlap was observed between the 2 groups for the change ratio of signal intensity on TOF-MRA. CONCLUSIONS: Diagnosis of cerebral hyperperfusion syndrome is indicated by an increase in the change ratio of signal intensity on TOF-MRA by more than approximately 1.5 times the preoperative levels.

Relationship between cytokine single nucleotide polymorphisms and sarcoidosis among Japanese subjects.

Several susceptibility genes for sarcoidosis have been identified, but their relationship to the clinical state and prognosis remains to be elucidated. The aim of this study was to elucidate the relationship between sarcoidosis and five single nucleotide polymorphisms (SNPs) of three cytokines expected to play an important role in the inflammatory response. A case-control study was performed with 208 unrelated patients who met the diagnostic criteria for sarcoidosis used in Japan since 2006, and 328 control subjects. Five SNPs were analyzed: interleukin (IL)-10-819T/C (rs1800871), IL-10-592A/C(rs1800872), IL-6-634C/G (rs1800796), tumor necrosis factor-alpha (TNF-alpha)-857C/T (rs1799724), and TNF-alpha -1031T/C (rs1799964). No significant differences in SNPs were observed between the total sarcoidosis and control groups. However, the prevalence of rs1800871 and rs1800872 polymorphisms differed significantly in the sarcoidosis with eye involvement group compared with the control group [rs1800871 TT (vs. TC + CC): OR = 1.67, P = 0.034; rs1800872 AA (vs. AC + CC): OR = 1.66, P = 0.036]. Analyzing the cardiac involvement group, the prevalence of the rs1799724 polymorphism was significantly different from that of the control group [rs1799724 TT (vs. CC + CT): OR = 6.01. P = 0.006]. We concluded that the rs1799724 C/T polymorphism may affect susceptibility to cardiac sarcoidosis, while the rs1800871 T/C and rs1800872A/C polymorphisms may affect susceptibility to sarcoidosis with eye involvement.

A case of delayed encephalopathy after carbon monoxide poisoning longitudinally monitored by diffusion tensor imaging.

A woman with DE after CO poisoning was longitudinally evaluated by DTI, performed during the following periods: at the phase of acute CO poisoning, the lucid interval, neurologic deterioration due to DE, and neurologic recovery. The present case revealed the long-term course of DTI parameters after CO poisoning and the usefulness of DTI for quantifying neurologic damage after CO poisoning.

Pain in neuromyelitis optica and its effect on quality of life: a cross-sectional study.

OBJECTIVE: To assess the features of pain and its impact on the health-related quality of life (HRQOL) in neuromyelitis optica (NMO). METHODS: We analyzed 37 patients with NMO or NMO spectrum disorders seen at the Department of Neurology, Tohoku University Hospital, Sendai, Japan, during the period from November 2008 to February 2009. A total of 35 of them were aquaporin-4 antibody-positive. We used Short Form Brief Pain Inventory (BPI) to assess pain and Short Form 36-item (SF-36) health survey to evaluate the HRQOL. Fifty-one patients with multiple sclerosis (MS) were also studied for comparison. RESULTS: Pain in NMO (83.8%) was far more common than in MS (47.1%). The Pain Severity Index score in BPI was significantly higher in NMO than in MS, and patients' daily life assessed by BPI was highly interfered by pain in NMO as compared with MS. Pain involving the trunk and both legs was much more frequent in NMO than in MS. SF-36 scores in NMO were lower than MS, especially in bodily pain. CONCLUSION: Our study showed that pain in NMO is more frequent and severe than in MS and that pain has a grave impact on NMO patients' daily life and HRQOL. Therapy to relieve pain is expected to improve their HRQOL.

[Off-pump coronary artery bypass grafting for single coronary artery; report of a case].

A 55-year-old male with single coronary artery complicated by angina pectoris was referred to our department for coronary artery bypass grafting (CABG) . Coronary arteriography could not identify the left coronary orifice. Right coronary arteriography showed that the circumflex branch (Cx) followed the course of the normal right coronary artery (RCA) , and the left anterior descending branch (LAD) followed the Cx. Other findings included 90% stenosis in #4 posterior descending (PD) of RCA. Off-pump CABG was successfully performed to D1 with the left internal thoracic artery graft and to #4PD with the radial artery graft.

Allogeneic stem cell transplantation in children with acute lymphoblastic leukemia after isolated central nervous system relapse: our experiences and review of the literature.

The prognosis of patients with acute lymphoblastic leukemia (ALL) and central nervous system (CNS) relapse has historically been very poor. Although chemo-radiotherapy has improved outcomes, some patients still have a poor prognosis after CNS relapse. Therefore, allogeneic hematopoietic stem cell transplantation (allo-SCT) has recently become an option for treatment of CNS leukemia; however, information, particularly on the long-term outcome of transplant recipients, is limited. We performed allo-SCT in eight pediatric patients with ALL (n=7) or T-cell type non-Hodgkin's lymphoma (n=1), who had isolated CNS relapse. All patients survived for a median of 70.5 (range, 13-153) months after SCT. Sequelae developed late in some patients: mental retardation (IQ=47) in one patient, severe alopecia in two patients, limited chronic graft-versus-host-disease in three patients, and amenorrhea and/or hypothyroidism in three patients. Except for a pre-school child with post transplant CNS relapse, six out of seven patients show normal school/social performance. Our results clearly indicate a high cure rate of isolated CNS relapse by allo-SCT in pediatric lymphoid malignancies; however, there needs to be further studies to determine which are the appropriate candidates for transplantation and what is the best transplant regimen to achieve high cure rate and maintain good quality of life.

Characterization of lipoxygenase-1 null mutants in barley.

This study describes the discovery and characterization of lipoxygenase-1 (LOX-1) null mutants in barley. Six lines did not exhibit any significant LOX activity in the silenced seed extract. Immunological analysis showed that these lines lacked the authentic LOX-1 protein. Genetic analysis of the F2 population revealed that this trait was governed by a single recessive gene located at the LoxA locus on chromosome 4H. The six LOX-1 null mutants shared similar features and the same unique polymorphism in a structural gene region, implying that these mutants might be derived from the same ancestral origin.

Eradication of hepatocellular carcinoma xenografts by radiolabelled, lipiodol-inducible gene therapy.

The promoter region of the early-growth response-1(Egr-1) gene has been shown to be activated by external radiation, thus making a selective tumoricidal effect possible. A previous experiment showed that the Egr-1 promoter can be activated by internal radiation using radioisotopes as well as external radiation. Internal radiation using I-131 lipiodol (I-131-Lip) has been established as one of the most useful therapeutic strategies against hepatoma. We herein linked the Egr-1 promoter to the herpes simplex virus-thymidine kinase (HSV-TK) gene, and investigated its efficacy in hepatoma gene therapy in combination with I-131-Lip. A luciferase assay showed the Egr-1-promoter activity to be markedly increased in hepatoma tissue specimens in an I-131-dose-dependent manner, whereas a less than two-fold increase in this activity was observed in other organs. In addition, the radioactivity derived from I-131 was selectively accumulated in the tumor tissue specimens. To examine the efficacy of EgrTK/ganciclovir (GCV) gene therapy in vivo, subcutaneous hepatoma xenografts in nude mice were transfected using a hemagglutinating virus of Japan (HVJ)-liposome vector. Complete tumor regression was observed in all the EgrTK-transfected tumors following combination treatment with I-131-Lip and GCV 42 days after treatment without any side effects (n=8). In contrast, the tumors continued to grow in all control mice (n=10). Furthermore, the serum alpha-fetoprotein levels decreased in the combination therapy group, while they increased in the controls. In conclusion, these data indicate that Egr-1 promoter-based gene therapy combined with internal radiation has a selective effect on hepatoma tumors while also showing an improved in vivo efficacy. This combination therapy might, therefore, be an effective human hepatoma gene therapy, even in advanced multiple cases.

Involvement of transforming growth factor-beta and thrombopoietin in the pathogenesis of myelodysplastic syndrome with myelofibrosis.

We investigated the cause of myelofibrosis and proliferation of megakaryocytes in myelodysplastic syndrome with myelofibrosis (MDS-MF (+)). Plasma-transforming growth factor-beta1 (PTGF-beta1) concentrations closely correlated with myelofibrosis grade in MDS-MF (+) and were higher than those in idiopathic myelofibrosis (IMF), essential thrombocythemia (ET), idiopathic thrombocytopenic purpura (ITP), MDS-without MF (MDS-MF (-)) or healthy volunteers (HV). Peripheral blood mononuclear cells from MDS-MF (+) patients expressed more TGF-beta1 mRNA than those from IMF, MDS-MF (-) or HV. When we immunostained bone marrow specimens of MDS-MF (+) for TGF-beta, the intensity of blasts was apparently higher than that of megakaryocytes, while in MDS-MF (-), megakaryocytes were immunostained with a similar intensity as that in MDS-MF (+), but blasts were negative for staining. In IMF, megakaryocytes, monocytes and small mononuclear cells representing CD34+ cells were all similarly stained with a much lower intensity than that of blasts in MDS-MF (+). The number of bone marrow megakaryocytes were increased the most in MDS-MF (+), followed by ET, ITP, MDS-MF (-) and NHL and correlated with plasma thrombopoietin (TPO) levels or with plasma TGF-beta1 levels, respectively, in each disease. Thus, in MDS-MF (+), both myelofibrosis and the increased megakaryocytes were ascribed to overproduction of TGF-beta1 from blasts.