Optimization for fast-scanning irradiation in particle therapy

In three-dimensional irradiation with pencil beam scanning, an extra dose is inevitably delivered to the irradiated site due to the finite reaction times of the beam delivery system, and it causes a severe distortion of the dose distribution in the target region. Since the amount of the extra dose is proportional to the beam intensity, the dose uniformity deteriorates as the beam intensity is increased in order to shorten the treatment time. In order to overcome this problem and shorten the treatment time, we have developed an optimization method in which the extra dose is integrated into the optimization process of the best weighting matrix. The effectiveness and applicability of the optimization method for spot and raster scanning irradiation were confirmed with computer simulations and also confirmed using irradiation experiments for spot scanning irradiation. The treatment time could be shortened to about one sixth of the time needed without taking the extra dose into account while obtaining the same degree of dose homogeneity in the target volume. A typical treatment time with the proposed method is about 15 s for the irradiation of a spherical target with an 80 mm diameter at 3 GyE.     

Distribution pattern of poliovirus potentially infectious materials in the phase 1b medical laboratories containment in conformity with the global action plan III

Background

The containment of poliovirus infectious/potentially infectious materials in all biomedical facilities in Nigeria remain crucial to maintaining gains recorded towards polio eradication. Activities involved in the Nigerian Poliovirus type 2-laboratory containment survey in line with the 3rd Global Action Plan III (GAP III) for poliovirus containment are documented in this study. Through these activities, the overall preparedness for poliovirus eradication in Nigeria is assessed.

Method

A cross-sectional survey was conducted from 19th September-31st October 2016 using structured Laboratory survey and inventory (LSI) questionnaires uploaded onto the SPSS software package in 560 biomedical facilities classified either as high risk or medium risk facilities across the 6 zones in Nigeria.

Results

In total, 560 biomedical facilities were surveyed in Nigeria in conformity with the GAP III. In total, 86% of the facilities surveyed were with laboratories while 14% were without laboratories.Twelve laboratories with poliovirus potentially infectious materials were identified in this exercise. In total, 50% of the 12 laboratories were under the ministry of education for research purposes. While 33% were among those laboratories surveyed in the phase 1a exercise without any recorded inventory, but have acquired some since the phase 1a survey.A total of 13,484 poliovirus infectious materials were found in the 12 laboratories. Only 8% of the materials were immediately destroyed while the remaining materials (62%) were found in Oyo and Borno states scheduled for destruction within 3–4 months according to WHO protocol for destruction of poliovirus infectious materials.

Conclusion

This study has revealed the successful containment of all poliovirus infectious materials in the laboratories surveyed. It has also revealed some surveillance gaps. We recommend that the surveillance system be improved to maintain the gains from the containment exercise and avoid reintroduction of infectious materials into biomedical facilities. This reduces the chances of viral reintroduction to the population in general.

     

Impact of turbulent blood flow in the aortic root on de novo aortic insufficiency during continuous-flow left ventricular-assist device support

Severe aortic insufficiency (AI) after implantation of continuous-flow left ventricular-assist device (LVAD) affects device performance and outcomes. However, the mechanism for the occurrence and progression of AI has not been elucidated. We investigated the impact of nonphysiological retrograde blood flow in the aortic root on AI after LVAD implantation. Blood flow pattern was analyzed in patients with and without AI (n = 3 each) who underwent LVAD implantation, by computational fluid dynamics with patient-specific geometries, which were reproduced using electrocardiogram-gated 320-slice computed tomographic images. The total volume of retrograde blood flow during one cardiac cycle (716 ± 88 mL) was higher and the volume of slow blood flow (<0.1 cm/s) (0.16 ± 0.04 cm³) was lower in patients with AI than in those without AI (360 ± 111 mL, P = .0495, and 0.49 ± 0.08 cm³, P = .0495, respectively). No significant difference in wall shear stress on the aortic valve was observed between the groups. Patients with AI had a perpendicular anastomosis at the distal ascending aorta and the simulation in the modified anastomosis model of patients with AI showed that the retrograde blood flow pattern depended on the angle and position of anastomosis. Computational fluid dynamics revealed strong retrograde blood flow in the ascending aorta and aortic root in patients with AI after LVAD implantation. The angle and position of LVAD outflow anastomosis might impact retrograde blood flow and de novo AI after LVAD implantation.     

Surgical site infection in spinal surgery: a comparative study between 2-octyl-cyanoacrylate and staples for wound closure

Background

Surgical site infection (SSI) after spinal surgery is a devastating complication. Various methods of skin closure are used in spinal surgery, but the optimal skin-closure method remains unclear. A recent report recommended against the use of metal staples for skin closure in orthopedic surgery. 2-Octyl-cyanoacrylate (Dermabond; Ethicon, NJ, USA) has been widely applied for wound closure in various surgeries. In this cohort study, we assessed the rate of SSI in spinal surgery using metal staples and 2-octyl-cyanoacrylate for wound closure.

Methods

This study enrolled 609 consecutive patients undergoing spinal surgery in our hospital. From April 2007 to March 2010 surgical wounds were closed with metal staples (group 1, n = 294). From April 2010 to February 2012 skin closure was performed using 2-octyl-cyanoacrylate (group 2, n = 315). We assessed the rate of SSI using these two different methods of wound closure. Prospective study of the time and cost evaluation of wound closure was performed between two groups.

Results

Patients in the 2-octyl-cyanoacrylate group had more risk factors for SSI than those in the metal-staple group. Nonetheless, eight patients in the metal-staple group compared with none in the 2-octyl-cyanoacrylate group acquired SSIs (p < 0.01). The closure of the wound in length of 10 cm with 2-octyl-cyanoacrylate could save 28 s and $13.5.

Conclusions

This study reveals that in spinal surgery, wound closure using 2-octyl-cyanoacrylate was associated with a lower rate of SSI than wound closure with staples. Moreover, the use of 2-octyl-cyanoacrylate has a more time saving effect and cost-effectiveness than the use of staples in wound closure of 10 cm in length.     

Artemin augments survival and axon regeneration in axotomized retinal ganglion cells

Artemin, a recently discovered member of the glial cell line‐derived neurotrophic factor (GDNF) family, has neurotrophic effects on damaged neurons, including sympathetic neurons, dopamine neurons, and spiral ganglion neurons both in vivo and in vitro. However, its effects on retinal cells and its intracellular signaling remain relatively unexplored. During development, expression of GFRα3, a specific receptor for artemin, is strong in the immature retina and gradually decreases during maturation, suggesting a possible role in the formation of retinal connections. Optic nerve damage in mature rats causes levels of GFRα3 mRNA to increase tenfold in the retina within 3 days. GFRα3 mRNA levels continue to rise within the first week and then decline. Artemin, a specific ligand for GFRα3, has a neuroprotective effect on axotomized retinal ganglion cells (RGCs) in vivo and in vitro via activation of the extracellular signal‐related kinase? and phosphoinositide 3‐kinase?Akt signaling pathways. Artemin also has a substantial effect on axon regeneration in RGCs both in vivo and in vitro, whereas other GDNF family members do not. Therefore, artemin/GFRα3, but not other GDNF family members, may be of value for optic nerve regeneration in mature mammals. © 2014 Wiley Periodicals, Inc.     

Endogenous Fructose Production and Fructokinase Activation Mediate Renal Injury in Diabetic Nephropathy

Diabetes is associated with activation of the polyol pathway, in which glucose is converted to sorbitol by aldose reductase. Previous studies focused on the role of sorbitol in mediating diabetic complications. However, in the proximal tubule, sorbitol can be converted to fructose, which is then metabolized largely by fructokinase, also known as ketohexokinase, leading to ATP depletion, proinflammatory cytokine expression, and oxidative stress. We and others recently identified a potential deleterious role of dietary fructose in the generation of tubulointerstitial injury and the acceleration of CKD. In this study, we investigated the potential role of endogenous fructose production, as opposed to dietary fructose, and its metabolism through fructokinase in the development of diabetic nephropathy. Wild-type mice with streptozotocin-induced diabetes developed proteinuria, reduced GFR, and renal glomerular and proximal tubular injury. Increased renal expression of aldose reductase; elevated levels of renal sorbitol, fructose, and uric acid; and low levels of ATP confirmed activation of the fructokinase pathway. Furthermore, renal expression of inflammatory cytokines with macrophage infiltration was prominent. In contrast, diabetic fructokinase–deficient mice demonstrated significantly less proteinuria, renal dysfunction, renal injury, and inflammation. These studies identify fructokinase as a novel mediator of diabetic nephropathy and document a novel role for endogenous fructose production, or fructoneogenesis, in driving renal disease.Diabetic nephropathy is the most common kidney disease causing ESRD worldwide and also one of the most difficult diseases to treat. To date, treatment includes tight blood glucose and BP control and inhibition of the renin-angiotensin-aldosterone system. These efforts typically slow but do not arrest the progression of kidney disease.¹ It is therefore imperative to better understand the mechanisms responsible for renal injury and to develop additional therapies.Recently, fructose has emerged as a potential nephrotoxin. Fructose-fed rats develop modest tubulointerstitial injury,² and fructose supplementation accelerates renal disease in the remnant kidney model.³ While all studies to date have focused on dietary fructose as the source of fructose, fructose can also be generated from glucose in diabetes because of the activation of the polyol pathway in the proximal tubule. To date, no studies have examined the role of this endogenous fructose production or fructoneogenesis in driving diabetic nephropathy. Therefore, we tested the hypothesis that mice lacking fructokinase-ketohexokinase (khk−/−) show protection from diabetic nephropathy, even in the absence of dietary fructose, as a result of their inability to metabolize endogenously produced fructose.     

Cytoreductive Surgery Under Aminolevulinic Acid-Mediated Photodynamic Diagnosis Plus Hyperthermic Intraperitoneal Chemotherapy in Patients with Peritoneal Carcinomatosis from Ovarian Cancer and Primary Peritoneal Carcinoma: Results of a Phase I Trial

Background

We conducted a phase I clinical trial to evaluate the sensitivity, specificity, and safety of cytoreductive surgery (CRS) under aminolevulinic acid-mediated photodynamic diagnosis (ALA-PDD) plus hyperthermic intraperitoneal chemotherapy (HIPEC) on 20 patients with peritoneal carcinomatosis (PC) from ovarian cancer and primary peritoneal carcinoma (PPC).

Patients and Methods

Patients took 5-aminolevulinic acid (5-ALA) at a dose of 20 mg/kg orally with 50 mL of water 2 h before surgery. During surgery, the abdominal cavity was observed under blue light (wavelength of 440 nm) before and after CRS plus HIPEC. Specimens were excised and submitted for pathological examination to evaluate the specificity of ALA-PDD. Postoperative course was closely monitored and detailed information was recorded.

Results

CRS under ALA-PDD plus HIPEC was performed 21 times in 20 patients with PC (16 ovarian cancer, 4 PPC) between June 2011 and October 2013. With the exception of 1 (5 %) patient, strong red fluorescence was detected in 19 patients with ovarian cancer, with a sensitivity of 95 %. All specimens from red fluorescent lesions were invaded by cancer cells, with a specificity of 100 %. No severe adverse events occurred during the perioperative period, with the exception of some abnormal laboratory results and mild complications. All patients were alive until the last follow-up.

Conclusion

ALA-PDD provided a high sensitivity and specificity in detecting peritoneal metastasis in patients with PC from ovarian serous carcinoma and PPC. CRS under ALA-PDD plus HIPEC was a feasible and safe treatment option for patients with PC from ovarian cancer and PPC.     

CD147/basigin reflects renal dysfunction in patients with acute kidney injury

Background

Acute tubular necrosis (ATN) describes a form of intrinsic acute kidney injury (AKI) that results from persistent hypoperfusion and subsequent activation of the immune system. A glycosylated transmembrane protein, CD147/basigin, is involved in the pathogenesis of renal ischemia and fibrosis. The present study investigated whether CD147 can reflect pathological features and renal dysfunction in patients with AKI.

Methods

Plasma and spot urine samples were collected from 24 patients (12 controls and 12 with ATN) who underwent renal biopsy between 2008 and 2012. In another study, patients undergoing open surgery to treat abdominal aortic aneurysms (AAAs) were enrolled in 2004. We collected urine and plasma samples from seven patients with AKI and 33 patients without AKI, respectively. In these experiments, plasma and urinary CD147, and urinary l-fatty acid-binding protein (l-FABP) levels were measured, and the former expression in kidneys was examined by immunostaining.

Results

In biopsy tissues of ATN with severe histological features, CD147 induction was strikingly present in inflammatory cells such as macrophages and lymphocytes in the injured interstitium, but not in damaged tubules representing atrophy. Both plasma and urinary CD147 levels were strikingly increased in ATN patients; both values showed greater correlations with renal dysfunction compared to urinary l-FABP. In patients who had undergone open AAA surgery, urinary and plasma CD147 values in AKI patients were significantly higher than in non-AKI patients at post-operative day 1, similar to the profile of urinary l-FABP.

Conclusion

CD147 was prominent in its ability to detect AKI and may allow the start of preemptive medication.     

Regorafenib in Japanese patients with solid tumors: phase I study of safety,efficacy, and pharmacokinetics

The safety, pharmacokinetics, and antitumor activity of the multikinase inhibitor regorafenib in Japanese patients was assessed in this multicenter, single-arm, phase I trial. Fifteen patients with treatment-refractory advanced solid tumors received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle until disease progression, unacceptable toxicity, or investigator or patient decision to stop. The median duration of treatment was 2.1 months (range, 0.9–20.1 months). At data cutoff, one patient was still receiving regorafenib in cycle 21. Reasons for treatment discontinuation were disease progression (n?=?12) and adverse events (liver enzyme elevation n?=?1; anemia n?=?1). Adverse events necessitated dose reduction in six patients, interruption of daily treatment in seven patients, and cycle delay in four patients. All patients experienced at least one drug-related adverse event, particularly gastrointestinal (87 %), dermatologic (73 %), or hematologic (67 %) events. There was no significant change in time to maximum concentration or terminal half-life of regorafenib and its active metabolites M2 and M5 between single dosing and 21-day continuous dosing. The area under the concentration–time curve was 2.1-fold higher for regorafenib, 5.2-fold higher for M2, and 37.3-fold higher for M5, and the maximum concentration was 2.0-fold, 4.8-fold, and 36.0-fold higher, respectively, after continuous dosing than after single dosing. One patient had a partial response (duration 10.5 months) and seven patients had stable disease. This study indicates that regorafenib 160 mg orally once daily (21 days on/7 days off treatment) can be given to Japanese patients who have solid tumors, without undue toxicity.