Prognostic and predictive values of tumour budding in stage IV colorectal cancer.

BACKGROUND: Tumour budding is an important prognostic feature in early-stage colorectal cancer, but its prognostic significance in metastatic disease has not been fully investigated. METHODS: Patients with stage IV disease who had primary colorectal tumour resection without previous chemotherapy or radiotherapy from January 2000 to December 2018 were reviewed retrospectively. Budding was evaluated at the primary site and graded according to the criteria of the International Tumor Budding Consensus Conference (ITBCC) (BD1, low; BD2, intermediate; BD3, high). Patients were categorized by metastatic (M1a, M1b) and resectional (R0/R1, R2/unresected) status. Subgroups were compared for overall (OS) and recurrence-free (RFS) survival in R0/R1 subgroups; R2/unresected patients were evaluated for the rate of tumour progression, based on change in tumour size from baseline. RESULTS: Of 371 patients observed during the study, 362 were analysed. Patients with BD3 had a lower 5-year OS rate than those with BD1 + BD2 (18·4 versus 40·5 per cent; P < 0·001). Survival analyses according to metastatic and resection status also showed that BD3 was associated with shorter OS than BD1 + BD2. In multivariable analysis, BD3 (hazard ratio (HR) 1·51, 95 per cent c.i. 1·11 to 2·10; P = 0·009), T4 status (HR 1·39) and R2/unresected status (HR 3·50) were associated with decreased OS. In the R0/R1 subgroup, the 2-year RFS rate was similar for BD3 and BD1 + BD2 according to metastatic status. There was no significant difference between BD3 and BD1 + BD2 for change in tumour size in the R2/unresected subgroup (P = 0·094). Of 141 patients with initially unresectable metastases who had chemotherapy, 35 achieved conversion from unresectable to resectable status. The conversion rate was significantly higher for BD1 + BD2 than for BD3 (36 versus 18 per cent; P = 0·016). CONCLUSION: Stage IV colorectal cancer with high-grade tumour budding according to ITBCC criteria correlates with poor prognosis.

ANTECEDENTES: La esofaguectomía por cáncer se asocia con un descenso de la calidad de vida relacionada con la salud (health-related quality of life, HRQoL) a largo plazo. El objetivo de este estudio fue evaluar el efecto de las comorbilidades sobre la HRQOL entre pacientes supervivientes de cánceres de esófago o de la unión gastroesofágicas después de 10 años o más. MÉTODOS: Este estudio incluye una cohorte de base poblacional recogida de forma prospectiva que incluía todos los pacientes operados de cáncer de esófago o de la unión gastroesofágica en Suecia en 2001-2005 con seguimiento hasta el 31 de diciembre de 2016. Todos los datos relacionados con las características de los pacientes y del tumor, detalles del tratamiento y HRQoL se recogieron en una base de datos prospectiva. Se utilizaron modelos de regresión multivariable ANCOVA, ajustados por edad, sexo, histología del tumor, estadio, y técnica quirúrgica, para calcular las puntuaciones medias ajustadas con los i.c. del 95% para todas las variables de la HRQoL. RESULTADOS: Un total de 92 (88%) supervivientes respondieron a los cuestionarios. En función del impacto de las comorbilidades en la salud en general, se clasificaron a los pacientes en los grupos de bajo versus alto impacto. Los resultados muestran que los pacientes en el grupo de alto impacto presentaban un descenso clínicamente significativo de la HRQoL y un aumento en el nivel de síntomas, pero las diferencias entre estos dos grupos no fueron estadísticamente significativas. CONCLUSIÓN: A los 10 años de la esofaguectomía por cáncer, las comorbilidades con un alto impacto sobre la salud general siguen contribuyendo en el deterioro de la HRQoL.

Analysis of electron energy distribution function in the Linac4 H⁻ source.

To understand the Electron Energy Distribution Function (EEDF) in the Radio Frequency Inductively Coupled Plasmas (RF-ICPs) in hydrogen negative ion sources, the detailed analysis of the EEDFs using numerical simulation and the theoretical approach based on Boltzmann equation has been performed. It is shown that the EEDF of RF-ICPs consists of two parts, one is the low energy part which obeys Maxwellian distribution and the other is high energy part deviated from Maxwellian distribution. These simulation results have been confirmed to be reasonable by the analytical approach. The results suggest that it is possible to enhance the dissociation of molecules and the resultant H(-) negative ion production by reducing the gas pressure.

Numerical study of plasma generation process and internal antenna heat loadings in J-PARC RF negative ion source.

A numerical model of plasma transport and electromagnetic field in the J-PARC (Japan Proton Accelerator Research Complex) radio frequency ion source has been developed to understand the relation between antenna coil heat loadings and plasma production/transport processes. From the calculation, the local plasma density increase is observed in the region close to the antenna coil. Electrons are magnetized by the magnetic field line with absolute magnetic flux density 30-120 Gauss which leads to high local ionization rate. The results suggest that modification of magnetic configuration can be made to reduce plasma heat flux onto the antenna.

Permanent acceptance of mouse cardiac allografts with CD40 siRNA to induce regulatory myeloid cells by use of a novel polysaccharide siRNA delivery system.

The CD40/CD154 co-stimulatory pathway is crucial in alloimmune response. We developed a novel small interfering RNA (siRNA) delivery system with a poly-dA extension at the 5'-end of the siRNA sense strand that was stably incorporated into 1,3-ß-glucan (schizophyllan, SPG). This was captured and incorporated into dendritic cells (DCs) through its receptor, Dectin-1, specifically silencing CD40 genes (siCD40) to exert immunoregulatory activity. siCD40/SPG-treated CBA mice permanently accepted B10 fully mismatched cardiac allografts. Consistent with graft survival, the infiltration of CD4(+), CD8(+) T cells into the graft was lower, and that the numbers of CD40(low)CD11c(+) DCs cells and CD4(+)Foxp3(+)cells were increased in both the graft and in the recipient spleen. In addition, naive CBA recipients given an adoptive transfer of splenocytes from the primary recipients with siCD40/SPG accepted a heart graft from donor-type B10, but not third-party Balb/c mice. In conclusion, the treatment with siCD40/SPG targeting DCs could generate antigen-specific Tregs, resulting in the permanent acceptance of mouse cardiac allografts. These findings have important implications for clarifying the mechanism underlying the induction of tolerance in DCs, and also highlight the potential of immunomodulation and the feasibility of siRNA-based clinical therapy in the transplantation field.

Equivalent circuit of radio frequency-plasma with the transformer model.

LINAC4 H(-) source is radio frequency (RF) driven type source. In the RF system, it is required to match the load impedance, which includes H(-) source, to that of final amplifier. We model RF plasma inside the H(-) source as circuit elements using transformer model so that characteristics of the load impedance become calculable. It has been shown that the modeling based on the transformer model works well to predict the resistance and inductance of the plasma.

Impact of sex incompatibility on the outcome of single-unit cord blood transplantation for adult patients with hematological malignancies.

Donor-recipient sex incompatibility has been associated with transplant outcomes in allogeneic hematopoietic SCT. Such outcomes might be because mHA encoded by Y chromosome genes could be immunological targets for allogeneic T cells and B cells to induce GVHD, GVL effect and graft failure. However, its effect on the outcome of cord blood transplantation (CBT) is yet to be clarified. We retrospectively analyzed 191 adult patients who received single-unit CBT after myeloablative conditioning for malignant disease in our institute. In multivariate analysis, male recipients with female donors had a higher incidence of extensive chronic GVHD (hazard ratio (HR) 2.97, P=0.02), and female recipients with male donors had a lower incidence of platelet engraftment (HR 0.56, P=0.02) compared with female recipients with female donors as the reference. Nevertheless, there was no increase in mortality following sex-incompatible CBT. These data suggested that donor-recipient sex compatibility does not have a significant impact on survival after myeloablative CBT for hematological malignancies.

Analysis of induced radionuclides in replacement parts and liquid wastes in a medical cyclotron solely used for production of 18F for [18F]FDG.

Radioactivities produced in replacement parts and liquid wastes in a medical cyclotron used to produce (18)F for [(18)F]FDG with 10MeV protons were analyzed. Nineteen radionuclides were found in the replacement parts and liquid wastes. Among them, long-lived (56)Co in the Havar foils is critical in terms of radioactive waste management. The estimated dose level of exposure for the operating staff during the replacement of parts was around 310µSv/y, which is smaller than the recommended dose limit for workers.

Hepatocytes produce tumor necrosis factor-α and interleukin-6 in response to Porphyromonas gingivalis.

BACKGROUND AND OBJECTIVE: The liver plays a major role in clearing systemic bacterial infections. In addition, inflammatory cytokines produced in the liver play a critical role in systemic cytokine levels. The aim of this study was to investigate the production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) by hepatocytes in response to periodontal pathogens. MATERIAL AND METHODS: The mouse hepatic carcinoma cell line Hepa-1.6 and the mouse macrophage-like cell line RAW 264 were co-cultured in Transwell insert plates. Cells were stimulated with bacterial extracts prepared from Porphyromonas gingivalis and the induction of TNF-α and IL-6 was measured using real-time PCR and ELISA. RESULTS: After stimulation with bacteria, the induction of TNF-α and IL-6 was observed in RAW 264 cells and Hepa-1.6 cells. Significant reduction of TNF-α mRNA expression in Hepa-1.6 cells was observed after treatment with antibody to TNF-α. CONCLUSION: The results obtained in the present study show that P. gingivalis extract induces TNF-α and IL-6 in an in vitro liver model and that macrophage-derived TNF-α mediates the induction of TNF-α in hepatocytes.

Host-derived MMP-13 exhibits a protective role in lung metastasis of melanoma cells by local endostatin production.

BACKGROUND: Although matrix metalloproteinases (MMPs) are implicated in tumourigenesis and cancer progression, the role of MMP-13 in melanoma cell metastases is poorly understood. METHODS: Lung metastases of mouse melanoma B16BL6 cells were analysed in MMP-13 knockout (KO) and wild-type (WT) mice after intravenous injection. The mRNA and protein expression of MMP-13 in lung tissues was analysed by RT-PCR, real-time PCR, immunoblotting and immunohistochemistry. The expression of SDF-1α, CXCR4 and endostatin, and effects of endostatin to cultured melanoma cells and lung metastases were also studied. RESULTS: Lung metastases of B16BL6 cells were significantly higher by 2.5-5.7-fold in MMP-13 KO mice than in WT mice. The expression of MMP-13 in WT mouse lung tissue was stimulated on day 1 after intravenous injection of the melanoma cells and MMP-13 was immunolocalised to vascular endothelial cells in the lungs. Endostatin formation, but not degradation of SDF-1α, in the lung tissue was associated with reduced lung metastasis in WT mice. Endostatin significantly inhibited migration of B16BL6 cells in monolayer wounding assay and remarkably suppressed Matrigel invasion and transendothelial invasion of the cells. In addition, lung metastases of melanoma cells in MMP-13 KO mice were reduced by intraperitoneal administration of endostatin. CONCLUSION: Our results suggest that MMP-13 is overproduced by endothelial cells in the lungs with melanoma cells and has a protective role in lung metastasis by local generation of endostatin.

Structural design of a newly developed pediatric circulatory assist device for Fontan circulation by using shape memory alloy fiber.

Total cavopulmonary connection (TCPC) is commonly applied for the surgical treatment of congenital heart disease such as single ventricle in pediatric patients. Patients with no ventricle in pulmonary circulation are treated along with Fontan algorithm, in which the systemic venous return is diverted directly to the pulmonary artery without passing through subpulmonary ventricle. In order to promote the pulmonary circulation after Fontan procedure, we developed a newly designed pulmonary circulatory assist device by using shape memory alloy fibers. We developed a pulmonary circulatory assist device as a non-blood contacting mechanical support system in pediatric patients with TCPC. The device has been designed to be installed like a cuff around the ePTFE TCPC conduit, which can contract from outside. We employed a covalent type functional anisotropic shape memory alloy fiber (Biometal, Toki Corporation, Tokyo Japan) as a servo actuator of the pulmonary circulatory assist device. The diameter of this fiber was 100 microns, and its contractile frequency was 2-3 Hz. Heat generation with electric current contracts these fibers and the conduit. The maximum contraction ratio of this fiber is about 7% in length. In order to extend its contractile ratio, we fabricated and installed mechanical structural units to control the length of fibers. In this study, we examined basic contractile functions of the device in the mock system. As a result, the internal pressure of the conduit increased to 63 mmHg by the mechanical contraction under the condition of 400 msec-current supply in the mock examination with the overflow tank of 10 mmHg loading.

[Antibiotic-resistant infectious thoracoabdominal aortic aneurysm; report of a case].

A 76-year-old female presented with constipation and anorexia Computed tomography (CT) revealed a saccular aneurysm (35 mm in diameter) directly over the root of the celiac artery, and she was referred to our department and was admitted. Klebsiella pneumoniae was detected in blood culture. Although antibiotics were administered, the inflammatory response was not improved. On day 8 after hospitalization, CT revealed the aneurysm increased. Therefore, surgery was performed. Aneurysm was observed adjacent to the celiac artery. The excised aorta included the descending thoracic aorta and the superior mesenteric artery, and was replaced with a rifampicin-soaked Vasctec Gelweave 24 mm vascular graft with branches. After hemostasis, omental implantation was performed around the vascular graft. Before surgery, sufficient antibiotics administration is desirable to bring the infection under control. However, if infection is uncontrollable with progressive enlargement of the aneurysm, as in this case, surgery is unavoidable. A combination of treatments was successful.

Hyaluronan inhibits expression of ADAMTS4 (aggrecanase-1) in human osteoarthritic chondrocytes.

BACKGROUND: Intra-articular injection of hyaluronan (HA) has been suggested to have a disease-modifying effect in osteoarthritis, but little is known about the possible mechanisms. OBJECTIVE: To investigate the effects of HA species of different molecular mass, including 800 kDa (HA800) and 2700 kDa (HA2700), on the expression of aggrecanases (ie, ADAMTS species), which play a key role in aggrecan degradation. METHODS: The effects of HA species on the expression of ADAMTS1, 4, 5, 8, 9 and 15 in interleukin 1alpha (IL1alpha)-stimulated osteoarthritic chondrocytes were studied by reverse transcription PCR and real-time PCR. Expression of ADAMTS4 protein and aggrecanase activity and signal transduction pathways of IL1, CD44 and intracellular adhesion molecule 1 (ICAM1) were examined by immunoblotting. RESULTS: IL1alpha treatment of chondrocytes induced ADAMTS4, and HA800 and HA2700 significantly decreased IL1alpha-induced expression of ADAMTS4 mRNA and protein. IL1alpha-stimulated aggrecanase activity in osteoarthritic chondrocytes was reduced by treatment with HA2700 or transfection of small interfering RNA for ADAMTS4. A similar result was obtained when HA2700 was added to explant cultures of osteoarthritic cartilage. HA2700 neither directly inhibited nor bound to ADAMTS4. Downregulation of ADAMTS4 expression by HA2700 was attenuated by treatment of IL1alpha-treated chondrocytes with antibodies to CD44 and/or ICAM1. The increased phosphorylation of IL1 receptor-associated kinase-1 and extracellular signal-regulated protein kinase1/2 induced by the IL1alpha treatment was downregulated by enhanced IRAK-M expression after HA2700 treatment. CONCLUSION: These data suggest that HA2700 suppresses aggrecan degradation by downregulating IL1alpha-induced ADAMTS4 expression through the CD44 and ICAM1 signalling pathways in osteoarthritic chondrocytes.

[Total aortic arch replacement for ruptured aortic arch aneurysm in a 93-year-old woman].

Semi-emergency total aortic arch replacement was performed in a 93-year-old woman with rupture of a true saccular aneurysm at the distal aortic arch. The patient had lived by herself before surgery. She was successfully treated and showed no post-operative cerebral complications. Total aortic arch replacement must be carefully planned, because this surgery is highly invasive and is associated with a high rate of complications. This surgery is sometimes inevitably performed as a life-saving procedure in very old patients. The surgical outcome however, is less favorable. Although we used the "Eaves" technique during surgery to decrease post-operative bleeding, the surgical invasiveness itself was not reduced. Further effort is needed to develop innovative procedures.

Plasma brain natriuretic peptide concentrations in patients undergoing pulmonary vein isolation.

OBJECTIVE: To examine whether raised plasma brain natriuretic peptide (BNP) concentrations decrease after successful pulmonary vein isolation (PVI) in patients with atrial fibrillation (AF). METHODS: 53 patients (mean age 53 years) with drug-refractory, paroxysmal lone AF underwent segmental ostial PVI. Blood samples were collected before and after PVI. BNP concentrations were determined by immunoassays. RESULTS: Median plasma BNP concentrations were significantly higher in patients with lone AF than in controls (patients with supraventricular tachyarrhythmias, n = 21) (64.6 (71.9) v 13.9 (7.8) pg/ml, p < 0.01). AF recurred in 21 patients after the initial PVI procedure (recurrent AF group), and the others were free from AF without antiarrhythmic drugs (non-recurrent AF group). BNP concentrations were significantly decreased by PVI in the non-recurrent AF group (38.9 (39.1) to 18.3 (16.1) pg/ml, p < 0.01) but not in the recurrent AF group. CONCLUSIONS: Raised plasma BNP concentrations decreased after successful segmental ostial PVI in patients with AF.

Increased AAI mode pacing threshold after termination of atrial fibrillation by acute administration of disopyramide phosphate.

AIMS: We studied changes in atrial pacing threshold after termination of atrial fibrillation (AF) by acute administration of disopyramide phosphate (DP) to elucidate the suitable setting for atrial pacing output before AF termination. METHODS AND RESULTS: Four patients with sick sinus syndrome implanted with AAI mode pacemakers were examined. Disopyramide phosphate (2 mg/kg body weight) was injected intravenously for termination of a total of eight AF episodes. The maximal pacing threshold after AF termination (5.2+/-0.8 V at 0.45 ms) was significantly higher than that at baseline (1.3+/-0.2 V at 0.45 ms; P<0.01) and the average increment was 433+/-68%. During a period free from AF, an acute administration of DP did not increase the atrial pacing threshold and serum disopyramide levels were not toxic. CONCLUSION: The increased atrial pacing threshold observed after AF termination cannot be explained by the action of DP alone. However, our results suggest that atrial pacing output should be set at the maximum value before DP is administered to induce AF termination in patients with AAI pacemaker-dependent bradyarrhythmias.

Interferon-gamma inhibits collagen phagocytosis in human fibroblasts by inducing subcortical actin assembly and reducing ability of beta1 integrin to bind to collagen.

OBJECTIVE: We investigated the possible roles of interferon-gamma (IFN-gamma) in modulation of extracellular and intracellular routes of collagen digestion by human fibroblasts. METHODS: Human gingival fibroblasts were treated with IFN-gamma, after which matrix metalloproteinase-1 (MMP-1) activation was determined. Following the IFN-gamma treatment, cells were further incubated with either activating antibody for beta1 integrin or actin monomer-sequestering agent latrunculin B before incubation with collagen-coated fluorescent beads. Thereafter, the binding and internalization of the beads were assessed. RESULTS: IFN-gamma had no significant effect on MMP-1 activation, however, it reduced the binding of collagen-coated beads in the minimum affinity range and, subsequently, internalization of the beads. The inhibitory effects of IFN-gamma were partially reversed by adding either the beta1 integrin activating antibody or latrunculin B. CONCLUSIONS: Although IFN-gamma does not appreciably moderate the extracellular route of collagen digestion by human fibroblasts, the reduced level of collagen phagocytosis by IFN-gamma in the cells may contribute to fibrosis in inflamed connective tissues. Further, IFN-gamma may decrease the binding of collagen and following phagocytosis in cells by inducing a subcortical actin assembly and reducing the ability of beta1 integrin to bind to collagen.

Direct measurement of nitric oxide during experimental cardiopulmonary bypass.

We developed a system to measure nitric oxide (NO) concentration during cardiopulmonary bypass in anaesthetized pigs (n = 6). A T-shaped connector, attached to an NO sensor, was mounted in the extracorporeal circuit at two measuring sites: proximal to the membrane oxygenator (venous side) and distal to the arterial line filter (arterial side). After performing a preliminary validation study, we measured plasma NO concentration before and during total cardiopulmonary bypass circulation (non-pulsatile flow 1.5 l/min) and without pulmonary ventilation. After establishing bypass, PaO2 was 318 - 393 mmHg; when PaO2 was decreased to 80 - 100 mmHg, plasma NO concentration in the arterial circuit fell by 39.2 +/- 15.6 nM. There was no observable change in plasma NO concentration at the venous circuit. This new system could be useful in monitoring NO concentration during cardiac surgery with cardiopulmonary bypass, and for understanding the possible pathophysiological roles of hyper-nitric oxaemia in cardiopulmonary bypass-related cardiovascular complications.

Enzyme replacement therapy in Japanese Fabry disease patients: the results of a phase 2 bridging study.

Fabry Disease (alpha-galactosidase A deficiency) is an X-linked hereditary disorder leading to the pathological accumulation of globotriaosylceramide (GL-3) in lysosomes, particularly in the vascular endothelium of the kidney, heart and brain. We report the results of an open-label phase 2 study that was undertaken to evaluate whether ethnic differences exist that would affect agalsidase beta (Fabrazyme) treatment of Fabry patients in the Japanese population, relative to safety and efficacy. The study design mirrored the design of the completed phase 3 clinical trial that led to approval of the product agalsidase beta. The 13 Japanese, male Fabry patients enrolled in the study received the enzyme replacement therapy over a period of 20 weeks as biweekly infusions. All selected efficacy end points showed improvements that were comparable with findings from the phase 3 study. These improvements included reductions of GL-3 accumulation in both kidney and skin capillary endothelial cells to (near) normal levels (92% of patients). Kidney and plasma GL-3 levels decreased by 51.9% and 100%, respectively, by ELISA. Renal function remained normal. Fabry-associated pain, and quality of life, showed improvement over baseline in multiple categories. Related adverse events were mild or moderate in intensity and mostly infusion-associated (fever and rigors). As expected, IgG antibody formation was observed in 85% of the patients, but had no effect on treatment response. These results suggest that treatment with agalsidase beta is safe and effective in Japanese patients with Fabry disease. With regard to safety and efficacy, no differences were observed as compared to the caucasian population.