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Background The effects of high-intensity immunity on coronavirus disease 2019 (COVID-19) remain unclear. Antibodies against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are preferentially induced in inpatients with COVID-19 compared with outpatients with milder disease, and immunosuppression is the standard therapy for severe cases. This study investigated the relationship between cross-reactive antibody production against seasonal human coronavirus and the clinical course of COVID-19. Methods Among the immunogenic epitopes of SARS-CoV-2, conserved peptides in human coronavirus OC43 were searched and synthesized. Enzyme-linked immunosorbent assay was designed to detect antibodies against synthesized peptides. Antibody titres against S2ʹ cleavage site epitopes near fusion peptides of SARS-CoV-2 and OC43 were determined in the sera of 126 inpatients with COVID-19. The correlation between antibody titres and clinical data was analysed. Results Inpatients with COVID-19 who produced antibodies against OC43 did not develop severe or fatal pneumonia. Antibody titres against the corresponding epitope of SARS-CoV-2 did not differ between inpatients with severe and mild COVID-19. Antibody titres against the OC43 epitope increased more than those against SARS-CoV-2 during the first 2 weeks of COVID-19. Conclusions Immunity to seasonal human coronavirus OC43 effectively enhanced recovery from COVID-19. Detecting cross-reactive antibodies to OC43 may help to predict prognosis for patients with COVID-19., Graphical abstract Image, graphical abstract

The spread of coronavirus disease 2019 (COVID-19) is having a profound effect on global health. In this study, we investigated early predictors of severe prognosis from the perspective of liver injury and risk factors for severe liver injury in patients with COVID-19.We examined prognostic markers and risk factors for severe liver injury by analyzing clinical data measured throughout the course of the illness and the disease severity of 273 patients hospitalized for COVID-19. We assessed liver injury on the basis of aminotransferase concentrations and fibrosis-4 (FIB-4) index on admission, peak aminotransferase concentration during hospitalization, aminotransferase peak-to-average ratio, and albumin and total bilirubin concentrations. Furthermore, we analyzed age, aspartate aminotransferase (AST) concentrations, FIB-4 index on admission, hypertension, diabetes mellitus (DM), dyslipidemia, cerebral infarction, myocardial infarction, and body mass index as mortality risk factors.We identified advanced age as a risk factor. Among biochemical variables, AST concentration and FIB-4 index on admission were associated with high mortality. AST on admission and peak AST during hospitalization were significantly higher in the non-surviving (n = 45) than the discharged group (n = 228). Multivariable Cox hazards analyses for mortality showed significant hazard ratios for age, peak AST, and FIB-4 index on admission (p = 0.0001 and 0.0108, respectively), but not in a model including AST and FIB-4 index on admission. Furthermore, the AST peak was significantly higher among non-surviving patients with DM than in those without DM.We found that advanced age, high AST, and FIB-4 index on admission and a higher peak AST during hospitalization are risk factors for poor COVID-19 prognosis. Furthermore, DM was a risk factor for exacerbation of liver injury among non-surviving patients. The AST concentration and FIB-4 index should be assessed periodically throughout hospitalization, especially in patients with high AST values on admission and those with DM.

Background and Purpose: High blood pressure increases bleeding risk during treatment with antithrombotic medication. The association between blood pressure levels and the risk of recurrent stroke during long-term secondary stroke prevention with thienopyridines (particularly prasugrel) has not been well studied. Methods: This was a post hoc analysis of the randomized, double-blind, multicenter PRASTRO-I trial (Comparison of Prasugrel and Clopidogrel in Japanese Patients With Ischemic Stroke-I). Patients with noncardioembolic stroke were randomly assigned (1:1) to receive prasugrel 3.75 mg/day or clopidogrel 75 mg/day for 96 to 104 weeks. Risks of any ischemic or hemorrhagic stroke, combined ischemic events, and combined bleeding events were determined based on the mean level and visit-to-visit variability, including successive variation, of systolic blood pressure (SBP) throughout the observational period. These risks were also compared between quartiles of mean SBP level and successive variation of SBP. Results: A total of 3747 patients (age 62.1±8.5 years, 797 women), with a median average SBP level during the observational period of 132.5 mm Hg, were studied. All the risks of any stroke (146 events; hazard ratio, 1.318 [95% CI, 1.094–1.583] per 10-mm Hg increase), ischemic stroke (133 events, 1.219 [1.010–1.466]), hemorrhagic stroke (13 events, 3.247 [1.660–6.296]), ischemic events (142 events, 1.219 [1.020–1.466]), and bleeding events (47 events, 1.629 [1.172–2.261]) correlated with increasing mean SBP overall. Similarly, an increased risk of these events correlated with increasing successive variation of SBP (hazard ratio, 3.078 [95% CI, 2.220–4.225] per 10-mm Hg increase; 3.051 [2.179–4.262]; 3.276 [1.172–9.092]; 2.865 [2.042–4.011]; 2.764 [1.524–5.016], respectively). Event rates did not differ between the clopidogrel and prasugrel groups within each quartile of SBP or successive variation of SBP. Conclusions: Both high mean SBP level and high visit-to-visit variability in SBP were significantly associated with the risk of recurrent stroke during long-term medication with either prasugrel or clopidogrel after stroke. Control of hypertension would be important regardless of the type of antiplatelet drugs. Registration: URL: https://www.clinicaltrials.jp ; Unique identifier: JapicCTI-111582.

The prognosis for leptomeningeal metastasis (LM) remains extremely poor regardless of intrathecal chemotherapy with various drugs, and thus, new treatments are necessary. Butyrate is an endogenous 4-carbon saturated fatty acid, has been investigated as an anti-tumor agent because of its multiple suppressive effects on several tumors. In this study, we investigated the cellular basis of sodium butyrate (SB), a sodium salt compound of butyrate, in vitro and evaluated the clinical potential of intrathecal SB administration for LM in vivo. We examined SB’s effects on Walker 256 rat mammary tumor cells with regard to cytotoxicity, cell morphology, colony formation, migration, and invasion. We also examined SB’s neurotoxicity for primary neurons and primary astrocytes. We finally evaluated the potency of continuous intrathecal SB administration in rats with intrathecally transplanted breast tumors as an LM model. Physiological SB concentrations (2–4 mM) induced growth suppression, morphological changes, and inhibition of migration and invasion, but did not exhibit neurotoxic effects on primary neurons and astrocytes. Continuous intrathecal SB administration in a rat LM model significantly increased survival periods with little neurotoxicity. Continuous intrathecal SB administration significantly improved prognoses in a rat LM model, which suggests that SB is a promising therapy for LM.

Background: GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic t...

Sodium butyrate (SB), a short chain (C-4) saturated fatty acid, is present in the human bowel at increased concentrations (~2 mM) as a food metabolite. It has been demonstrated that SB exerts an anti-tumor effect as a histone deacetylase inhibitor; however, its precise mechanism of action remains to be elucidated. The present study focused on the mechanisms underlying the effects of SB on glioblastoma (GB) cell proliferation, motility and invasion. In human GB A172 cells, flow cytometry and a Boyden chamber assay demonstrated that physiological concentrations of SB (0.25-4.00 mM) dose-dependently inhibited cell proliferation and invasion. SB also affected cellular morphology, with increases in cell area and the number of focal adhesions observed. However, the phosphorylation (Y397 site) of focal adhesion kinase (FAK) was increased, while that of myosin light chain (S19 site) was unaltered. All of these SB-induced effects were reversible and attenuated following SB withdrawal. In addition, A172 cells treated with SB exhibited positivity for senescence-associated (SA) β-galactosidase (gal) staining and elevated protein expression of p53 and p21 in a time- and dose-dependent manner, whereas the expression of p21 mRNA decreased. Knockdown of p21 expression using small interfering RNA reversed the inhibition of cell growth inhibition and positivity for SA β-gal staining, but did not reverse the inhibition of cell motility and enhanced phosphorylation of FAK. This suggests that cells require p21 to induce senescence but not for SB-mediated decreased motility. Therefore, the current study demonstrated that SB inhibits GB cell proliferation, induces cells to senesce and inhibits tumor cell invasion, indicating that it may be developed as a novel therapeutic strategy to treat GB.

Background: Patients with minor acute ischemic stroke or transient ischemic attack are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was the first trial with ticagrelor in patients with acute ischemic stroke or transient ischemic attack in which the efficacy and safety of ticagrelor were compared with those of aspirin. The main safety objective was assessment of PLATO (Platelet Inhibition and Patient Outcomes)–defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH). Methods: An independent adjudication committee blinded to study treatment classified bleeds according to the PLATO, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions. The definitions of ICrH and major bleeding excluded cerebral microbleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population. Results: A total of 13 130 of 13 199 randomized patients received at least 1 dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (hazard ratio, 0.83; 95% confidence interval, 0.52–1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (4 on ticagrelor and 9 on aspirin) were hemorrhagic strokes, and 4 (2 in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in 6 and 13, traumatic in 3 and 3, and procedural in 3 and 2 patients on ticagrelor and aspirin, respectively. In total, 9 fatal bleeds occurred on ticagrelor and 4 on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independently of bleeding classification, PLATO, TIMI, or GUSTO, the relative difference between treatments for major/severe bleeds was similar. Nonmajor bleeds were more common on ticagrelor. Conclusions: Antiplatelet therapy with ticagrelor in patients with acute ischemic stroke or transient ischemic attack showed a bleeding profile similar to that of aspirin for major bleeds. There were few ICrHs. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01994720.

Object Malignant gliomas are often highly invasive and can migrate along blood vessels. The purpose of the current study was to identify the substance in human serum and/or cerebrospinal fluid (CSF) that promotes glioma cell migration. Methods The authors used a Boyden chamber cell migration assay to study the effect of serum from patients with glioma and healthy volunteers on chemotaxis of A172 human glioma cells. Heat inactivation, trypsinization, and ultra-filtration of serum were used to establish the nature of the active factor. Vitronectin and fibronectin were chosen for further investigations; chemotactic effects were studied in both serum and CSF. Results Serum from both patients with glioma and healthy volunteers was found to promote chemotaxis of human glioma cells. This activity was greatly reduced by heat inactivation or trypsinization. Fractionation of the serum by ultrafiltration through membranes with various pore sizes showed that the active molecule was larger than 50 kD. Antibodies against integrin αv or αvβ5 or arginine-glycine-aspartic acid–containing peptides, both of which block the vitronectin–glioma cell interactions, significantly reduced serum-induced cell migration, whereas blocking the interaction of glioma cells with fibronectin had no effect. Furthermore, the ability of serum to promote the migration of A172 or T98G glioma cells was suppressed by immunodepletion of vitronectin and restored by the addition of exogenous vitronectin. The migration of glioma cells induced by CSF collected from the postoperative cavity of a malignant glioma patient was also reduced by blocking the interaction of glioma cells with vitronectin. Conclusions These results suggest that vitronectin is one of the major factors in serum- and CSF-induced glioma cell migration.

The small GTP-binding protein Rho and its target Rho-associated kinase trigger an intracellular signaling cascade that controls actin cytoskeleton and plays an essential role in cell motility and adhesion. A specific Rho-associated kinase inhibitor, Y-27632, has been reported to inhibit cancer invasion. Clinically, disseminated tumor cells in the cerebrospinal fluid invade the intraparenchymal region, damaging the brain and nerves, resulting in fatal brain stem dysfunction, despite intrathecal chemotherapy. To expand therapeutic options for this devastating neoplastic meningitis, we evaluated the potential use of intrathecal Y-27632 administration by employing Walker 256 cells, a rat mammary cancer cell line. Y-27632 dose-dependently inhibited chemotactic and invasive activity of Walker 256 cells. Y-27632 also inhibited the phosphorylation level of regulatory myosin light chain in vitro, but the effect was temporary and was considerably diminished within 16 hours. Y-27632 induced striking morphologic changes in Walker 256 cells, as evidenced by decreased cell-matrix adhesion in culture dishes and three-dimensional collagen I gels, and slightly inhibited colony formation in soft agar. Nevertheless, this drug treatment did not affect Walker 256 cell growth rate. We were able to administer continuous delivery of this inhibitor using an osmotic pump and maintaining drug concentration of 10 μmol/L within the brain. Importantly, this concentration of Y-27632 showed minimal neurotoxicity both in vitro and in vivo. We found that an intrathecal therapy, combining 5-fluoro-2′-deoxyuridine with Y-27632, significantly increased the survival time of rats bearing meningeal carcinomatosis in comparison with animals treated with 5-fluoro-2′-deoxyuridine alone. Taken together, our findings indicate that continuous intrathecal administration of Y-27632 could be a promising therapeutic method when combined with chemotherapy for treating human neoplastic meningitis.

We have previously reported that repeated intravenous administration of cis-diamminedichloroplatinum(CDDP)prevented local recurrence of metastatic brain tumors after surgical total excision; however, data on CDDP distribution in the postoperative cavity after intravenous CDDP administration are not available. In the present study, we evaluated the penetration of total platinum(Pt)into the cerebrospinal fluid(CSF)and the effect of intravenous administration of 20%mannitolon total Pt distribution in the plasma and CSF. Total Pt levels in the plasma and CSF were determined immediately after intravenous infusion of CDDP(80mg/m2)for 1 hour, with or without pre-intravenous infusion of 20% mannitol(200mL), in 11 patients with brain metastasis from lung cancer. CSF samples were obtained via Ommaya reservoirs placed in the anterior horn of the lateral ventricle(CSF-V)and the postoperative cavity(CSF-C). Spinal CSF (CSF-L)was also obtained in the last 4 patients of the series via spinal drainage. CDDP was administered intravenously without mannitol 10 days after brain tumor excision, and 1 week after the initial administration of CDDP, CDDP was intravenously administered again after intravenous mannitol administration. CDDP was always administered intravenously at 1:00 PM to rule out the influence of circadian variation. Plasma and CSF were sequentially sampled after intravenous CDDP administration, and their Pt levels were analyzed for Pt content by using atomic absorption spectroscopy. The area under the concentration time curve(AUC)was calculated for plasma and CSF using the moment method. The AUC for total Pt in plasma showed a significantly higher level with the administration of mannitol than without the administration of mannitol(p0.01, paired t-test). Total Pt levels(AUCs and peak concentrations)in CSF-C were much higher than were those in CSF-V and CSF-L both with and without the administration of mannitol. The ratio(%)of CDDP penetration into CSF(CSF AUC/plasma AUC)was much higher for CSF-C than for CSF-V(p0.0001)both with and without mannitol administration. However, the CSF penetration ratio with mannitol administration did not differ significantly from that without mannitol administration. Thus, the administration of mannitol did not significantly increase the penetration ratio of total Pt. Creatinine clearance was moderately reduced in all patients during the first administration of CDDP. However, 7 of the 11 patients showed an increase in creatinine clearance after the second administration of CDDP with mannitol.

A 60-year-old man presented with a brain metastasis from renal cell carcinoma (RCC). Computer tomography revealed a homogeneously enhanced tumor, 3.0 cm in maximum diameter, in the right medial temporal lobe. Cerebral angiography revealed that the tumor was mainly fed by the right posterior cerebral artery. Surgery was performed via right temporal craniotomy. After craniotomy, under ultrasonography (US) guidance, a total of 3.0 ml of ethanol was injected into the tumor to diminish the intratumoral vascular flow. Ultrasonographic guidance was very useful in monitoring the intratumoral vascular flow. After a marked decrease in the vascular flow, the tumor was totally removed using piecemeal technique. During surgery, only minimal bleeding from the tumor was noted. The postoperative course was uneventful, with no evidence of injected ethanol-related complications. In conclusion, this can be a safe, easy, and effective therapeutic technique for diminishing vascular flow within brain tumors rich in vascularity, such as brain metastases from RCC.

Malignant gliomas encompassing the eloquent areas cannot be removed totally and their surgical extirpation is followed by adjuvant therapy for the residual tumor. Recently, we have employed fibrin glue as a vehicle for the sustained release of ACNU (nimustine hydrochloride) by spray application following subtotal tumor removal in two patients with recurrent malignant gliomas. Follow-up MRI at six months demonstrated no neuroradiological evidence of tumor recurrence in the site of operation. We conclude, this novel mode of Intra-operative local chemotherapy by spray application of fibrin glue containing antineoplastic agent is effective in the control of residual tumor progression and may also prevent local recurrence and hence suggests its possible role as an adjuvant therapy in the management of malignant gliomas. [Neurol Res 2000; 22: 181-184]

Skull metastases from hepatocellular carcinoma (HCC) are extremely rich in vascularity, which sometimes makes surgery dangerous. For minimally invasive surgery, it is very important to diminish the intratumoral vascular flow preoperatively. We report the case of a 69-year-old man with a giant skull base metastasis from HCC that was successfully removed after two sessions of direct ethanol injection into the tumor as a preoperative treatment to diminish the intratumoral vascular flow. Direct ethanol injection is a modification of percutaneous ethanol injection therapy, which is widely used in the treatment of primary HCC. In this article, we describe in detail the practical procedures and the usefulness of this treatment for a giant skull base metastasis from HCC.

To evaluate the possible intrathecal use of 5-fluoro-2'-deoxyuridine (FdUrd) for neoplastic meningitis, its antitumor activity and neurotoxicity in vivo were assessed. FdUrd at doses in the range 5-100 microg/animal was effective against meningeal carcinomatosis using Walker 256 carcinoma cells in rats and MM46 mammary cancer cells in mice and against meningeal gliomatosis using 203 glioma cells in mice. After four intrathecal injections, FdUrd at these doses also showed minimal neurotoxicity in the C57BL/6 mouse brain. To estimate the mechanism of FdUrd efficacy, thymidine phosphorylase (TPase) and thymidine kinase (TK), key enzymes in the metabolism of FdUrd, were measured in rat, mouse and normal human brain tissue, and in human brain tumor tissues and cerebrospinal fluid (CSF) from patients with malignant brain tumors including meningeal carcinomatosis. TPase levels were lower in brain and malignant brain tumors than in other organs and their tumors. Moreover, the activity of TPase in the gray matter of human brain, which faces the cerebrospinal fluid across the cortical surface and into which malignant cells invade in meningeal carcinomatosis, was lower than that in the white matter. TK was undetectable, and TPase was detected (at very low concentrations) in only 4 of 56 patients with brain tumors or meningeal carcinomatosis. These findings indicate that brain tissue and CSF are favorable sites for FdUrd chemotherapy because the rate of conversion of FdUrd to 5-FU would be minimal. In conclusion, FdUrd is potentially useful for intrathecal treatment of neoplastic meningitis from primary brain tumors and systemic cancer.

Intrathecal administration of 5-fluoro-2′-deoxyuridine (FdUrd) was performed in patients with meningeal dissemination of malignant tumors during the period from January 1996 to September 1998, and they were followed up until February 1999. The study population consisted of 23 patients: 12 with lung cancer, 4 with breast cancer, 2 with colon cancer, 1 with malignant lymphoma, 2 with glioblastoma and 2 with metastatic brain tumors of unknown origin. FdUrd was administered intrathecally through an Ommaya reservoir placed in the lateral ventricle initially at a dose of 1 µg twice per week, and the dose was increased to 10 µg and administration schedule was also increased every day. Headache and nuchal pain were relieved in all patients regardless of responsiveness to intrathecal FdUrd therapy as determined from the findings in the cerebrospinal fluid (CSF). Patients showed no side effects during the course of intrathecal chemotherapy except for slight nausea in two patients and dull headache in one. Sixteen of the 23 patients showed decreased cell number in the cerebrospinal fluid (CSF). Positive cytological findings in CSF became negative in 6 of the 23 patients, and the levels of CSF tumor markers were decreased in 14. Responsiveness to intrathecal administration of FdUrd was defined as ‘response’ when both the cell number and tumor markers were decreased in both ventricular and spinal CSF or when the cell number was decreased in cases in which the tumor markers were not detected. Overall, 16 of the 23 patients (70%) showed complete or partial responses to intrathecal FdUrd therapy as determined from CSF findings.

We investigated 5-fluoro-2'-deoxyuridine (FdUrd) as a potential agent for intrathecal treatment of malignant brain tumors with meningeal dissemination. We examined the neurotoxicity of FdUrd in vitro using primary cultures of neurons from C57BL/6 mice (ED14). Tumoricidal activity was also studied in four glioma cell lines and one medulloblastoma cell line. In addition, thymidine phosphorylase (TPase) and thymidine kinase (TK), which are key enzymes for FdUrd metabolism, were measured in the cerebrospinal fluid (CSF) of 36 patients with brain tumors. The antitumor activity of FdUrd for murine glioma cells was approximately 20- to 200-fold higher than that of 5-fluorouracil (5-FU). Against human cell lines, it was 3- to 500-fold higher than that of 5-FU. The neurotoxic effect of FdUrd on cultured neurons was far less than that of 5-FU or 5-fluorouridine (FUrd). Cerebrospinal fluid contained no detectable thymidine phosphorylase in most patients with brain tumors. Several studies have indicated that FdUrd is rapidly converted to 5-FU in the presence of thymidine phosphorylase, so that a high dose of FdUrd must be administered to obtain good efficacy. However, a high dose FdUrd frequently cause severe toxicity. In contrast, the data obtained here suggest that no enzymatic conversion of FdUrd to 5-FU should occur in the CSF. In addition, FdUrd has an excellent antitumor activity and minimal neurotoxicity. We therefore conclude that intrathecal FdUrd is a potential therapy for CSF dissemination of malignant brain tumors.

Platinum (Pt) levels in plasma and cerebrospinal fluid (CSF) in patients with malignant glioma were determined after initiation of selective intraarterial chemotherapy with a combination of VP-16 (etoposide) and CDDP (cisplatin), and were compared with the CSF Pt levels in patients with metastatic brain tumors after intravenous or intracarotid administration of VP-16 and CDDP. CSF Pt levels were also compared for various administration routes, doses, CSF sampling routes and blood-CSF barriers in metastatic brain tumor. Changes in the blood-CSF barrier to CDDP during treatment in a patient with meningeal lymphoma and in a patient recovering from surgical removal of a metastatic brain tumor were also examined by periodic administration of CDDP. All CSF samples were taken through Ommaya reserviors placed in the anterior horn of the lateral ventricle or the postoperative cavity. The mean peak CSF/plasma total Pt ratio (T/T ratio) and the mean CSF total Pt/plasma ultrafiltrable Pt ratio (T/U ratio) were highest (15.0% and 24.4%, respectively) following selective intraarterial infusion of CDDP in patients with malignant glioma, followed by intravenous infusion in meningeal carcinomatosis (11.5% and 18.9%), intracarotid administration (5.4% and 8.7%) and intravenous infusion (60 mg/m2 2.5% and 100 mg/m2 2.9%; and 60 mg/m2 3.5% and 100 mg/m2 7.7%) in patients with the solid type of metastatic brain tumor. In CSF obtained from the postoperative cavity in cases of metastatic brain tumor, T/T and T/U ratios were extremely high (40.9% and 62.4%). However, the CSF Pt level even after selective intraarterial administration of CDDP in malignant glioma was 0.51-1.64 micrograms/ml total Pt and 0.43-1.08 micrograms/ml ultrafiltrable Pt. Even the CSF level obtained from the postoperative cavity was 1.0-4.7 micrograms/ml total Pt. These low levels of total and ultrafiltrable Pt are considered not to be cytotoxic to disseminated cells in the CSF space and to normal brain cells. As for changes in the blood-CSF barrier, repeated administration of CDDP showed that the rate of entry of Pt into the CSF decreased in parallel with improvements apparent on CT scans in the patient with meningeal lymphoma, and also showed that the blood-CSF barrier to Pt was gradually repaired after the metastatic brain tumor had been removed.

A 54-year-old female presented with a spinal intramedullary meningioma manifesting as extremely slow development of dysesthesia in the extremities. Sagittal T1-weighted resonance imaging showed fusiform enlargement of the cervical spinal cord with an area of low-signal intensity suggestive of syringomyelia extending bidirectionally up to the medulla oblongata and downward from the homogeneously enhanced intramedullary space-occupying lesion. The tumor was confirmed to be intramedullary mass with no dural attachment, and was totally removed en bloc. Histological examination showed transitional type of meningioma. The tumor specimen was positive for epithelial membrane antigen, and included glial fibrillary acidic protein-positive fibers, which were thought to be surrounding neural tissues trapped by the nodularity of the tumor in the growing process.

A 62-year-old female presented with rapid aggravation of long-standing facial spasm occurring within a few months. Neuroimaging and angiography demonstrated compression of the root exit zone (REZ) of the facial nerve by an ipsilateral saccular aneurysm at the left vertebral artery (VA)-posterior inferior cerebellar artery bifurcation, in addition to the elongated VA. Neck clipping of the aneurysm and decompression of the REZ from the elongated VA and clipped aneurysm resulted in complete disappearance of the facial spasm. The aneurysm had very thin walls and was apparently about to rupture. Aggravation of long-standing hemifacial spasm may be a warning sign for rapid growth and rupture of a causative aneurysm.

Between 1978 and 1989, 44 patients underwent 44 thoracotomies and 55 craniotomies for nonsmall cell lung carcinoma (NSCLC) and its brain metastases. Patients ages ranged from 20 to 75 years. There were no intraoperative mortalities. The 2-, 3-, and 5-year survival rates following the initial craniotomy were 23%, 10%, and 10%, respectively. Patient survival did not differ with respect to solitary or multiple metastases or the sequence of surgery for primary lesion and brain metastases. Moreover, there was no significant difference in survival between patients treated by surgery alone and those receiving surgery followed by whole brain radiotherapy. After 1985, in vitro tissue culture was attempted using freshly resected specimens of brain metastases obtained from 30 consecutive cases. Of those specimens, nine (30%) were successfully established as permanent cell lines. Eight of those cell lines revealed DNA-aneuploid pattern on flow cytometric analysis. The remaining cell line was not analyzed. Karyotype analysis was also performed in eight of nine established cell lines. Two adenocarcinoma cell lines showed the presence of +3p- chromosome, and three showed +7q- chromosome as recurrent chromosomal abnormalities. These findings provide new evidence concerning the presence of 3p- and/or 7q- marker chromosomes in certain adenocarcinoma cell lines established from brain metastases. The prognosis was poorer in the group with in vitro tumor growth than that in the group showing no in vitro tumor growth. These cell lines established from brain metastases may be useful materials not only for studying the biological characteristics and chemo-sensitivity testing, but also for estimating prognoses after resection of brain metastases.

We measured the level of myelin basic protein (MBP) in the cerebrospinal fluid (CSF) of patients with various kinds of tumors, including malignant tumors, using radioimmunoassay. The CSF had been obtained by lumbar puncture through an Ommaya reservoir or a shunt device placed in the lateral ventricle. The level of MBP was high (> 4 ng/ml) in the patients with meningeal dissemination of malignant tumors, but in those who showed a good response to chemotherapy and/or radiation, it decreased or returned to the normal level, with improvement on the computed tomography and magnetic resonance imaging, cytological, general CSF, and neurological findings. Of seven malignant gliomas without CSF dissemination, six showed an elevated level of MBP before selective intra-arterial chemotherapy with a combination of etoposide and cisplatin administered via a microcatheter placed at A1, M1, P1-P2, and the basilar top. All CSF specimens obtained during the period of the intra-arterial chemotherapy showed an abnormally high (> 4 ng/ml) level of MBP that exceeded the prechemotherapy level. The MBP level decreased or returned to normal in the patients with a good response to chemotherapy after intra-arterial chemotherapy. In some patients with multiple metastatic brain tumors, the MBP level was elevated before treatment and returned to normal after treatment (surgical removal, chemotherapy, and/or irradiation) in all except one. Thus, there was a clear correlation between the timing of treatment and changes in imaging studies and MBP levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Parenchymal brain tumors, which were metastases of primary lung cancer, were surgically removed from 25 patients. During the operation, patients were administered (intravenous or intracarotid) 100 mg/sq m of cis-diamminedichloroplatinum (CDDP) and postoperatively, they received intravenous CDDP at 3-month intervals for 1 year. The results of this mode of treatment were compared with those obtained in 25 patients who underwent the same surgery but received other anticancer agents and in 39 patients who received no postoperative chemotherapy. Patients in the CDDP-treated group survived much longer than both of the other treatment groups. In the CDDP, but not in the other two groups, survival was significantly longer in patients who had undergone resection of their lung tumors than in those who had not. The stage of lung cancer was not found to significantly influence survival time among CDDP-treated patients. Brain metastasis was the cause of death in 12% of the patients who received CDDP, in 16% those treated with other drugs, and in 26% of those who received no chemotherapy. The incidence of local and remote intracranial tumor recurrence, including meningeal carcinomatosis, was similar in the three groups. However, the mean interval from resection of the metastatic brain tumor to local or remote recurrence was longer in the CDDP-treated group than in the other two groups, and the 2-year-survival rate was significantly higher after CDDP administration. These results suggest that CDDP may be useful in the therapy of metastatic brain tumors derived from lung cancer.

The distribution of cis-diamminedichloroplatinum (CDDP) was studied in 23 patients undergoing surgical resection of brain tumors metastatic from lung cancer. CDDP (100 mg/m2) was administered intravenously (i.v.) or intra-arterially (IA) at the time of surgery, and various fluids and tissues were sampled for measurement of drug concentration. Comparison of the two routes of administration disclosed that the plasma level was slightly lower after IA than after i.v. infusion, whereas there was no difference between the two routes in terms of drug diffusion into the brain tissue adjacent to the tumor. However, IA administration resulted in an intratumoral drug concentration twice as high as that achieved with i.v. infusion. The tumor:plasma and tumor:adjacent brain ratios of drug concentration after IA injection were also twice those measured after i.v. administration. The distribution pattern of CDDP is characteristic of water-soluble agents. All patients experienced tolerable nausea and vomiting. Creatinine clearance was moderately reduced in ten cases, but no serious renal toxicity was observed. Seizures occurred postoperatively in nine patients. Infrequent side effects were myelosuppression, ototoxicity, and postoperative intracranial bleeding. All adverse effects disappeared with conservative treatment or no intervention.

A 42-year-old male presented with a rare extracranial meningioma manifesting as right facial swelling, facial nerve paresis, and hearing disturbance. Neurological imaging revealed a primarily extra-axial tumor extending from the temporal base to the subcutaneous space in the parietal region, and partially into the intra-axial region of the temporal lobe through the dura mater, with a small intracerebral hematoma and a small mass in the porus acusticus destroying the temporal bone, the floor of the middle fossa, zygomatic arch, and porus acusticus. Malignant meningioma was confirmed by histological examination after subtotal tumor removal via the transzygomatic approach. Subdural fluid accumulation like hematoma occurred 5 days after surgery and malignant cells were found in the fluid drained by skull trephination. Subsequently, radiation therapy with a total dose of 60 Gy was administered. One year later, he complained of head and neck pain with motor and sensory disturbances in the right upper extremity, and then developed tetraparesis. Cervical x-ray films demonstrated a compression fracture of the C3 vertebral bone and radiolucent areas at C2-4 levels, while computed tomography showed the tumor invading the subcutaneous space and compressing the spinal cord. He died of respiratory distress. Autopsy revealed that the tumor originated in the temporal region and had directly extended to the cervical region.

The angiographic features of left spontaneous carotid-cavernous sinus fistula and multiple dural arteriovenous malformations that developed after transvenous embolization are described. A dural arteriovenous malformation involving the left sigmoid sinus was demonstrated, along with a marked decrease in size of the left carotid-cavernous sinus fistula and the disappearance of venous drainage from the left cavernous to the right cavernous sinus after embolization with spring coils via the left superior ophthalmic vein. The dural arteriovenous malformation of the left sigmoid sinus subsequently extended to the transverse sinus after partial embolization of the sigmoid sinus. Finally, a dural arteriovenous malformation involving the left transverse sinus developed, with the disappearance of the arteriovenous malformation affecting the sigmoid sinus and left carotid-cavernous sinus fistula following complete embolization of the sigmoid sinus via the left transverse sinus.

A 54-year-old woman was admitted to the hospital for evaluation of meningitis. Tuberculous meningitis was suspected initially because of general findings and a high adenosine deaminase activity (ADA) value in the cerebrospinal fluid. Administration of antituberculous drugs was not effective. Computed tomography scanning revealed progression of ventricular enlargement. A ventriculo-peritoneal shunt was placed upon diagnosis of hydrocephalus due to meningitis. The presence of a large abdominal cyst formation was demonstrated. Cryptococcus was detected in the cyst fluid, leading to a diagnosis of cryptococcal meningitis. Intravenous administration of fluconazole (400 mg/day) was begun. Excision of the cyst was performed when Cryptococcus was no longer detected in the cyst fluid. The patient recovered uneventfully.

Patient 1 was a 53-year-old man who had a very rare primary pulmonary meningioma that developed in the left lingular segment. When this report was written, 7 years had passed since he underwent operation, and no recurrence of the meningioma had been detected. In Patient 2, a 61-year-old woman, multiple pulmonary metastases were confirmed 19 years after she had undergone operation for multiple cerebellar meningiomas, and the metastases were resected. After 2 years, multiple intraperitoneal metastases were found, and thus aggressive surgery was performed. Currently, 22 years after the operation for the primary cerebellar meningioma, the patient is alive without any subjective symptoms, although intraperitoneal metastases have recurred. To date, only four cases (all in women) of primary pulmonary meningioma have been reported. Case 1 reported in this article is thus the first case in a male patient to be reported, and, in addition, this patient also has the first reported case to have been evaluated for more than 5 years. In Case 2, however, each of the excised extracranial tumor lesions was histologically homogeneous and showed a hemangiopericytomatous pattern. The histologic picture of those tumor lesions was exactly the same as the picture of a small portion of the cerebellar meningiomas excised 19 years earlier. Thus, all those extracranial tumor lesions were diagnosed to be metastatic meningiomas. However, it is difficult to explain why there had been no symptoms for as long as 19 years until the pulmonary metastases were discovered.

A controlled randomized study was carried out to evaluate the effects of chemotherapy in patients with brain metastases from lung carcinoma. One hundred patients were randomly divided into three groups at the time of diagnosis or after surgery for metastases. Group A received radiotherapy alone; Group B received radiotherapy and chloroethylnitrosoureas (methyl-CCNU, 100-120 mg/m2, or ACNU 80-100 mg/m2, every 6-8 weeks), and Group C received radiotherapy and a combination of chloroethylnitrosoureas and tegafur (300 mg/m2. daily). Of the 100 patients, 88 could be evaluated. The reduction rates of the tumors of the patients in whom tumor was not surgically removed or not totally removed were compared. Complete resolution of the tumor was noted in 29, 69, and 63% of the patients in Groups A, B, and C, respectively, Tumor regression of ⩾50% was seen in 36, 69. and 74% of the patients in Groups A, B, and C, respectively. The difference in the response rates of Groups A and C was statistically signficiant (P

A 59-year-old male developed peripheral oculomotor nerve paresis due to compression by the left posterior cerebral artery (PCA), which was successfully treated by microvascular decompression. Two months later, a similar oculomotor nerve paralysis due to the same mechanism occurred contralaterally and was also treated by microvascular decompression. The previous condition was probably caused by arteriosclerotic changes in the PCA, and the following condition by postsurgical adhesion of the arachnoid membrane. The possibility of vascular compression should be considered when oculomotor nerve palsy rapidly develops, although not proven by angiography.

The authors report on a surgical case of cavernous angioma in the pontomedullary region. A 60-year-old male exhibited a progressive neurological deficit consisting mainly of bulbar paresis and cerebellar signs, without ictal episodes, and computed tomographic scans showed growth of the lesion over 3 years. On preoperative assessment, a glial tumor was suspected to coexist with a cavernous angioma. The vascular malformation was totally excised successfully. This case also revealed an unusual familial occurrence.

Intrathecal administration of MTX and/or Ara-C through the Ommaya system placed in a ventricle has been accepted as a standard therapy for leptomeningeal carcinomatosis. Recently, sustained-release cytosine arabinoside, a depot cytosine arabinoside liposomal injection: DepoCyt, has been reported to be useful for the treatment of leptomeningeal carcinomatosis in Canada, Europe, and the USA. Phase I study of NS-101, DepoCyt in Japan, was performed in patients with leptomeningeal carcinomatosis from solid tumors using the continuous reassessment method (CRM). NS-101 was administered twice through the Ommaya system placed in the lateral ventricle with an interval of 2 weeks. A dose of 25 mg was initially tried in a patient and then a dose of 50 mg was administered in 8 patients. The recommended dose of NS-101 was estimated from pharmacodynamics and tolerance from CRM, and the clinical effectiveness of NS-101 was also assessed. We also compared the present data with the reported data from Europe and the USA. As a result, free Ara-C was maintained over the estimated effective concentration for 2 weeks, and no pharmacodynamic differences were confirmed among Japan, Europe and the USA. Maximum tolerated dose was determined to be 50 mg. Complete cytological response of cerebrospinal fluid (CSF) was obtained in a patient, and CSF cytological conversion of either ventricle or lumbar CSF from positive to negative was observed in four patients. Neurological improvements in 3 pts and no sign of worsening in one patient were observed, and grade IV toxicity based on National Cancer Institute-Common Toxicity Criteria was not encountered. In conclusion, NS-101 was effective for leptomeningeal carcinomatosis from solid tumors and the estimated maximum tolerated dose was 50 mg as approved in Europe and the USA.

Brain metastasis, rarely observed as a tumor recurrence after curative surgery for thoracic esophageal cancers (TEC), has been increasingly observed with improvement of the clinical outcome of TEC.Records of 254 TEC patients who developed recurrent cancers after curative surgery during 1984-2002 revealed 11 patients (4.3%) with symptomatic brain metastasis, which were classified as five without extra-cranial disease (Brain type) and six with other metastatic diseases (Systemic type).Brain metastases were significantly associated with an advanced clinical stage and perioperative chemotherapy, which had been undergone by 73% of the brain metastasis patients, but only 23% for non-brain metastasis patients (p = 0.0008). Comparing to Systemic type, Brain type showed longer duration from esophagectomy to brain metastasis and tended to be more effective for perioperative chemotherapy. All Brain type but only two Systemic type brain metastases were removed by surgery. The average survival after brain metastasis was 17.7 months for the Brain type patients (two alive without tumor recurrence), but only 38.5 days for the Systemic type patients. The histological hallmark of Brain type metastasis was medullary tumor growth with mature tumor vessels, while Systemic type showed invasive tumor growth with naive capillaries.Postoperative brain metastasis in TEC patients is not rare, especially in an advanced clinical stage following perioperative chemotherapy. Surgical removal of brain metastasis might be the most promising treatment unless tumor metastasis in other organs is evident.

A patient with left testicular cancer and metastases to retroperitoneal lymph nodes, lung, and brain was treated by chemotherapy, radiotherapy and surgery, and obtained the state of no evidence of disease, but 10 years after radiotherapy, a glioblastoma multiforme tumor appeared in the brain. This is the first report of a glioma appearing after radiotherapy in a testicular cancer patient.

OBJECTIVE: Previously, we reported a good clinical treatment effect of intrathecal chemotherapy by repeated bolus administration of 5-fluoro-2′-deoxyuridine (FdUrd) for neoplastic meningitis (NM). Moreover, we detected no side effects or neurotoxicity despite the long-term repetition of intrathecal administration. On the basis of these findings, continuous intrathecal chemotherapy (CIC) with FdUrd for patients with NM was attempted using a simple pump system. We evaluated the usefulness of CIC with FdUrd for the treatment of NM. METHODS: A total of 25 patients were enrolled in this study. FdUrd (1.0 mg/d) was administered using a balloon pump system. CIC was continued as long as possible. Eight patients received whole-brain irradiation (3 Gy × 10) simultaneously with CIC. The effects of the treatment were analyzed in terms of improvement in neurological signs and symptoms and the findings of ventricular and lumbar cerebrospinal fluid analysis 2 and 4 weeks after CIC was initiated and on magnetic resonance imaging scans 2 months after CIC began. RESULTS: No apparent toxicity has been observed to date. Evidence of a cerebrospinal fluid response was observed in 13 patients. Headache and nausea were improved in all patients, and cranial nerve impairment was improved in 12 patients. A magnetic resonance imaging response was observed in only 5 patients. Overall response was observed in 15 patients when cases of stable disease were excluded from the responding cases. Survival time from the commencement of CIC (mean ± standard error of the mean) was 255 ± 30 days in 25 patients. CONCLUSION: This therapy may be useful, especially as a maintenance therapy for NM.

To investigate and classify the ophthalmic artery (OA) flow patterns in patients with occlusive carotid artery disease (OCAD).Forty-three patients (52 eyes) with documented OCAD ofor =70% underwent orbital color Doppler imaging. The eyes were first divided into four groups by peak systolic velocity in OA (PSV(OA)): group A, PSV(OA)or = 0; group B, 0PSV(OA)or = 10; group C, 10PSV(OA)or = 40; and group D, PSV(OA)40 cm/s, then further classified by the shape of the OA flow wave. The groups were then compared with respect to the collateral pathway (Co-Path), severity of the OCAD, and systemic diseases.Eyes with unidirectional reverse flow (group A(1)) had a Co-Path from the ipsilateral external carotid artery and 70%-100% OCAD. Eyes with bidirectional reverse flow (group A(2)) had no Co-Path, 75% OCAD, and impending ischemic heart disease (IHD). Group B eyes had dome-shaped OA flow waves with no Co-Path and 99%-88% OCAD. Group C(1) eyes, with normal flow waves, had a Co-Path from the contralateral internal carotid artery and 100% OCAD. Group C(2) eyes, with triangular-shaped flow waves, had no Co-Path, 93%-70% OCAD, and IHD. Group D eyes had normal high flow waves with no Co-Path, 75% OCAD, and hypertension.The OA flow patterns were variously affected by collateral pathway, severity of OCAD, and systemic diseases.

We describe a rare case of cervical canal stenosis at the level of the atlas, presenting with cervical myelopathy as an initial symptom. A 5 5-year-old man was admitted to our hospital with a 4-month history of gait disturbance and clumsiness in both hands. He had no history of trauma, and showed left-sided hemihyperesthesia and mild quadriplegia with exaggerated deep tendon reflexes. Plain cervical tomography revealed marked spinal canal stenosis, with the diameter of 8.0 mm at the level of the atlas. Magnetic resonance imaging demonstrated severe compression of the spinal cord at the atlas, with an extensive high intensity area indicating edema on T 2 -weighted images. The patient showed an excellent recovery after laminectomy of the atlas combined with decompression of the lower posterior fossa of the foramen magnum and dural plasty.

To achieve local control of malignant glioma, we designed a postoperative stereotactic radiotherapy using a micro-multileaf collimator (micro-MLC). The purpose of this study was to clarify the feasibility of this treatment. The treatment was performed in six patients who met the following eligibility criteria: (1) supratentorial tumor, (2) residual tumor volumeor = 40 cm3, and (3) Karnofsky performance statusor = 70. The three planning target volumes (PTVs), which consisted of restricted PTV (RPTV), intermediate PTV (IPTV), and extended PTV (EPTV), defined as the residual tumor plus a 1 cm, 2 cm, and 3 cm margins, respectively, and total dose delivery of 60-68 Gy, 52-60 Gy, and 44-52 Gy to the isocenters of RPTV, IPTV, and EPTV, respectively, in 4 Gy per fraction at five fractions per week, were established. The beam arrangement and the conformal blockade with a micro-MLC for the optimal treatment plan were designed. The treatment plans showed the high dose conformation to EPTV, the appropriate dose gradients in the three PTVs with the high dose homogeneity to RPTV, and the tolerated dose to critical structures. Following the plans, treatment was performed. The clinical findings more than 12 months after the treatment supported its possible use. We conclude that this treatment is feasible at least in selected patients.

Sodium butyrate (SB) -C-4 saturated fatty acid (short-chain fatty acids) present in the human bowel membrane in the quite high concentration (2 mM) as food metabolites. It was previously reported that SB showed anti-tumor effect as HDAC inhibitor, however, the precise mechanism has not been elucidated yet. Here, we focused on the role of SB on cancer cell growth, motility and invasion. Physiological concentration of SB (0.25-4 mM) induced inhibition of cell growth, colony formation in soft agar, in vitro motility and invasiveness with Boyden chamber and wound healing assay in a dose-dependent fashion using human glioblastoma (A172) cells and rat mammary Walker 256 cells. SB also affected the morphology of both cells, namely spread out with marked stress fibers bridging focal adhesions. Phosphorylation levels of focal adhesion kinase (Y577 and Y397 sites) were increased but that of myosin light chain (S19 site) was not altered. All of these biological effects of SB were reversible, and recovered after withdrawal. In contrast, HDAC inhibitor trichostatin A inhibited cancer cell growth irreversibly but not affected motility, invasiveness and morphology. In addition, A172 cells treated with SB showed positivity for senescence-associated β-gal (SA-β gal) staining with elevated expression levels of p53 and p21 proteins in a time and dose-dependent manner. In contrast, mRNA level of p21 was sharply declined after the treatment with SB. Knocking down of p21 protein expression by siRNA reversed both the growth inhibition and positivity for SA-β gal staining but not the inhibition of invasiveness. Thus p21 was required for cellular senescence but not for the decrease in motility induced by SB. Further, SB increased the expression of isocitrate dehydrogenase 1 (IDH1), critical enzyme for glioblastoma progression and metabolism. Finally, intrathecal administration of SB effectively inhibited the invasion of Walker256 cells into the brain and elongated the animal (rat) survival in vivo. Collectively, SB inhibited growth with induced cellular senescence, inhibited invasion and modulated the expression of IDH-1, and thus would be a good candidate for anti-invasive therapy of brain tumor without severe adverse effects. Citation Format: Hidemitsu Nakagawa, Masahiro Shindou, Satoru Sasagawa, Kazuyuki Itoh. Sodium butyrate induced cellular senescence, inhibited invasion and modulated cellular metabolism in glioblastoma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3143. doi:10.1158/1538-7445.AM2014-3143

Bilateral and simultaneous selective venous sampling from the cavernous sinus, inferior petrosal sinus, jugular vein and peripheral vein was performed in 13 patients with hyperprolactinemia in whom dynamic magnetic resonance imaging failed to reveal pituitary adenoma. The prolactin level in peripheral veins of the patients on admission ranged from 35 to 141 ng ml(-1), with a mean value of 69 ng ml(-1). All patients showed disturbance of menstruation or galactorrhea. The indication for surgery in the present study was extremely rare; the patients each wanted to become pregnant and had an intolerance of dopamine agonists. Trans-sphenoidal surgery was performed based on the results of selective venous sampling. The postoperative levels of prolactin were normalized in nine of the patients and normal pituitary function was preserved after surgery. The present study revealed a correspondence of laterality of the peak prolactin level with the main tumor location in patients with latent prolactinoma. However, the tumor/nontumor ratio did not necessarily coincide with the pattern of tumor location, and tumor location was accurately predicted in only 70% of the cases. Selective venous sampling directly from central veins is useful for diagnosis of microprolactinoma.

The usefulness of the in vitro chemosensitivity test, the collagen gel droplet embedded culture drug- sensitivity test (CD-DST, Int J Oncol 11: 449, 1997), in cisplatin-based combined chemotherapy for postoperative recurrent tumors in non-small cell lung cancer (NSCLC) patients was retrospectively analyzed. CD-DST data for cisplatin (or carboplatin), etoposide, 5-fluorouracil, mitomycin C, and vindesine were obtained in 311 surgically resected primary lesions. Of them, 25 patients were practically treated with first-line cisplatin- or carboplatin-based chemotherapy for postoperative initial recurrence. Nine (36%) of them responded to the combined chemotherapy for recurrent lesions, including one with complete remission, whereas 16 did not, with no change in 5 and progression in 11. Seven (70%) of 10 patients receiving combined chemotherapy using two or three in vitro sensitive chemoagents showed good responses, whereas there was no responder among the patients receiving chemotherapy including no in vitro sensitive chemoagents. In particular, of 11 patients showing good sensitivity to cisplatin or carboplatin on CD-DST, 8 (73%) responded to chemotherapy, whereas only one (7%) of 14 patients showing cisplatin- or carboplatin-resistance on CD-DST was a responder. Thus, CD-DST results for the chemoagents, especially cisplatin or carboplatin, correlated with chemotherapeutic response, indicating that the CD-DST analysis of surgically resected primary NSCLC tumors is a practically useful indicator of the clinical effect of first-line cisplatin-based combined chemotherapy for postoperative recurrence.

A rare case of systemic multiple aneurysms located in the extracranial internal carotid artery, intracranial vertebral artery, and intraperitonial arteries is described. A 56-year-old woman was referred to our hospital with suspected rupture of an aneurysm of the right extracranial internal carotid artery. Digital subtraction angiography demonstrated a giant aneurysm in the right extracranial internal carotid artery and an aneurysm of fusiform type of the left intracranial vertebral artery. The extracranial carotid artery aneurysm was successfully resected, with end-to-end anastomosis of the internal carotid artery, preserving the cranial nerves. Five days later, an aneurysm of the left hepatic artery ruptured unexpectedly and was treated with emergency surgery. Other aneurysms in the liver and spleen were identified on postoperative celiac angiography. The patient subsequently underwent an operation for a left intracranial vertebral artery aneurysm by proximal clipping.

Polymorphonuclear neutrophil elastase is a neutral protease released by activated polymorphonuclear neutrophils and plays a crucial role in maintaining host defense. However, under certain conditions, this enzyme damages normal tissue and facilitates infiltration of tumor cells. In this study, surgical specimens were obtained from the tumor core and infiltrating margin of the glioma of 12 patients with astrocytoma of varying degrees of malignancy, and the specimens were tested for the presence of elastase by immunohistochemical analysis. Polymorphonuclear neutrophil elastase was not present in the tumor core of any of the 12 cases. Elastase was expressed in areas of tumor infiltration of the brain in all four glioblastoma cases, three of the four anaplastic astrocytoma cases, and none of the four low-grade astrocytoma cases. There was a higher percentage of elastase-positive polymorphonuclear neutrophils in the infiltrating margin of tumors with greater degree of malignancy. Polymorphonuclear neutrophils are recruited to malignant gliomas, and the elastase released by these cells aids in the infiltration of gliomas.

A 47-year-old male presented with frequent transient ischemic attacks (TIAs) of weakness of the left upper extremity. Computed tomography demonstrated multiple infarcts in the right cerebral hemisphere. Cerebral angiography showed marked atheromatous changes at the siphon of the right internal carotid artery, characterized by wall irregularities and heterogeneous filling. Indium-111-labeled platelet scintigraphy demonstrated abnormal tracer accumulation at the right carotid siphon. Following right carotid artery ligation, this abnormal platelet deposition was resolved and no further TIA was experienced. This suggests that the release of microthrombi from thrombogenic carotid atheroma contributes to embolic stroke.

Sodium butyrate (SB) -C-4 saturated fatty acid (short-chain fatty acids) present in the human bowel membrane in the quite high concentration (2 mM) as food metabolites. It was previously reported that SB showed anti-tumor effect as HDAC inhibitor, however, the precise mechanism has not been elucidated yet. Here, we focused on the role of SB on cancer cell growth, motility and invasion. Physiological concentration of SB (0.25-4 mM) induced inhibition of cell growth (2D), colony formation in soft agar, in vitro motility and invasiveness with Boyden chamber and wound healing assay in a dose-dependent fashion using human fibrosarcoma (HT1080), glioblastoma (A172) cells and rat mammary Walker 256 cells. SB also affected the morphology of HT1080, A172 and Walker 256 cells, namely spread out with marked stress fibers bridging focal adhesions. Phosphorylation levels of focal adhesion kinase (Y577 and Y397 sites) were increased but that of myosin light chain (S19 site) was not altered. All of these biological effects of SB were reversible, and recovered after withdrawal. In contrast, HDAC inhibitor trichostatinA inhibited cancer cell growth irreversibly but not affected motility, invasiveness and morphology. In addition, HT1080 and A172 cells treated with SB showed positivity for senescence-associated β-gal (SA-β gal) staining with elevated expression levels of p53 and p21 proteins in a time and dose-dependent manner. In contrast, mRNA level of p21 was sharply declined after the treatment with SB. Knocking down of p21 protein expression by siRNA reversed both the growth inhibition and positivity for SA-β gal staining but not the inhibition of invasiveness. Thus p21 was required for cellular senescence but not for the decrease in motility induced by SB. Further, proteasome inhibitor, MG132 decreased the cellular growth and inhibited motility and invasiveness of the HT1080 and A172 cells, and showed similar all these biological effects of SB. Finally, intrathecal administration of SB effectively inhibited the invasion of Walker256 cells into the brain and elongated the animal (rat) survival in vivo. Collectively, SB inhibited growth with induced cellular senescence, inhibited invasion by distinct mechanism, and thus would be a good candidate for anti-invasive therapy without severe adverse effects. Citation Format: Kazuyuki Itoh, Kiyoko Yoshioka, Hidemitsu Nakagawa. Sodium butyrate induced cellular senescence and inhibited invasion of cancer cells with distinct mechanism. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2624. doi:10.1158/1538-7445.AM2013-2624

Thirteen patients with meningeal carcinomatosis were treated by ventriculolumbar perfusion using methotrexate (MTX) and cytosine arabinoside (Ara-C). MTX (10-30 mg) and Ara-C (40 mg) were infused at 8- to 12-hour intervals on six or nine occasions via an Ommaya reservoir placed in the lateral ventricle. Nine of thirteen patients had evaluable response (69% response rate with a mean survival of 8.8 months among responders) and ventriculolumbar perfusion therapy was effective in improving cerebral, cranial nerve, and spinal root signs and symptoms, especially sensorimotor disturbance in the lower limbs. Three of the six bedridden patients became ambulatory without assistance and two of the four patients who were walking with assistance became ambulatory without assistance. Urinary incontinence also markedly improved, except in one nonresponder. Lumbar cerebrospinal fluid parameters (cytological findings and tumor markers) also improved in association with the clinical improvement. Our pilot results were encouraging, especially the improvement of sensorimotor function in the lower limbs. However, the toxicity was unacceptable when compared with that of standard intrathecal chemotherapy. Thus, this therapy needs to be investigated further to establish the most appropriate drug doses and perfusate volume to reduce toxicity as well as determine its true efficacy in the treatment of meningeal carcinomatosis.