Severe stenosis of the internal carotid artery and intracerebral hematoma associated with neurofibromatosis type 1: a case report

Neurofibromatosis Type 1 produces a broad spectrum of clinical manifestations as a result of widespread dysplasia of mesodermal and neuroectodermal tissues. One of the most serious aspects of the disease relates to the arterial involvement that may occur. We report a case of severe stenosis of the internal carotid artery and intracerebral hemorrhage associated with neurofibromatosis Type 1. A 49-year-old female was admitted to our hospital after she had suddenly become comatose. On admission, she demonstrated a decerebrate posture in response to painful stimuli, and was assessed as grade 200 according to the Japan Coma Scale. Physical examination disclosed widespread cutaneous neurofibromas and cafe-au-lait spots. Computed tomography of the head revealed a right putaminal extensive hematoma, with a maximum diameter of 7 cm. The hematoma was removed. After this surgical treatment, cerebral angiography was performed. It showed severe stenosis of the terminal portion of the right internal carotid artery associated with a fine telangiectatic network, indicating the presence of moyamoya vessels in the basal ganglia. Although intracranial hemorrhage associated with neurofibromatosis type 1 is a rare condition, fine telangiectatic collateral vessels caused by occlusive cerebrovascular disease, intracranial aneurysms, brain tumors, or hypertension caused by pheochromocytoma or stenosis of the renal artery should be considered as the cause of hemorrhage.     

Dissecting aneurysm of the anterior cerebral artery requiring surgical treatment--case report

A 45-year-old male presented with spontaneous dissecting aneurysm in the anterior cerebral artery manifesting as headache persisting for several days and speech disturbance. Neurological and laboratory examinations showed no abnormalities. Magnetic resonance imaging revealed infarction in the right cingulate gyrus. Angiography revealed occlusion of the right A2. Repeat angiography 8 months later showed a saccular aneurysm had developed. The interhemispheric approach exposed the aneurysm at the junction between the right frontopolar artery and the pericallosal artery. The aneurysm was fusiform due to the right A2 dissection. The aneurysm was trapped and resected. One month after the operation, the patient was discharged without neurological deficits. Cases of dissecting aneurysms in the anterior cerebral artery with ischemic onset are usually treated conservatively. Cases requiring surgery include those due to trauma, growing aneurysms, giant aneurysms, and uncontrolled hypertension. Some dissecting aneurysms of the distal anterior cerebral artery require only resection without bypass surgery.     

Inhibitory Effect of Macrolides on Interleukin-8 Secretion From Cultured Human Nasal Epithelial Cells

The mechanism of macrolide therapy in chronic sinusitis patients is unclear. The authors studied the effect of macrolides on interleukin (IL)-8 secretion from cultured human nasal epithelial cells. Epithelial cells harvested from the nasal polyps of patients with chronic sinusitis were primary-cultured, and secreted IL-8 in culture media was measured by enzyme immunoassay. The cells secreted considerable amounts of IL-8 constitutively and in response to lipopolysaccharide. The secretion was significantly inhibited by 10^?5 M of erythromycin, clarithromycin, roxithromycin, and josamycin. 10^?6 M erythromycin still showed the inhibitory effect, whereas the same concentration of josamycin did not. These results indicate that macrolide antibiotics may act as an immunomodulator to reduce IL-8 in inflammatory sites and, at least partially, account for the clinically discrepant effects between 14- and 16-membered ring macrolides in long-term low-dose therapy for chronic sinusitis.     

FK317, a novel substituted dihydrobenzoxazine, exhibits potent antitumor activity against human tumor xenografts in nude mice.

The antitumor effects of FK317, a novel substituted dihydrobenzoxazine, were evaluated using human tumor xenografts (small cell lung cancer, non-small cell lung cancer, stomach cancer, colon cancer, pancreatic cancer, breast cancer, cervical cancer and ovarian cancer). Tumor growth-inhibitory effects and the effective dose-range of FK317 were much stronger and broader, respectively, than those of reference drugs such as mitomycin C, adriamycin, cisplatin, taxol and irinotecan. Furthermore, the body weight decrease and myelosuppression in FK317-treated mice were less than in the animals given any of the reference drugs. To explain this tumor selectivity, the distribution of FK317 was investigated after dosing tumor-bearing mice with the 14C-labelled compound. The concentration of FK317 in tumor tissues was relatively low, and long tumor retention was not observed. However, thin-layer chromatographic separation revealed that the radioactivity in the tumor resided mainly in strongly cytotoxic metabolites, while that in other tissues resided mainly in non-cytotoxic metabolites. These results suggest that FK317 shows strong antitumor activity without side effects, and one reason for this is its specific metabolite pattern. FK317 is now undergoing phase I clinical trials.     

Anti-cachectic effect of FK317, a novel anti-cancer agent, in colon26 and LX-1 models in mice.

The effects of FK317 (11-acetyl-8-carbamoyloxymethyl-4-formyl-6- methoxy-14-oxa-1,11-diazatetracyclo[7.4.1.0(2, 7). 0(10, 2] tetradeca-2,4,6-trien-9-yl acetate), a novel anti-cancer agent, on murine adenocarcinoma colon26- and human lung carcinoma LX-1-induced cachexia were investigated in mice. Mice bearing colon26 or LX-1 s.c. lost weight and became cachectic, associated with tumor growth. FK317 and mitomycin C (MMC) inhibited the growth of both tumors. FK317 ameliorated the weight loss induced by the presence of colon26 or LX-1, while MMC enhanced it. An attenuation of the reduction in the weights of epididymal fat, gastrocnemius muscle and carcass was observed in FK317-treated tumor-bearing mice in both cachexia models, but not in MMC-treated mice. The decreases in the circulating levels of triglyceride, glucose and non-esterified fatty acid, which were induced by the presence of colon26, was partially inhibited by treatment with FK317. Overall, this study revealed that FK317 is a potent anti-cancer drug with anti-cachectic activity, suggesting that FK317 has potential utility for the treatment of cancer.     

Cytotoxic Mechanisms of FK317, a New Class of Bioreductive Agent with Potent Antitumor Activity

FK317 is a member of a new class of bioreductive agents that exhibit strong cytotoxicity against various human cancer cells. The effect of FK317 was found to be stronger than that of mitomycin C (MMC), adriamycin (ADR) or cisplatin (CDDP). Alkaline elution analysis indicated that FK317 formed interstrand DNA-DNA and DNA-protein cross-links in cells. On the other hand, no DNA single-strand breaks were observed in the cells treated with FK317. In a cell-free system the deacetylated metabolites produced cross-linked DNA under reductive conditions, though FK317 itself did not form DNA-DNA cross-links. In order to elucidate the metabolic activation mechanisms, we established an FK317-resistant subline from human non-small cell lung cancer cells (Lu99) by stepwise and brief exposure (1 h) to FK317. The resistant subline (Lu99/317) showed cross-resistance to MMC and carboquone (CQ), but not to ADR or CDDP. DT-diaphorase, which is one of the activation enzymes of MMC and CQ, was deficient in Lu99/317 cells as determined by enzyme activity assay. However, the levels of NADPH:cytochrome P450 reductase, which is another activation enzyme for MMC and CQ, were comparable in resistant and parent cell lines. Treatment of the cells with dicumarol, an inhibitor of DT-diaphorase, reduced the cytotoxicity of FK317 to Lu99 cells, but not to Lu99/317 cells. These results indicate that deacetylation of FK317 is necessary for its reductive activation, and deacetylated FK317 is reduced by DT-diaphorase to form an active metabolite, which produces DNA-DNA interstrand and DNA-protein cross-links that lead to cell death.     

Cetuximab delivery and antitumor effects are enhanced by mild hyperthermia in a xenograft mouse model of pancreatic cancer

Even with current promising antitumor antibodies, their antitumor effects on stroma‐rich solid cancers have been insufficient. We used mild hyperthermia with the intent of improving drug delivery by breaking the stromal barrier. Here, we provide preclinical evidence of cetuximab + mild hyperthermia therapy. We used four in vivo pancreatic cancer xenograft mouse models with different stroma amounts (scarce, MIAPaCa‐2; moderate, BxPC‐3; and abundant, Capan‐1 and Ope‐xeno). Cetuximab (1 mg/kg) was given systemically, and the mouse leg tumors were concurrently heated using a water bath method for 30 min at three different temperatures, 25°C (control), 37°C (intra‐abdominal organ level), or 41°C (mild hyperthermia) (n = 4, each group). The evaluated variables were the antitumor effects, represented by tumor volume, and in vivo cetuximab accumulation, indirectly quantified by the immunohistochemical fluorescence intensity value/cell using antibodies against human IgG Fc. At 25°C, the antitumor effects were sufficient, with a cetuximab accumulation value (florescence intensity/cell) of 1632, in the MIAPaCa‐2 model, moderate (1063) in the BxPC‐3 model, and negative in the Capan‐1 and Ope‐xeno models (760, 461). By applying 37°C or 41°C heat, antitumor effects were enhanced shown in decreased tumor volumes. These enhanced effects were accompanied by boosted cetuximab accumulation, which increased by 2.8‐fold (2980, 3015) in the BxPC‐3 model, 2.5‐ or 4.8‐fold (1881, 3615) in the Capan‐1 model, and 3.2‐ or 4.2‐fold (1469, 1922) in the Ope‐xeno model, respectively. Cetuximab was effective in treating even stroma‐rich and k‐ras mutant pancreatic cancer mouse models when the drug delivery was improved by combination with mild hyperthermia.     

Delayed improvement of autonomic nervous abnormality after the Maze procedure: time and frequency domain analysis of heart rate variability using 24 hour Holter monitoring

Objective—To analyse heart rate variability in patients with atrial fibrillation after the Maze procedure, to investigate whether the procedure damages the cardiac autonomic fibres supplying the sinus node.
Design and patients—Time and frequency domain analyses of RR variability were performed using 24 hour Holter monitoring one month after surgery in 12 patients with atrial fibrillation who underwent the Maze procedure (Maze group) and in seven patients who underwent cardiac surgery without the Maze procedure (control group). Mean RR intervals (mRR) and the standard deviation of successive RR intervals (SDRR) were determined by time domain analysis, and high frequency (HF), low frequency (LF), and total power (TP) spectral components of RR variability were calculated by frequency domain analysis. Holter monitoring was also performed at six and 12 months after cardiac surgery in the Maze group.
Results—Circadian variation (mean (SD)) in mRR (daytime to night time difference: 119 (60) v 302 (143) ms), SDRR (daytime: 8.4 (3.3) v 37.0 (12.0) ms), TP (daytime: 46.7 (16.0) v 171.8 (30.4) ms), HF (daytime: 19.6 (9.9) v 36.7 (7.1) ms²), and LF/HF (daytime: 0.31 (0.07) v 1.18 (0.46)) was decreased in the Maze group at one month compared with the control group (p < 0.01), but showed improvement at six and 12 months (p < 0.05).
Conclusions—Surgery combined with the Maze procedure markedly suppressed the circadian variation of heart rate over a 24 hour period within one month after surgery, mainly because of damage to the innervation of the sinus node. However, at six and 12 months there was restoration of circadian variation, probably as the result of reinnervation of the sinus node.

Keywords: autonomic nervous system;  heart rate variability;  Maze procedure     

Cardiac sarcoidosis underlies idiopathic dilated cardiomyopathy: importance of mediastinal lymphadenopathy in differential diagnosis.

BACKGROUND: Cardiac sarcoidosis is frequently overlooked or misdiagnosed as idiopathic dilated cardiomyopathy (DCM), primarily because of difficulties in its diagnosis. This is a crucial issue because appropriate therapy with immunosuppressive agents can be initiated if early diagnosis is achieved. METHODS AND RESULTS: Thoracic computed tomography (CT) was retrospectively analyzed in detail with special reference to lymph node swelling (LNS) in the mediastinum of 8 patients diagnosed with idiopathic DCM who underwent left ventriculoplasty (LVP), and were later proven to have active cardiac sarcoidosis by histological evaluation of the resected myocardium. Twenty age-matched patients with idiopathic DCM who also underwent LVP served as controls. On conventional chest radiographs, none of the cardiac sarcoidosis patients exhibited lymph node involvement, including bilateral hilar lymphadenopathy. However, CT demonstrated significant mediastinal LNS in 7 (88%) of them and in only 1 (5%) of the 20 controls. There was a significant difference in the incidence of LNS in the 2 groups (p=0.00005). CONCLUSION: Evaluation of mediastinal lymphadenopathy by CT is an easy and valuable initial screening method for distinguishing cardiac sarcoidosis from idiopathic DCM.