Prophylactic Radiation Therapy Versus Standard of Care for Patients With High-Risk Asymptomatic Bone Metastases: A Multicenter, Randomized Phase II Clinical Trial.

PURPOSE: External-beam radiation therapy (RT) is standard of care (SOC) for pain relief of symptomatic bone metastases. We aimed to evaluate the efficacy of radiation to asymptomatic bone metastases in preventing skeletal-related events (SRE). METHODS: In a multicenter randomized controlled trial, adult patients with widely metastatic solid tumor malignancies were stratified by histology and planned SOC (systemic therapy or observation) and randomly assigned in a 1:1 ratio to receive RT to asymptomatic high-risk bone metastases or SOC alone. The primary outcome of the trial was SRE. Secondary outcomes included hospitalizations for SRE and overall survival (OS). RESULTS: A total of 78 patients with 122 high-risk bone metastases were enrolled between May 8, 2018, and August 9, 2021, at three institutions across an affiliated cancer network in the United States. Seventy-three patients were evaluable for the primary end point. The most common primary cancer types were lung (27%), breast (24%), and prostate (22%). At 1 year, SRE occurred in one of 62 bone metastases (1.6%) in the RT arm and 14 of 49 bone metastases (29%) in the SOC arm (P < .001). There were significantly fewer patients hospitalized for SRE in the RT arm compared with the SOC arm (0 v 4, P = .045). At a median follow-up of 2.5 years, OS was significantly longer in the RT arm (hazard ratio [HR], 0.49; 95% CI, 0.27 to 0.89; P = .018), which persisted on multivariable Cox regression analysis (HR, 0.46; 95% CI, 0.23 to 0.85; P = .01). CONCLUSION: Radiation delivered prophylactically to asymptomatic, high-risk bone metastases reduced SRE and hospitalizations. We also observed an improvement in OS with prophylactic radiation, although a confirmatory phase III trial is warranted.

A robust control system for targeting melanoma by a supermolecular DDMC/paclitaxel complex.

A DEAE-dextran-MMA copolymer (DDMC)-paclitaxel (PTX) conjugate was prepared using PTX as the guest and DDMC as the host. The resistance of B16F10 melanoma cells to PTX was confirmed, while the DDMC-PTX conjugate showed excellent anticancer activity that followed the Hill equation. The robustness in the tumor microenvironment of the allosteric system was confirmed via BIBO stability. This feedback control system, explained via a transfer function, was very stable and showed the sustainability of the system via a loop, and it showed superior anti-cancer activity without drug resistance from cancer cells. The block diagram of this signal system in the tumor microenvironment used its loop transfer function G(s) and the dN(s) of the external force. This indicial response is an ideal one without a time lag for the outlet response. The cell death rate of DDMC-PTX is more dependent on the Hill coefficient n than on the Michaelis constant Km. This means that this supermolecular reaction with tubulin follows an "induced fit model".

Biphasic modulation by mGlu5 receptors of TRPV1-mediated intracellular calcium elevation in sensory neurons contributes to heat sensitivity.

BACKGROUND AND PURPOSE: Elevation of glutamate, an excitatory amino acid, during inflammation and injury plays a crucial role in the reception and transmission of sensory information via ionotropic and metabotropic receptors. This study aimed to investigate the mechanisms underlying the biphasic effects of metabotropic glutamate mGlu5 receptor activation on responses to noxious heat. EXPERIMENTAL APPROACH: We assessed the effects of intraplantar quisqualate, a non-selective glutamate receptor agonist, on heat and mechanical pain behaviours in mice. In addition, the effects of quisqualate on the intracellular calcium response and on membrane currents mediated by TRPV1 channels, were examined in cultured dorsal root ganglion neurons from mice. KEY RESULTS: Activation of mGlu5 receptors in hind paw transiently increased, then decreased, the response to noxious heat. In sensory neurons, activation of mGlu5 receptors potentiated TRPV1-mediated intracellular calcium elevation, while terminating activation of mGlu5 receptors depressed it. TRPV1-induced currents were potentiated by activation of mGlu5 receptors under voltage clamp conditions and these disappeared after washout. However, voltage-gated calcium currents were inhibited by the mGlu5 receptor agonist, even after washout. CONCLUSIONS AND IMPLICATIONS: These results suggest that, in sensory neurons, mGlu5 receptors biphasically modulate TRPV1-mediated intracellular calcium response via transient potentiation of TRPV1 channel-induced currents and persistent inhibition of voltage-gated calcium currents, contributing to heat hyper- and hypoalgesia.

Impact of NADiA ProsVue PSA slope on secondary treatment decisions after radical prostatectomy.

BACKGROUND: Selecting appropriate candidates for postprostatectomy radiotherapy is challenging, because adverse pathological features cannot accurately predict clinical recurrence. Biomarkers that identify residual disease activity may assist clinicians when counseling patients on the risks, benefits and costs of secondary treatment. NADiA ProsVue PSA slope results ≤2.0 pg ml(-1) month(-1) are predictive of a reduced risk of clinical recurrence; however, its clinical utility has not yet been studied. METHODS: We prospectively enrolled men treated by radical prostatectomy in a multicenter, institutional review board-approved clinical trial. At postsurgical follow-up, investigators (N=17) stratified men into low-, intermediate- or high-risk groups for prostate cancer recurrence based on clinicopathological findings and other factors. Investigators documented their initial treatment plan for each subject and serially collected three serum samples for ProsVue testing. After the ProsVue result was reported, investigators recorded whether or not the initial treatment plan was changed. The proportion of cases referred for secondary treatment before and after ProsVue was reported, and the significance of the difference determined. RESULTS: Complete assessments were reported for 225 men, 128 (56.9%) of whom were stratified into intermediate- and high-risk groups. Investigators reported that they would have referred 41/128 (32.0%) at-risk men for secondary treatment. However, after results were known, they referred only 15/128 (11.7%) men. The difference in proportions (-20.3%, 95% confidence interval (CI) -29.9 to -10.3%) is significant (P<0.0001). Odds of a referral was significantly reduced after results were reported (odds ratio 0.28, 95% CI 0.15-0.54, P<0.0001). CONCLUSIONS: Knowledge of a ProsVue result had significant impact on the final treatment plan. A ProsVue result ⩽2.0 pg ml(-1) month(-1) significantly reduced the proportion of men at risk of recurrence who otherwise would have been referred for secondary treatment.

Association of serum arginase I with L-arginine, 3-nitrotyrosine, and exhaled nitric oxide in healthy Japanese workers.

The associations of serum arginase I with serum L-arginine, serum 3-nitrotyrosine, and fractional exhaled nitric oxide (FENO) were evaluated cross-sectionally in healthy Japanese workers. The serum median (minimum-maximum) levels of arginase I, 3-nitrotyrosine, and FENO in healthy people (n = 130) were 14.6 (0.94-108.1) ng/mL, 81.0 (0.27-298.6) pmol/mg protein, and 14.0 (5.0-110.0) parts per billion, respectively. Significant correlations of arginase I with FENO, L-arginine, 3-nitrotyrosine, and percent predicted forced expiratory volume in 1 s (FEV1 (% predicted)) were observed, and correlations of FENO with immunoglobulin E (IgE), NOx, arginase I, and sex and allergy were also observed. By multiple regression analysis, arginase I showed positive associations with FENO and 3-nitrotyrosine, and a negative association with L-arginine; and FENO showed positive associations with IgE and NO2(-) + NO3(-) (NOx), and a negative association with L-arginine, as well as an association with sex. Moreover, logistic regression analysis showed linear inverse associations of arginase I and 3-nitrotyrosine with L-arginine, and showed linear positive associations of FENO with IgE and NOx. It was concluded that serum arginase I might regulate serum L-arginine and 3-nitrotyrosine via L-arginine, and that IgE or NOx might regulate FENO in a healthy Japanese population.

Two receptors are involved in the central functions of kynurenic acid under an acute stress in neonatal chicks.

Intracerebroventricular (i.c.v.) injection of kynurenic acid (KYNA) had sedative and hypnotic effects during stress in neonatal chicks. However, its mechanism has not been clarified. KYNA is an endogenous antagonist of the α7 nicotinic acetylcholine (α7nACh) receptor and N-methyl-d-aspartate (NMDA) receptor. Therefore, this study clarified the mechanism of sedative and hypnotic effects of KYNA in the brain during an acute stress. In Experiment 1, to investigate the relationship between KYNA and the α7nACh receptor, KYNA was injected i.c.v. with galantamine, an agonist of the allosteric potentiating site of the α7nACh receptor. Galantamine did not attenuate the effect of KYNA, but higher levels of galantamine caused harmful effects. In Experiment 2, the role of the NMDA receptor was investigated using the NMDA receptor antagonist (+)-MK-801, d-serine which has high affinity to a co-agonist glycine site at the NMDA receptors, NMDA as the NMDA receptor agonist, and 2,3-pyridinedicarboxylic acid (QUIN), an agonist of the NMDA receptor subgroup containing the subunits NR2A and NR2B. The behavioral changes following KYNA were partially attenuated by QUIN alone. In conclusion, we suggest that KYNA functioned via the simultaneous inhibition of the α7nACh receptor and NMDA receptor subgroup containing the subunits NR2A and NR2B.

Safety of snake antivenom immunoglobulins: efficacy of viral inactivation in a complete downstream process.

Viral safety remains a challenge when processing a plasma-derived product. A variety of pathogens might be present in the starting material, which requires a downstream process capable of broad viral reduction. In this article, we used a wide panel of viruses to assess viral removal/inactivation of our downstream process for Snake Antivenom Immunoglobulin (SAI). First, we screened and excluded equine plasma that cross-reacted with any model virus, a procedure not published before for antivenoms. In addition, we evaluated for the first time the virucidal capacity of phenol applied to SAI products. Among the steps analyzed in the process, phenol addition was the most effective one, followed by heat, caprylic acid, and pepsin. All viruses were fully inactivated only by phenol treatment; heat, the second most effective step, did not inactivate the rotavirus and the adenovirus used. We therefore present a SAI downstream method that is cost-effective and eliminates viruses to the extent required by WHO for a safe product.

Evaluation of urinary hydrogen peroxide as an oxidative stress biomarker in a healthy Japanese population.

The usefulness of urinary hydrogen peroxide (H(2)O(2)) as an oxidative stress biomarker was evaluated in 766 healthy Japanese. The mean level of urinary concentrations of H(2)O(2) was 5.66 ± 8.27 µmol/g creatinine, and was significantly higher in females than in males. Significant correlations of H(2)O(2) were observed with age, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), insulin, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and exercise habit in females. In both sexes, H(2)O(2) showed a significant correlation with 8-OHdG. By a multiple logistic regression analysis, urinary H(2)O(2) was positively associated with urinary 8-OHdG and TC and was inversely associated with insulin. By stratification of sex and age, the association of urinary H(2)O(2) with TC was positive in both sexes under 50 years old and was inverse in males over 50 years old, and that with insulin was inverse in males over 50 years old and in females under 50 years old. Moreover, by stratification of sex and age, a positive association of H(2)O(2) with exercise and an inverse association of H(2)O(2) with alcohol consumption became clear in males under 50 years old, although there were no significant odds for H(2)O(2) after adjustment for covariates. In conclusion, the present results suggest that urinary H(2)O(2) is a useful biomarker for oxidative stress, showing an association with 8-OHdG, TC, and insulin independently.

Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations.

Despite initial dramatic response, epidermal growth factor receptor (EGFR) mutant lung cancer patients always acquire resistance to EGFR-tyrosine kinase inhibitors (TKIs). Gatekeeper T790M mutation in EGFR is the most prevalent genetic alteration underlying acquired resistance to EGFR-TKI, and EGFR mutant lung cancer cells are reported to be addictive to EGFR/Akt signaling even after acquired T790M mutation. Here, we focused on Akt kinase-interacting protein1 (Aki1), a scaffold protein of PI3K (phosphoinositide 3-kinase)/PDK1 (3-phosphoinositide-dependent protein kinase)/Akt that determines receptor signal selectivity for non-mutated EGFR, and assessed its role in EGFR mutant lung cancer with or without gatekeeper T790M mutation. Cell line-based assays showed that Aki1 constitutively associates with mutant EGFR in lung cancer cells with (H1975) or without (PC-9 and HCC827) T790M gatekeeper mutation. Silencing of Aki1 induced apoptosis of EGFR mutant lung cancer cells. Treatment with Aki1 siRNA dramatically inhibited growth of H1975 cells in a xenograft model. Moreover, silencing of Aki1 further potentiated growth inhibitory effect of new generation EGFR-TKIs against H1975 cells in vitro. Aki1 was frequently expressed in tumor cells of EGFR mutant lung cancer patients (53/56 cases), including those with acquired resistance to EGFR-TKI treatment (7/7 cases). Our data suggest that Aki1 may be a critical mediator of survival signaling from mutant EGFR to Akt, and may therefore be an ideal target for EGFR mutant lung cancer patients, especially those with acquired EGFR-TKI resistance due to EGFR T790M gatekeeper mutation.

Intracerebroventricular injection of kynurenic acid attenuates corticotrophin-releasing hormone-augmented stress responses in neonatal chicks.

In the brain of neonatal chicks, tryptophan has a sedative effect, and a part of this effect might be dependent upon its metabolite, serotonin. However, the functional mechanisms have not been fully clarified, since l-tryptophan produces kynurenic acid (KYNA) through the kynurenine pathway. The present study aimed to clarify the effect of KYNA on the stress response upon social isolation. Intracerebroventricular injection of KYNA induced a strong sedative effect under stress compared with the effect of l-tryptophan, with or without intracerebroventricular injection of corticotrophin-releasing hormone (CRH). KYNA dose-dependently induced sedative and hypnotic effects under CRH-augmented social isolation stress. Taken together, these results indicate that KYNA is a likely candidate for the sedative and hypnotic effects of tryptophan under acutely stressful conditions.

Treprostinil, a prostacyclin analog, ameliorates ischemia-reperfusion injury in rat orthotopic liver transplantation.

Prostaglandins have been evaluated for their ability to reduce IRI after liver transplantation; however, poor stability, side effects and the inability to show a significant difference in primary endpoint have limited their clinical application. Treprostinil, a prostacyclin (PGI(2) ) analog, has a higher potency and longer elimination half-life than other commercially available PGI(2) analogs. We examined the efficacy of treprostinil to prevent IRI during OLT. OLT was performed in syngeneic Lewis rats after 18 h of cold preservation (4°C) in the UW solution. IRI significantly increased serum ALT and AST levels, neutrophil infiltration, hepatic necrosis and mRNA levels of proinflammatory cytokines post-OLT, while treatment with treprostinil decreased all the parameters. Cold storage of liver grafts significantly reduced ATP levels and treprostinil restored energy levels in liver grafts early postreperfusion. In addition, treprostinil preserved the sinusoidal endothelial cell lining and reduced platelet deposition early post-transplantation compared to placebo. Hepatic tissue blood flow was significantly compromised in the placebo group, whereas treprostinil maintained blood-flow similar to normal levels. Treprostinil protected the liver graft against IRI during OLT. Treprostinil has the potential to serve as a therapeutic option to protect the liver graft against I/R injury in patients undergoing OLT.

Ex vivo application of carbon monoxide in UW solution prevents transplant-induced renal ischemia/reperfusion injury in pigs.

I/R injury is a major deleterious factor of successful kidney transplantation (KTx). Carbon monoxide (CO) is an endogenous gaseous regulatory molecule, and exogenously delivered CO in low concentrations provides potent cytoprotection. This study evaluated efficacies of CO exposure to excised kidney grafts to inhibit I/R injury in the pig KTx model. Porcine kidneys were stored for 48 h in control UW or UW supplemented with CO (CO-UW) and autotransplanted in a 14-day follow-up study. In the control UW group, animal survival was 80% (4/5) with peak serum creatinine levels of 12.0 +/- 5.1 mg/dL. CO-UW showed potent protection, and peak creatinine levels were reduced to 6.9 +/- 1.4 mg/dL with 100% (5/5) survival without any noticeable adverse event or abnormal COHb value. Control grafts at 14 days showed significant tubular damages, focal fibrotic changes and numerous infiltrates. The CO-UW group showed significantly less severe histopathological changes with less TGF-beta and p-Smad3 expression. Grafts in CO-UW also showed significantly lower early mRNA levels for proinflammatory cytokines and less lipid peroxidation. CO in UW provides significant protection against renal I/R injury in the porcine KTx model. Ex vivo exposure of kidney grafts to CO during cold storage may therefore be a safe strategy to reduce I/R injury.

Effect of sonoporation on cationic liposome-mediated IFNbeta gene therapy for metastatic hepatic tumors of murine colon cancer.

To examine the efficacy of ultrasound-mediated gene therapy in the treatment of hepatic cancer, we performed cationic liposome-mediated interferon-beta (IFNbeta) gene therapy combined with sonoporation, using metastatic hepatic tumors of murine colon cancer. The combination of liposome/DNA treatment and ultrasound gave higher transgene IFNbeta expression in Colon26 colon adenocarcinoma cells than that with microbubble/DNA in combination with ultrasound and that with liposome/DNA alone. Cationic liposome-mediated IFNbeta gene therapy combined with ultrasound showed an antitumor effect in vitro and combination use of the anticancer drug cis-diamminedichloroplatinum (CDDP) showed a synergistic effect with the IFNbeta gene therapy. The survival of mice with metastatic hepatic tumor of Colon26 cells was significantly prolonged by cationic liposome-mediated IFNbeta gene therapy alone, and sonoporation had a synergistic effect on prolongation of survival and inhibition of tumor growth rate in these mice. Combination use of CDDP with IFNbeta gene therapy also showed a synergistic effect on prolongation of survival and inhibition of tumor growth rate. In conclusion, ultrasound-mediated gene therapy for the treatment of hepatic cancers may be effective in a clinical setting.

Spinal cord hemangioblastomas in von Hippel-Lindau disease.

STUDY DESIGN: Retrospective data analysis. OBJECTIVE: To clarify the clinical features and surgical management of spinal cord hemangioblastomas in patients with von Hippel-Lindau disease (VHL). SETTING: Clinical VHL Research Group in Japan, Japan. METHODS: Forty-eight out of 66 patients with associated spinal cord hemangioblastoma among 142 VHL patients were retrospectively examined with respect to clinical features, accompanying lesions and outcome of surgical treatment. RESULTS: Among these 48 patients, 46 of them (95.8%) also had a central nervous system (CNS) hemangioblastoma at another site: 42 (87.5%) with cerebellar hemangioblastoma and 11 (22.9%) with brain stem hemangioblastoma. Twenty-three patients (47.9%) had more than one spinal cord hemangioblastoma. The 48 patients with spinal cord hemangioblastomas collectively had a total of 74 tumors. The tumor was accompanied with a syrinx in 64 and without it in 10 patients. Forty of the 48 patients underwent surgical treatment for their spinal cord hemangioblastomas, and 7 of these 40 underwent surgical treatment twice. When functional changes in the patients after these 47 operations were examined by postoperative evaluation by McCormick's classification, 39 of these operations (83.0%) resulted in improvement/no change and 8 (17.0%) in aggravation of symptoms. CONCLUSION: Von Hippel-Lindau disease patients bearing spinal cord hemangioblastomas mostly had a CNS hemangioblastoma at another site. These tumors can be removed in the majority of VHL patients without aggravation. In these patients, when the timing of treatment for spinal cord hemangioblastoma is determined, the probability of occurrence and treatment of other lesions should be considered.

Novel quantum criticality in CeRu2Si2 near absolute zero observed by thermal expansion and magnetostriction.

We report linear thermal expansion and magnetostriction measurements for CeRu2Si2 in magnetic fields up to 52.6 mT and at temperatures down to 1 mK. At high temperatures, this compound showed Landau-Fermi-liquid behavior: The linear thermal expansion coefficient and the magnetostriction coefficient were proportional to the temperature and magnetic field, respectively. In contrast, a pronounced non-Fermi-liquid effect was found below 50 mK. The negative contribution of thermal expansion and magnetostriction suggests the existence of an additional quantum critical point.

Mutations in the quinolone resistance determining region in Staphylococcus epidermidis recovered from conjunctiva and their association with susceptibility to various fluoroquinolones.

BACKGROUND: Staphylococcus epidermidis is one of the prominent pathogens in ocular infection. The prevalence of mutations in the quinolone resistance determining region (QRDR) area in S epidermidis isolated from the ocular surface and its association with fluoroquinolone resistance has not been fully elucidated. METHODS: Mutations in the QRDR of gyrA, gyrB, parC, and parE genes of 138 isolates of S epidermidis recovered from the human conjunctival flora were analysed. The minimal inhibitory concentrations (MICs) of four fluoroquinolones (levofloxacin, gatifloxacin, moxifloxacin and tosufloxacin) against these isolates were also determined using agar dilution methods. RESULTS: The MIC(90) values of levofloxacin, gatifloxacin, moxifloxacin and tosufloxacin were 3.13, 1.56, 0.78 and 3.13 microg/ml, respectively. The MIC values of all fluoroquinolones showed a bimodal distribution (susceptible strain and less susceptible strain). Mutations with amino acid substitution in the QRDR were present in 70 (50.7%) isolates. 19 different combinations of mutations were detected: 3 isolates (2.2%) had four mutations, 8 (5.8%) had three mutations, 43 (31.2%) had double mutations and 16 (11.6%) had single mutations. Isolates with mutations in the QRDR of both gyrA and parC (n = 53) were less susceptible to fluoroquinolones. CONCLUSIONS: The present findings show that approximately half the S epidermidis isolates from the normal human conjunctiva have mutation(s) in the QRDR. The presence of mutations in both gyrA and parC is strongly associated with reduced susceptibility to fluoroquinolones.

Morphological study of aneurysms at the junction of the superior cerebellar artery.

SUMMARY: Superior cerebellar artery (SCA) aneurysms sometimes involve the origin of the SCA making treatment difficult. We focused on the morphological characteristics of SCA aneurysms and adjacent vascular structures to apply clinical decision-making for the treatment strategy. Sixty-nine SCA aneurysms, including 34 ruptured and 35 unruptured ones, had been treated for over 12 years. Multiple aneurysms were associated in 30 patients. The pattern of the neck position of aneurysms was classified into three types: Type A: no SCA-involved type; Type B: half involved type with SCA originating from the aneurysmal neck; Type C: pure SCA aneurysm with all the neck mounting on SCA. Morphological and clinical analysis was done between ruptured and unruptured aneurysms and among the three types. There was no difference in patient profile between ruptured and unruptured aneurysms. The angle formed by the posterior cerebral artery and SCA on the aneurysm side was obtuse in 62 (90%) patients. From the morphological point of view the SCA-involved type (types B + C) was significantly more prevalent in ruptured aneurysms (77%). Bleb formation was particular in ruptured aneurysms. As for the treatment, the risk of SCA occlusion and incomplete and attempted operation was particularly high in cases with SCA-involved type. Although SCA aneurysms may grow due to the hemodynamic stress at the opened bifurcation between the PCA and SCA, the neck shifting to the origin of SCA, particularly in ruptured lesions,may suggest some other etiological mechanism. SCA-involved type aneurysms had a high treatment risk of SCA occlusion and tended to incomplete treatment to avoid such ischemic complications.

Dural arteriovenous fistula at the anterior condylar confluence.

SUMMARY: We reviewed the records of eight patients with a dural arteriovenous fistula (DAVF) close to the hypoglossal canal and determined the angioarchitecture of the clinical entity at the anterior condylar confluence. Eight patients with DAVF received endovascular treatment at our institute over the past five years. Imaging with selective three-dimensional angiography and thin-slice computed tomography were used to identify the fistula and evaluate the drainage pattern. Based on the angiographic findings, the ascending pharyngeal artery was the main feeder in all cases, and the occipital, middle meningeal, posterior auricular, and posterior meningeal arteries also supplied the DAVF to varying degrees. Contralateral contribution was found in five patients. The main drainage route was the external vertebral plexus via the lateral condylar veins in four patients, the inferior petrosal sinus in three patients, and the internal jugular vein via the connecting emissary veins in one patient. Selective angiography identified the shunt point at the anterior condylar confluence close to the anterior condylar vein. Shunt occlusion with transvenous coil packing was performed in all cases; transarterial feeder embolization was also used in three patients. Two patients treated with tight packing of the anterior condylar vein developed temporary or prolonged hypoglossal palsy. Based on our results, the main confluence of the shunt is located at the anterior condylar confluence connecting the anterior condylar vein and multiple channels leading to the extracranial venous systems. To avoid postoperative nerve palsy, the side of the anterior condylar vein in the hypoglossal canal should not be densely packed with coils. Evaluating the angioarchitecture using the selective three-dimensional angiography and tomographic imaging greatly helps to determine the target and strategy of endovascular treatment for these DAVF.

Problems in the current diagnostic standards of clinical N1 non-small cell lung cancer.

BACKGROUND: Although clinical N1 (cN1) non-small cell lung cancer (NSCLC) is considered to be locoregional, the postoperative outcome is disappointing, with a 5 year survival of less than 50%. One possible reason may be that cN1disease diagnosed by current standard imaging modalities often contains unexpected N2 disease. This study was conducted to evaluate the surgical and pathological results of patients with cN1 NSCLC. METHODS: Among 1782 patients with NSCLC who underwent intended curative resection from 1993 to 2003, 143 patients were identified as having cN1 disease and were enrolled in this study. The clinicopathological records and CT films of each patient were retrospectively reviewed to identify predictors for pN2-3 disease. RESULTS: The pathological nodal status was pN0 in 23% (n = 33), pN1 in 47% (n = 67) and pN2-3 in 30% (n = 43) of patients. Patients with pN2-3 showed a significantly worse 5 year survival rate of 38% compared with patients with pN0 (68%) and pN1 (60%) (p = 0.017 and 0.007, respectively). Multivariate analysis showed that adenocarcinoma histology was a significant predictor for pN2-3 disease (OR 3.312, 95% CI 1.439 to 7.784; p = 0.005). The presence of N1 node separate from the main tumour on CT scans tended to predict pN2-3 disease although this did not reach statistical significance (OR 2.103, 95% CI 0.955 to 4.693; p = 0.066). Pathological N2-3 disease was found in 53% of patients with adenocarcinoma with a separate N1 pattern and in only 12% of patients with non-adenocarcinoma with a continuous N1 pattern. CONCLUSIONS: The diagnosis of N1 status by contrast enhanced CT scans is unsatisfactory with a high rate of unexpected pN2 disease. To avoid infertile lung resection, patients with CT diagnosed N1 adenocarcinoma, especially with a separate N1 pattern on CT, should be considered for additional invasive node biopsy modalities, including mediastinoscopy.

Human neural stem cells target and deliver therapeutic gene to experimental leptomeningeal medulloblastoma.

Medulloblastomas are highly malignant neuroectodermal cerebellar tumors of children. One of the reasons for the difficulty for the treatment of medulloblastomas is their inherent tendency to metastasize through the cerebrospinal fluid (CSF) pathway leading to leptomeningeal dissemination. Recently, genetically modified neural stem cells (NSCs) were shown to have the capability of selectively migrating into glioma mass and delivering therapeutic agents with significant therapeutic benefits. In the present study, we applied the NSC strategy to target medulloblastomas, particularly their leptomeningeal dissemination. We used NSCs that were retrovirally transduced with the cytosine deaminase gene (CD-NSCs). In vitro studies demonstrated that CD-NSCs had sufficient migratory activity toward medulloblastoma cells and exerted a remarkable bystander effect on these cells following the application of 5-fluorocytosine (5-FC). It is noteworthy that neutralization of the hepatocyte growth factor blocked their migration In animal studies using our leptomeningeal dissemination model, CD-NSCs implanted directly into CSF space were shown to distribute diffusely within the disseminated tumor cells and could provide remarkable antitumor effect after intraperitoneal administration of 5-FC. Furthermore, CD-NSC treatment followed by 5-FC administration prolonged survival periods significantly in experimental animals. Our data suggest that the CD-NSC strategy can also be applied to target leptomeningeal dissemination of medulloblastomas.