Cooperative effects of adenoviral vector-mediated interleukin 12 gene therapy with radiotherapy in a preclinical model of metastatic prostate cancer.

We investigated the potential benefits of combining adenoviral vector mediated in situ interleukin-12 (AdmIL-12) gene therapy with radiation therapy (XRT) to enhance therapeutic efficacy. In a metastatic mouse prostate cancer cell line, 178-2 BMA, AdmIL-12+XRT demonstrated enhanced therapeutic activities in vitro as determined by clonogenic survival, apoptosis, and mIL-12 levels. At the molecular level, increased expression of tumor necrosis factor-alpha mRNA was specific for the combined therapy. In a subcutaneous 178-2 BMA in vivo model, the combination of AdmIL-12+XRT produced statistically significant tumor growth suppression compared to control vector Adbetagal, Adbetagal XRT, or AdmIL-12 as monotherapy. In addition, significant prolongation of survival was demonstrated for the combination of AdmIL-12+XRT. The combination of AdmIL-12+XRT significantly suppressed both spontaneous and pre-established lung metastases, and led to a prolonged elevation of serum IL-12 and significantly increased natural killer (NK) activities. Importantly, in vivo depletion of NK cells resulted in significant attenuation of the antimetastatic activities of AdmIL-12 alone or AdmIL-12+XRT. These combined effects suggest that AdIL-12 gene therapy together with radiotherapy may achieve maximal tumor control (both local and systemic) in selected prostate cancer patients via radio-gene therapy induced local cytotoxicity and local and systemic antitumor immunity.

Adenoviral vector-mediated RTVP-1 gene-modified tumor cell-based vaccine suppresses the development of experimental prostate cancer.

We previously identified a novel p53 target gene, RTVP-1, that possesses unique cytotoxic and immunostimulatory activities which make it potentially useful for cancer gene therapy. To test the therapeutic potential of RTVP-1 in a gene-modified tumor cell-based vaccine model, we used an adenoviral vector capable of efficient transduction and expression of RTVP-1 (AdRTVP-1), together with a highly metastatic mouse prostate cancer cell line (178-2 BMA). A vaccine was prepared with 178-2 BMA cells transduced with AdRTVP-1 or a control adenoviral vector expressing beta-galactosidase (Adbetagal). After irradiation of the cells, syngeneic 129/Sv mice were vaccinated three times at weekly intervals. After 3 weeks, they were challenged with orthotopic 178-2 BMA cells. After 21 days, fewer than 60% of the RTVP-1-cell-vaccinated mice developed tumors compared to 100% of the control mice. The RTVP-1-cell vaccine significantly reduced primary tumor wet weight compared with control Adbetagal-cell vaccine (P<0.0001 at 7 and 14 days). Experimental metastasis to lung was also significantly reduced (P=0.0377), and survival significantly increased (P=0.0002). In addition, significantly increased NK and CTL activities were demonstrated in the AdRTVP-1-cell-vaccinated mice. These findings indicate that RTVP-1 gene-modified cell-based vaccines may be useful in the prevention of recurrent prostate cancer.

Therapeutic effects of adoptive splenocyte transfer following in situ AdIL-12 gene therapy in a mouse prostate cancer model.

We developed a preclinical prostate cancer model to study the feasibility of adoptive immunotherapy for residual tumor following neo-adjuvant in situ adenoviral-vector-mediated interleukin 12 (AdIL-12) gene therapy. Splenocytes were obtained from mice with orthotopic 178-2 BMA metastatic mouse prostate cancers treated previously with AdIL-12, or a vector with the IL-12 genes plus the costimulatory gene B7-1 (AdIL-12/B7), or a control gene (Adbetagal). The splenocytes were subsequently injected intravenously into syngeneic mice bearing orthotopic 178-2 BMA tumors generated 3 days previously. Significant orthotopic tumor growth suppression was achieved with splenocytes derived from mice whose tumors had been injected with AdIL-12 compared to splenocytes from control Adbetagal mice (P = 0.0005) and splenocytes from AdIL-12/B7-treated mice significantly suppressed spontaneous lung metastases compared to splenocytes from control mice (P = 0.0356). Adoptive transfer of splenocytes from either AdIL-12 (P = 0.004) or AdIL-12/B7 (P = 0.009)-treated mice significantly prolonged survival relative to controls. Transfer of NK and tumor-specific CTL activities was detected and depletion of CD4+ and CD8+ T cells by in vitro antibody-mediated complement lysis of the splenocytes prior to injection abrogated the effects. Systemic IL-12 administration delivered by intramuscular AdIL-12 injection enhanced the antitumor effects of adoptive splenocyte transfer and boosted the CTL response. Our data provide evidence that this form of adoptive immunotherapy can enhance the effectiveness of neo-adjuvant in situ IL-12 gene therapy in cases of persistent malignancy.

[Usefulness of a new mechanical detachable coil for neurovascular intervention].

The electrolytically detachable platinum coil (Guglielmi Detachable Coil: GDC) is a safe and efficient endovascular tool for treatment of cerebral aneurysms. However, the GDC still has some problems, including a prolonged detaching time and high cost. The Detach Coil System (DCS) is a newly developed platinum detachable coil for the treatment of neurovascular diseases. This has a mechanical "screw" detachment system, which can be detached faster than the GDC. The platinum coil is mounted to the tip of the delivery wire by the "screw" system. For detaching the coil, 20-25 times anti-clockwise rotation of the delivery wire using a "detach locking device" is required. We report our preliminary clinical experience of using the DCS in 11 patients. This series included 5 sacral aneurysms, 3 dissecting aneurysms, and 3 dural arteriovenous fistulas. Seventy-five coils were used in total, of which 5 coils were retrieved and 70 coils were implanted. The detaching time of each DCS was 15-20 seconds, which was much faster than that of the GDC. All lesions were successfully treated without symptomatic complications. In the limited number of cases, our result suggest that the DCS allowed safe and fast endovascular treatment of neurovascular disease at a lower cost.

[Use of the GDC for embolization of a tumor fed by a cavernous branch of the internal carotid artery].

Currently, embolization of small branches of the internal carotid artery (ICA) can be embolized through superselective microcatheterization, followed by the injection of liquid or particulate embolic materials. Often, however, a microcatheter cannot be placed in a stable enough position to allow an endovascular surgeon to perform a safe embolization, and the reflux of embolic agents into the main trunk of the ICA is a major concern. Meticulous technique and a detailed knowledge of the vascular anatomy of the cavernous sinus region are necessary to maximize devascularization of the lesion and to minimize the risk of complications. This report describes the case of a patient with a hypervascular tumor whose feeding vessel from the cavernous ICA was successfully occluded with polyvinyl alcohol (PVA) combined with a regular Guglielmi detachable coil (GDC). A 62-year-old woman had a left-sided petroclival meningioma, which was diagnosed based on computed tomography and magnetic resonance studies. Transfemoral angiographic studies demonstrated that the tumor was fed by intracavernous branches of the left ICA. We believed that another embolic agent would have presented a risk of reflux into the ICA, with possible unwanted occlusion of normal intracranial arteries. A single GDC was sufficient to occlude the feeding artery, and the patient underwent successful surgery 3 days after the endovascular procedure. The GDC can eliminate the ICA supply to hypervascular tumors safely when liquid or particle embolic materials would present a risk of reflux into normal arteries. This device can be positioned and repositioned and can be detached without mechanical force. It may also decrease the risk of unwanted embolization of normal intracranial arteries.

Treatment of androgen-independent prostate cancer with dexamethasone: a prospective study in stage D2 patients.

PURPOSE: In order to evaluate the efficacy of dexamethasone in the treatment of Japanese men with androgen-independent prostate cancer, a prospective study was conducted using prostate-specific antigen (PSA) as a primary end-point. METHODS: Nineteen Japanese men with stage D2 androgen-independent prostate cancer were registered and treatment was started. After ruling out anti-androgen withdrawal syndrome, they were treated with dexamethasone (1.5 mg daily). Patients were monitored for PSA, symptoms, radiologic response, survival rate, time to disease progression, time to treatment failure and complications. RESULTS: Prostate-specific antigen levels decreased in nine patients (50.0%); five (27.8%) showed a 50% or greater decrease and two (11.1%) showed an 80% or greater decrease. For the nine patients, the mean duration of PSA response was 7.3 months and the median duration was 2.1 months (range, 1.2-27.5+). Bone pain, which was noted in 13 patients at study entry, improved in seven patients (53.8%). Of nine patients who had serial radiographic examinations with bone scan, three (33%) showed partial response, two (22%) were stable and four (44%) showed disease progression. Treatment was well tolerated, except for one patient who suffered a severe pulmonary infection. CONCLUSION: Dexamethasone decreased PSA levels and produced subjective symptomatic improvement in the patients with stage D2 androgen-independent prostate cancer.

Transrectal ultrasound for monitoring murine orthotopic prostate tumor.

BACKGROUND: The mouse orthotopic prostate tumor model has been recognized as an ideal preclinical animal model simulating the anatomical and biological milieu of the prostate. In comparison with the subcutaneous tumor model, the only disadvantage of this model is the difficulty of chronological tumor growth monitoring. We have applied recent endoluminal ultrasound technology, transrectal ultrasonography (TRUS), to the monitoring of mouse orthotopic prostate tumors. METHODS: A 6 Fr. 20 MHz catheter-based radial scan probe was used and TRUS was performed without any prior preparation including anesthesia. Orthotopic tumors were initiated by inoculation of 5000 RM-9 cells into the dorsal prostate of 12-week-old C57BL/6 male mice. The tumor growth was monitored by TRUS from day 3 to day 21. In addition, TRUS was performed to detect tumor growth suppression after intraperitoneal administration of cis-diamminedichloroplatinum (CDDP). RESULTS: By ultrasound, tumors became detectable 7 days after tumor cell inoculation. TRUS images were clear and parallel to actual tumor growth. The tumor volume (X) calculated by TRUS correlated significantly with the actual tumor weight (Y) measured at autopsy; Y = 101.653 + 1.174X (R = 0.930, P < 0.001). Similarly, tumor growth suppression induced by CDDP was clearly detected by TRUS with reasonable accuracy. CONCLUSIONS: A high resolution TRUS allows simple and reliable monitoring of in situ tumor growth and growth suppression, making the mouse orthotopic prostate tumor model more efficient.

[Brain abscess and ventriculitis associated with entrapment of the lateral ventricle appearing more like remarkable brain edema than ventricular dilatation--a case report].

We present a case with brain abscess associated with entrapment of the lateral ventricle appearing more like remarkable brain edema in the temporo-occipital lobe than ventricular dilatation. A 72-year-old man suffering from headache and vomiting visited our clinic. CT and MRI showed brain abscess in the right parieto-occipital lobe, associated with ventriculitis. Lumbar puncture also revealed purulent meningitis. Both symptoms and CSF findings improved after administration of antibiotics. The improved condition continued for two months after admission, but disturbed consciousness and left hemiparesis than appeared. MRI and CT showed entrapment of the lateral ventricle and brain edema of the right temporo-occipital region without ventricular dilatation. Because brain edema was thought to be caused by transudate of the CSF through the ventricular wall, lobectomy of the right temporal lobe and opening of the temporal horn were carried out. Although left hemiparesis and disturbed consciousness and brain edema disappeared after the operation, subdural effusion appeared. Using a subdural-peritoneal shunt, the subdural effusion was prevented and disappeared. In this case, we thought Hounsfield Unit (HU) of the brain edema caused by transudate of CSF through the ventricular wall (12.6) was markedly lower than that of so-called vasogenic edema (25.1) due to active inflammation. Measurement of the HU seemed to be a useful means to differentiate the types of brain edema in this situation from that of vasogenic edema caused by brain abscess, and thus a means for selection of the appropriate treatment.

Coil embolization of intradural pseudoaneurysms caused by arterial injury during surgery: report of two cases.

Intradural pseudoaneurysms arose in two patients as a result of arterial injury incurred during surgery. In the first patient, the pseudoaneurysm developed in the middle cerebral artery, at the site of vessel perforation during aneurysmal surgery. In the second patient, the pseudoaneurysm developed in the anterior communicating artery after removal of a tuberculum sellae meningioma. These aneurysms had small ostia and were successfully embolized with electrolytically detachable coils. The clinical features and the treatment of intracranial pseudoaneurysms are discussed.

[Transvenous embolization for cavernous dural arteriovenous shunts: about the intracranial venous approach to the cavernous sinus].

Recently, the first choice of therapy for cavernous dural arteriovenous shunts (CdAVS) is transvenous embolization. Usually the approach routes for cavernous sinus are the inferior petrosal sinus (IPS), the superior ophthalmic vein (SOV) in most cases and the superior petrosal sinus (SPS) in rare case. But, it is difficult for us to treat patients in whom there are no extracranial veins through which to approach the cavernous sinus, with transvenous embolization. We presented the case in which intracranial transvenous approach to the cavernous sinus and transvenous embolization were performed and in which we achieve good results. In this article, we presented a case with Barrow's type D CdAVS and cortical venous drainage. At first, transarterial embolization was performed to decrease the amount of venous drainage for the purpose of eliminate convulsions and consciousness disturbance. However, cortical venous drainage continued. Moreover bilateral dilated SOVs normalized and bilateral IPSs were not visible, so we decided that it was impossible to carry out the transvenous embolization via extracranial veins. Transvenous embolization to the left cavernous sinus via the intracranial ophthalmic vein between the superior ophthalmic fissure and the inferior ophthalmic fissure after craniotomy was performed. Then, the transvenous embolization to the right cavernous sinus was carried out through the right superficial middle cerebral vein after craniotomy. The results were good and chemosis and bilateral abducens palsy diminished immediately. Trans-intracranial venous embolization for CdVAS is a very useful therapy when no extracranial veins exist for transvenous embolization.

[A case of a scalp arteriovenous fistula associated with Rendu-Osler-Weber disease treated by direct percutaneous embolization].

We present a case of Rendu-Osler-Weber disease (hereditary hemorrhagic telangiectasia) accompanied by a scalp arteriovenous fistula, which was successfully treated by direct percutaneous embolization. A 51-year-old man, who had multiple vascular telangiectases and pulmonary arteriovenous fistulae, developed an enlarging pulsatile mass of the scalp anterior to the site of the previous craniotomy for a brain abscess in the right occipital lobe. Angiography demonstrated a high-flow arteriovenous fistula between the right superficial temporal artery and a varix. Percutaneous injection of pure ethyl alcohol was planned but seemed risky because of the major drainage being into the bilateral cavernous sinuses through the superior ophthalmic veins. A 24-gauge plastic needle was placed in the right superficial temporal artery just proximal to the fistula, and 0.7 ml of a mixture consisting of n-butyl cyanoacrylate and lipiodol in a ratio of 1:1 was injected. Then, the varix was directly punctured, and retention of the contrast medium was confirmed under manual compression by the placement of a circular ring. Embolization of the varix using 1.0 ml of 70% glucose solution and a subsequent 1.0 ml of pure ethyl alcohol was performed with compression, resulting in total occlusion of the fistula. The scalp mass resolved gradually and there was no evidence of recanalization. We conclude that direct percutaneous embolization is the first therapeutic choice for a scalp arteriovenous fistula with multiple shuntings associated with Rendu-Osler-Weber disease. Dangerous venous drainage should be eliminated before performing embolization with ethyl alcohol.

Suicide gene therapy for urogenital cancer: current outcome and prospects.

Viral-mediated transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene has been demonstrated by several investigators to confer sensitivity to nucleoside analogs such as ganciclovir (GCV) in a variety of tumor cells including brain, prostate, bladder, kidney, ovary, head and neck, lung, pancreas, and liver cancers. Fourteen suicide gene clinical protocols using adenovirus vectors have been conducted, including four in prostate cancer. Two additional protocols for prostate cancer are in preparation in Japan and the Netherlands. A study conducted at Baylor College of Medicine was the first to demonstrate the safety of HSV-tk plus GCV therapy for human prostate cancer and the anticancer activity of gene therapy in this disease. However, it is still in the early stage of its development, with a number of problems to be overcome. Systemic delivery, specific introduction, and specific expression of the target gene are the major issues to be managed in order to establish a clinically relevant treatment strategy.

Prediction of the virulencies of some enveloped viruses from the structure of the cleavage recognition site of viral glycoproteins essential for infectivity. I. Calculation of interaction energy.

Some evidences have been found that virulency in paramyxoviruses depends on the sensitivity of the cleavage recognition site of the F glycoprotein to serine type proteases. In this report, the interaction energies between the active site of trypsin and the cleavage recognition sites in paramyxoviruses are calculated. Results show that van der Waals energy and electrostatic energy contribute to the sensitivity. The virulencies of some myxo- and retro-viruses are then predicted on the basis of the two calculated interaction energy values.

Increased mucosal ornithine decarboxylase activity in large bowel with multiple tumors, adenocarcinoma, and adenoma.

The polyamine biosynthetase, ornithine decarboxylase (ODC), involved in tumor promotion, was investigated in grossly normal mucosa obtained from surgically resected large bowel; 48 cases with and six cases without large bowel cancer. The mucosal ODC activity was significantly higher in 17 multiple tumor cases bearing adenocarcinoma(s) plus adenoma(s) than in 31 solitary tumor cases bearing one adenocarcinoma alone. It was higher in the mucosa of the two groups of cases than in the mucosa of individuals without large bowel cancer. Furthermore, the enzyme activity in left-sided cancer cases was significantly higher than that in right-sided cancer cases. Carcinoma tissue showed a remarkable high level of enzyme activity, compared with the normal mucosa. The results indicate the larger the number of tumors the higher the level of the ODC activity in the normal mucosa, particularly in left-sided cancer cases. It is concluded that the mucosal ODC may provide a good biological marker to detect individuals at higher risk for large bowel cancer due to exogenous or endogenous factors, and thus contribute to the prevention of mortality from large bowel cancer.

Metabolism of non-protein energy-substrates in septic rats receiving parenteral nutrition.

The influences of sepsis on the metabolism of fatty acid and glucose in rats receiving parenteral nutrition were investigated. The caecum, with its blood supply, was ligated in 10 rats to produce peritonitis and sepsis (septic rats). Twelve rats (control rats) did not undergo this procedure. Five septic rats and six control rats received glucose as a sole nonprotein calorie (septic-glucose rats), and the remaining five septic rats (septic-lipid rats) and six control rats received the same parenteral solution for the first 44 hours, but 25% of the nonprotein calorie was replaced by 10% lipid emulsion for the last 24 hours. At the termination of the parenteral nutrition, 14C-linoleic acid or 14C-glucose was injected as a bolus in the tail vein, and their degradations to 14CO2 and incorporations into the endogenous fat were compared among the three groups. It was demonstrated that the sepsis accelerated the oxidation of fatty acid but did not affect that of glucose. Hepatic lipogenesis with both fatty acid and glucose was accelerated by an infusion of glucose under a septic condition, while it was inhibited by an infusion of lipid emulsion.

Nitrogen-sparing effect of lipid emulsion in septic dogs.

Effects of intravenously administered lipid emulsion on the nitrogen balance in dogs with intraabdominal infection were investigated. The nitrogen balance in dogs supported by parenteral nutrition (PN) with glucose alone was superior to that in dogs supported by PN with glucose and lipid emulsion, in the absence of intraabdominal infection. On the other hand, the nitrogen balance in dogs supported by PN with glucose and lipid emulsion was superior to that with glucose alone, in the presence of intraabdominal infection. Dogs with intraabdominal infection had an insulin-resistance inability to effectively utilize glucose.

Effects of hemodynamic changes induced by hyper- or hypothermia on intravenous lipid clearance rate and lipoprotein lipase activity in dogs.

Hyper- and hypothermia was induced in dogs by peritoneal perfusion with warm or cold Lactate-Ringer's solution, the objective being to alter cardiac output. Changes in cardiac index, intravenous lipid clearance rate (K-value), and lipoprotein lipase (LPL) activity, concomitantly with changes of the temperature of the mixed venous blood were investigated. The cardiac index increased significantly with the hyperthermia and there was a close correlation between the cardiac index and the K-value. The LPL activity did not change significantly with changes in blood temperature, and the correlation between the LPL activity and the K-value was not significant. The hemodynamics has to be considered when attempting to discuss the intravenous lipid clearance rate.

Clearance rate of intravenously administered lipid in postoperative patients.

Elimination rate (K) of intravenously given triglyceride was studied in seventeen patients who underwent elective abdominal operations, and levels of adrenaline, noradrenaline, insulin and blood sugar were simultaneously measured, as stress-indices. All these indices, except for the insulin/blood sugar ratio, increased post-operatively. The postoperative K value increased significantly in comparison with the preoperative value. There was no significant correlation between K value and any of the stress-indices. These results suggest that the initial catabolism of the lipid emulsion triglyceride is enhanced by surgical stress.