Role of tumour location and surgical extent on prognosis in T2 gallbladder cancer: an international multicentre study.

BACKGROUND: In gallbladder cancer, stage T2 is subdivided by tumour location into lesions on the peritoneal side (T2a) or hepatic side (T2b). For tumours on the peritoneal side (T2a), it has been suggested that liver resection may be omitted without compromising the prognosis. However, data to validate this argument are lacking. This study aimed to investigate the prognostic value of tumour location in T2 gallbladder cancer, and to clarify the adequate extent of surgical resection. METHODS: Clinical data from patients who underwent surgery for gallbladder cancer were collected from 14 hospitals in Korea, Japan, Chile and the USA. Survival and risk factor analyses were conducted. RESULTS: Data from 937 patients were available for evaluation. The overall 5-year disease-free survival rate was 70·6 per cent, 74·5 per cent for those with T2a and 65·5 per cent among those with T2b tumours (P = 0·028). Regarding liver resection, extended cholecystectomy was associated with a better 5-year disease-free survival rate than simple cholecystectomy (73·0 versus 61·5 per cent; P = 0·012). The 5-year disease-free survival rate was marginally better for extended than simple cholecystectomy in both T2a (76·5 versus 66·1 per cent; P = 0·094) and T2b (68·2 versus 56·2 per cent; P = 0·084) disease. Five-year disease-free survival rates were similar for extended cholecystectomies including liver wedge resection versus segment IVb/V segmentectomy (74·1 versus 71·5 per cent; P = 0·720). In multivariable analysis, independent risk factors for recurrence were presence of symptoms (hazard ratio (HR) 1·52; P = 0·002), R1 resection (HR 1·96; P = 0·004) and N1/N2 status (N1: HR 3·40, P < 0·001; N2: HR 9·56, P < 0·001). Among recurrences, 70·8 per cent were metastatic. CONCLUSION: Tumour location was not an independent prognostic factor in T2 gallbladder cancer. Extended cholecystectomy was marginally superior to simple cholecystectomy. A radical operation should include liver resection and adequate node dissection.

ANTECEDENTES: En el cáncer de vesícula biliar, la ubicación del tumor subdivide el estadio T2 en tumores con invasión del lado peritoneal y del lado del hígado (T2a y T2b). Para los tumores que invaden el lado peritoneal (T2a) se sugiere que se puede obviar la resección hepática sin que ello comprometa el pronóstico. Sin embargo, este argumento no ha sido validado. El estudio tuvo como objetivo investigar el valor pronóstico de la localización del tumor en el cáncer de vesícula biliar T2 y establecer la extensión adecuada de la resección quirúrgica. MÉTODOS: Se recogieron los datos clínicos de pacientes que se sometieron a cirugía por cáncer de vesícula biliar en 14 hospitales de Corea, Japón, Chile y Estados Unidos. Se realizaron análisis de la supervivencia y de los factores de riesgo. RESULTADOS: Se dispuso de datos de 937 pacientes para ser evaluados. La tasa de supervivencia global libre de enfermedad a los 5 años fue del 70,6%, y las de T2a y T2b del 74,5% y 65,5% (P = 0,028). Con respecto a la resección hepática, la colecistectomía extendida presentó una tasa mejor de supervivencia libre de enfermedad a los 5 años que la colecistectomía simple (73,0% versus 61,5%, P = 0,012). La tasa de supervivencia libre de enfermedad a los 5 años fue marginalmente mejor para la colecistectomía extendida que para la colecistectomía simple tanto en T2a (76,5% versus 66,1%, P = 0,094) como en T2b (68,2% versus 56,2%, P = 0,084). Las tasas de supervivencia libre de enfermedad a los 5 años no fueron diferentes entre la resección hepática en cuña y la segmentectomía S4b+S5 (74,1% versus 71,5%, P = 0,720). En el análisis multivariable, los factores de riesgo independientes para la recidiva fueron la presencia de síntomas (cociente de riesgos instantáneos, hazard ratio, HR 1,52, P = 0,002), la resección R1 (HR 1,96, P = 0,004) y el estadio N1/N2 (N1 HR 3,40, P < 0,001; N2 HR 9,56, P < 0,001). El 70,8% de las recidivas eran metastásicas. CONCLUSIÓN: La localización del tumor no fue un factor pronóstico independiente en el cáncer de vesícula biliar T2. La colecistectomía extendida fue marginalmente superior que la colecistectomía simple. La cirugía radical debe incluir una resección hepática y una linfadenectomía adecuada.

Effect of hypothermia treatment on gentamicin pharmacokinetics in neonates with hypoxic-ischaemic encephalopathy: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Hypothermia is the current standard therapy for asphyxiated neonates with hypoxic-ischaemic encephalopathy (HIE). Gentamicin is used for the empirical treatment of early-onset neonatal sepsis. We investigated the influence of hypothermia treatment on gentamicin pharmacokinetics and suggested the appropriate dosing recommendations for gentamicin in neonates with HIE receiving hypothermia treatment. METHODS: We searched studies published until February 2017 in MEDLINE using PubMed, EMBASE and the Cochrane Library. Three independent reviewers screened the literature and extracted data from each study. All of the studies that reported the blood concentrations or pharmacokinetic parameters of gentamicin in hypothermic neonates with HIE were included in this review. Articles were excluded if they were not original research. RESULT AND DISCUSSION: A total of 8 observational studies met the inclusion criteria. Meta-analyses were performed in which the mean difference of gentamicin for the trough concentration and clearance between hypothermic and normothermic neonates were 0.81 mg/L (95% confidence interval [-0.07, 1.69]) and -0.21 mL/kg/min (95% confidence interval [-0.31, -0.12]), respectively. The factors affecting gentamicin clearance in hypothermic neonates with HIE were gestational age, birthweight and serum creatinine. WHAT IS NEW AND CONCLUSION: Gentamicin clearance is decreased in neonates with HIE receiving hypothermia treatment compared to those not receiving hypothermia treatment. Modified gentamicin dosing regimens are required to avoid potential toxicity related to higher concentrations during hypothermia treatment.

Surgical treatment of solid pseudopapillary neoplasms of the pancreas and risk factors for malignancy.

BACKGROUND: The aim of this study was to identify clinical predictors of malignancy and surgical strategies for pancreatic solid pseudopapillary neoplasm (SPN) by analysis of surgical outcomes at a single institution. METHODS: All patients who underwent surgery for SPN between 1995 and 2010 were identified. Histopathology slides of all patients were reviewed by a specialized pathologist and the neoplasms were classified according to the criteria of the World Health Organization 2010. RESULTS: Of the 106 patients identified, 85 (80·2 per cent) were female, and the median age was 36 (range 10-65) years. Median tumour size was 4·5 (range 1·0-15·0) cm. Some 17 patients (16·0 per cent) were classified as having a high-grade malignant SPN. Tumour size of at least 5 cm was associated with high-grade malignant potential (P = 0·022). Although lymph nodes were removed from 40 patients (37·7 per cent), there were no nodal metastases. A total of five patients underwent en bloc resection of adjacent structures, including two with portal vein involvement. After a median follow-up of 56·9 months, two patients with high-grade malignant SPN had evidence of tumour recurrence in the lymph nodes and liver. CONCLUSION: SPN with a diameter of 5 cm or more is associated with a high-grade malignant phenotype. Complete surgical removal is associated with low recurrence rates.

Surgical strategies for non-functioning pancreatic neuroendocrine tumours.

BACKGROUND: The purpose of this study was to identify management strategies for non-functioning pancreatic neuroendocrine tumours (NF-PNETs) by analysis of surgical outcomes at a single institution. METHODS: Archived records of patients with NF-PNETs who underwent surgery between 1994 and 2010 were reviewed. RESULTS: Among 125 patients, the median tumour size was 2·5 (range 0·15-20·5) cm. Of the 51 NF-PNETs with a diameter of no more than 2 cm, 12 (24 per cent) were diagnosed as carcinoma. Overall 20 patients (16·0 per cent) had metastases to the lymph nodes. The minimum size of the tumour with lymph node metastasis was 1·2 cm. Having a NF-PNET of 2 cm or larger significantly increased the probability of a poorly differentiated carcinoma (P = 0·006), and having a NF-PNET of at least 2·5 cm significantly increased the probability of lymph node metastasis (P = 0·048). The 5-year cumulative survival rate after curative resection was 89·7 per cent. During a median follow-up of 31·5 months, there were 27 recurrences (23·1 per cent) and 13 disease-specific deaths (11·1 per cent) among the 117 patients who had an R0 resection. All patients who underwent repeat operations were alive without additional recurrence after a mean(s.d.) follow-up of 27·1(18·0) months. CONCLUSION: Curative surgery should be performed for control of primary NF-PNETs. Lymph node dissection for NF-PNETs of 2·5 cm or larger and at least node sampling for tumours with a diameter of 1 cm or more are recommended. Debulking surgery should be considered for advanced tumours.

Ion homeostasis and apoptosis.

Alterations in the transmembrane gradients of several physiological ions may influence programmed cell death. In particular, recent data suggest that increases in intracellular calcium may either promote or inhibit apoptosis, depending on the level, timing and location, whereas loss of intracellular potassium promotes apoptosis.

Oligodendrocytes from forebrain are highly vulnerable to AMPA/kainate receptor-mediated excitotoxicity.

Little is known of the molecular mechanisms that trigger oligodendrocyte death and demyelination in many acute central nervous system insults. Since oligodendrocytes express functional alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate-type glutamate receptors, we examined the possibility that oligodendrocyte death can be mediated by glutamate receptor overactivation. Oligodendrocytes in primary cultures from mouse forebrain were selectively killed by low concentrations of AMPA, kainate or glutamate, or by deprivation of oxygen and glucose. This toxicity could be blocked by the AMPA/kainate receptor antagonist 6-nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-dione (NBQX). In vivo, differentiated oligodendrocytes in subcortical white matter expressed AMPA receptors and were selectively injured by microstereotaxic injection of AMPA but not NMDA. These data suggest that oligodendrocytes share with neurons a high vulnerability to AMPA/kainate receptor-mediated death, a mechanism that may contribute to white matter injury in CNS disease.

Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord.

Transplantation approaches using cellular bridges, fetal central nervous system cells, fibroblasts expressing neurotrophin-3 (ref. 6), hybridoma cells expressing inhibitory protein-blocking antibodies, or olfactory nerves ensheathing glial cells transplanted into the acutely injured spinal cord have produced axonal regrowth or functional benefits. Transplants of rat or cat fetal spinal cord tissue into the chronically injured cord survive and integrate with the host cord, and may be associated with some functional improvements. In addition, rats transplanted with fetal spinal cord cells have shown improvements in some gait parameters, and the delayed transplantation of fetal raphe cells can enhance reflexes. We transplanted neural differentiated mouse embryonic stem cells into a rat spinal cord 9 days after traumatic injury. Histological analysis 2-5 weeks later showed that transplant-derived cells survived and differentiated into astrocytes, oligodendrocytes and neurons, and migrated as far as 8 mm away from the lesion edge. Furthermore, gait analysis demonstrated that transplanted rats showed hindlimb weight support and partial hindlimb coordination not found in 'sham-operated' controls or control rats transplanted with adult mouse neocortical cells.

Accident prevention activity and accident experience in the Republic of Korea military.

INTRODUCTION: According to data released by the Korea National Statistical Office, the number of accidents has been decreasing since 2012. However, a considerable number of deaths related to safety accidents (23-46 deaths) are still reported annually. This study aimed to observe the correlation between accident prevention activities in the Republic of Korea (ROK) military and the incidence of safety accidents. METHODS: The study used data from the 2014-2015 Military Health Survey and included 13 618 responses (Army: 8414 (61.8%); Navy/Marine: 2262 (16.6%); Air Force: 2942 (21.6%)) from the ROK military personnel. Accident experiences and thoughts on accident prevention activities were self-reported. Multiple logistic regression analysis was used to examine the validity of accident prevention activity and accident experience. RESULTS: Of the 13 618 military personnel who responded, 12.0% reported experiencing safety accidents in the military and 1020 (7.5%) felt that accident prevention activities in the military were insufficient. On logistic regression analysis, we found a significant difference (insufficiency OR=1.56, CI 1.31 to 1.86). In particular, military personnel who belong to the Army and Navy were more likely to think that accident prevention activities were insufficient. In addition, military personnel who experienced falls/slips, crash, and laceration/puncture wound/amputation/penetrating wound accidents were more likely to think accident prevention activities were insufficient. CONCLUSIONS: Our study found that accident prevention activities in the military and accident experiences were related. It is necessary for the ROK Ministry of Defense, Army, Navy and Air Force headquarters to re-evaluate their accident prevention systems.

Beta-N-methylamino-L-alanine neurotoxicity: requirement for bicarbonate as a cofactor.

Ingestion of the excitotoxic cycad seed amino acid beta-N-methylamino-L-alanine may be responsible for the neuronal degeneration associated with Guam amyotrophic lateral sclerosis-parkinsonism-dementia in man. However, the basis for the central neurotoxicity of beta-N-methylamino-L-alanine has been unclear, as it lacks the omega acidic (or equivalent electronegative) moiety characteristic of other excitatory amino acids. beta-N-methylamino-L-alanine produced neurotoxic and neuroexcitatory effects in murine cortical cell cultures only when physiological concentrations of bicarbonate were available in the extracellular bathing medium. Bicarbonate may interact noncovalently with beta-N-methylamino-L-alanine to produce, in combination, a molecular configuration that activates glutamate receptors.

Neurons containing NADPH-diaphorase are selectively resistant to quinolinate toxicity.

Exposure of cultures of cortical cells from mouse to either of the endogenous excitatory neurotoxins quinolinate or glutamate resulted in widespread neuronal destruction; but only in the cultures exposed to quinolinate, an N-methyl-D-aspartate agonist, was there a striking preservation of the subpopulation of neurons containing the enzyme nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d). Further investigation revealed that neurons containing NADPH-d were also resistant to the toxicity of N-methyl-D-aspartate itself but were selectively vulnerable to the toxicity of either kainate or quisqualate. Thus, neurons containing NADPH-d may have an unusual distribution of receptors for excitatory amino acids, with a relative lack of N-methyl-D-aspartate receptors and a relative preponderance of kainate or quisqualate receptors. Since selective sparing of neurons containing NADPH-d is a hallmark of Huntington's disease, the results support the hypothesis that the disease may be caused by excess exposure to quinolinate or some other endogenous N-methyl-D-aspartate agonist.

Zinc selectively blocks the action of N-methyl-D-aspartate on cortical neurons.

Large amounts of zinc are present in synaptic vesicles of mammalian central excitatory boutons and may be released during synaptic activity, but the functional significance of the metal for excitatory neurotransmission is currently unknown. Zinc (10 to 1000 micromolar) was found to have little intrinsic membrane effect on cortical neurons, but invariably produced a zinc concentration-dependent, rapid-onset, reversible, and selective attenuation of the membrane responses to N-methyl-D-aspartate, homocysteate, or quinolinate. In contrast, zinc generally potentiated the membrane responses to quisqualate or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate and often did not affect the response to kainate. Zinc also attenuated N-methyl-D-aspartate receptor-mediated neurotoxicity but not quisqualate or kainate neurotoxicity. The ability of zinc to specifically modulate postsynaptic neuronal responses to excitatory amino acid transmitters, reducing N-methyl-to-aspartate receptor-mediated excitation while often increasing quisqualate receptor-mediated excitation, is proposed to underlie its normal function at central excitatory synapses and furthermore could be relevant to neuronal cell loss in certain disease states.

Neuroprotective effects of glutamate antagonists and extracellular acidity.

Glutamate antagonists protect neurons from hypoxic injury both in vivo and in vitro, but in vitro studies have not been done under the acidic conditions typical of hypoxia-ischemia in vivo. Consistent with glutamate receptor antagonism, extracellular acidity reduced neuronal death in murine cortical cultures that were deprived of oxygen and glucose. Under these acid conditions, N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-kainate antagonists further reduced neuronal death, such that some neurons tolerated prolonged oxygen and glucose deprivation almost as well as did astrocytes. Neuroprotection induced by this combination exceeded that induced by glutamate antagonists alone, suggesting that extracellular acidity has beneficial effects beyond the attenuation of ionotropic glutamate receptor activation.

The calcium channel blocker nifedipine attenuates slow excitatory amino acid neurotoxicity.

High concentrations of potent N-methyl-D-aspartate (NMDA) agonists can trigger degeneration of cultured mouse cortical neurons after an exposure of only a few minutes; in contrast, selective non-NMDA agonists or low levels of NMDA agonists require exposures of several hours to induce comparable damage. The dihydropyridine calcium channel antagonist nifedipine was used to test whether this slow neurotoxicity is mediated by a calcium influx through voltage-gated channels. Nifedipine had little effect on the widespread neuronal degeneration induced by brief exposure to high concentrations of NMDA but substantially attenuated the neurotoxicity produced by 24-hour exposure to submaximal concentrations of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate, kainate, or quinolinate. Calcium ion influx through dihydropyridine-sensitive, voltage-dependent calcium channels may be an important step in the neuronal injury induced by the prolonged activation of NMDA or non-NMDA glutamate receptors.

Potentiated necrosis of cultured cortical neurons by neurotrophins.

The effects of neurotrophins on several forms of neuronal degeneration in murine cortical cell cultures were examined. Consistent with other studies, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 all attenuated the apoptotic death induced by serum deprivation or exposure to the calcium channel antagonist nimodipine. Unexpectedly, however, 24-hour pretreatment with these same neurotrophins markedly potentiated the necrotic death induced by exposure to oxygen-glucose deprivation or N-methyl-D-aspartate. Thus, certain neurotrophins may have opposing effects on different types of death in the same neurons.

NMDA receptor-mediated K+ efflux and neuronal apoptosis.

Neuronal death induced by activating N-methyl-D-aspartate (NMDA) receptors has been linked to Ca2+ and Na+ influx through associated channels. Whole-cell recording from cultured mouse cortical neurons revealed a NMDA-evoked outward current, INMDA-K, carried by K+ efflux at membrane potentials positive to -86 millivolts. Cortical neurons exposed to NMDA in medium containing reduced Na+ and Ca2+ (as found in ischemic brain tissue) lost substantial intracellular K+ and underwent apoptosis. Both K+ loss and apoptosis were attenuated by increasing extracellular K+, even when voltage-gated Ca2+ channels were blocked. Thus NMDA receptor-mediated K+ efflux may contribute to neuronal apoptosis after brain ischemia.

The role of zinc in selective neuronal death after transient global cerebral ischemia.

Zinc is present in presynaptic nerve terminals throughout the mammalian central nervous system and likely serves as an endogenous signaling substance. However, excessive exposure to extracellular zinc can damage central neurons. After transient forebrain ischemia in rats, chelatable zinc accumulated specifically in degenerating neurons in the hippocampal hilus and CA1, as well as in the cerebral cortex, thalamus, striatum, and amygdala. This accumulation preceded neurodegeneration, which could be prevented by the intraventricular injection of a zinc chelating agent. The toxic influx of zinc may be a key mechanism underlying selective neuronal death after transient global ischemic insults.

Mediation of neuronal apoptosis by enhancement of outward potassium current.

Apoptosis of mouse neocortical neurons induced by serum deprivation or by staurosporine was associated with an early enhancement of delayed rectifier (IK) current and loss of total intracellular K+. This IK augmentation was not seen in neurons undergoing excitotoxic necrosis or in older neurons resistant to staurosporine-induced apoptosis. Attenuating outward K+ current with tetraethylammonium or elevated extracellular K+, but not blockers of Ca2+, Cl-, or other K+ channels, reduced apoptosis, even if associated increases in intracellular Ca2+ concentration were prevented. Furthermore, exposure to the K+ ionophore valinomycin or the K+-channel opener cromakalim induced apoptosis. Enhanced K+ efflux may mediate certain forms of neuronal apoptosis.

21-Aminosteroids attenuate excitotoxic neuronal injury in cortical cell cultures.

We studied the protective efficacy of novel 21-aminosteroids against several forms of neuronal injury in murine cortical cell cultures. Concentrations of 200 nM to 20 microM partially attenuated the damage induced by glucose deprivation, combined oxygen-glucose deprivation, or exposure to NMDA; maximal protection was less than that produced by NMDA antagonists, but the combination of a 21-aminosteroid plus an NMDA antagonist produced a greater benefit than either drug alone. 21-Aminosteroid addition did not attenuate NMDA-induced whole-cell current, but did block almost all of the damage induced by exposure to iron, a protective action consistent with inhibition of free radical-mediated lipid peroxidation. Lipid peroxidation may be a downstream event mediating a portion of the injury triggered by excess stimulation of NMDA receptors.

Selective potentiation of NMDA-induced neuronal injury following induction of astrocytic iNOS.

Nitric oxide (NO) produced by the constitutive NO synthase (cNOS) in neurons has been implicated in mediating excitotoxic neuronal death. In our murine cortical cell culture system, NMDA neurotoxicity was not blocked by addition of the NOS inhibitors, NG-nitro-L-arginine or aminoguanidine. However, following activation of inducible NOS in astrocytes by interleukin-1 beta plus interferon-gamma, NMDA but not kainate neurotoxicity was markedly potentiated. This selective potentiation of NMDA neurotoxicity was blocked by NOS inhibition or antioxidants (superoxide dismutase/catalase or Tempol) and could be mimicked by NO generators (SIN-1 or SNAP) or the oxygen radical generator, pyragallol. These results raise the possibility that NO production by astrocytes may contribute to NMDA receptor-mediated neuronal death, perhaps through interaction with oxygen radicals.

Bicarbonate dependence of glutamate receptor activation by beta-N-methylamino-L-alanine: channel recording and study with related compounds.

beta-N-methylamino-L-alanine (BMAA) is a neurotoxic glutamate agonist possibly responsible for the neuronal degeneration found in the Guam amyotrophic lateral sclerosis-Parkinsonism-dementia complex. The basis for glutamate receptor activation by BMAA has been unclear, as BMAA lacks the omega electronegative moiety characteristic of other excitatory amino acids. We recently reported that the neuroexcitatory and neurotoxic effects of BMAA depend strongly on the presence of bicarbonate ions and proposed that an interaction between bicarbonate and the beta amino group of BMAA produces a molecular configuration appropriate for activating glutamate receptors. We now report that bicarbonate potentiates the ability of BMAA to open NMDA receptor-activated channels in isolated membrane patches. Furthermore, the neurotoxic and neuroexcitatory effects of two structural analogs of BMAA, DL-2,4-diaminobutyrate and DL-2,3-diaminopropionate, were also potentiated by bicarbonate. These findings support the bicarbonate cofactor hypothesis for BMAA action and provide direct evidence that it may be generalizable to certain other compounds.