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PubMed2005

Round-window anatomical considerations in intratympanic drug therapy for inner-ear diseases.

Our aim was to elucidate the importance of anatomical aspects in planning local therapies for inner-ear diseases. The study undertakes the anatomical evaluation, from a surgical-approach perspective, of the relationship between the false and true round-window membranes. As our design, we chose a human temporal bone dissection study, for which we used 20 fresh temporal bones. After an exploratory tympanotomy and atticotomy, we drilled the anterosuperior (promontory) edge of the round-window niche until the true round-window membrane was completely exposed. We registered the presence or absence and the extent of the false round-window membranes on the round-window niche. We found false round-window membranes obstructing the round-window niche partially or completely in five temporal bones (25%). Complete obstruction was present in one temporal bone (5%). We found mucoperiosteal folds obstructing the round-window niche partially or completely in a significant proportion of the ears. These anatomical particularities could account, at least partially, for the great variability of the results of intratympanic therapies for inner-ear diseases.

Humans↗
PubMedDate not supplied

Melanoma: etiology, treatment, and dental implications.

Melanoma is one of the most serious skin cancers. It arises from neural crest-derived melanocytes located in the epidermis or dermis of the skin. Melanoma also can arise from melanocytes located in other regions of the body such as the eye, meninges, digestive tract, mucosal surfaces, or lymph nodes. There are no proven causes of melanoma but the most commonly associated factor is episodic exposure to the sun. Melanoma is a common cancer that has been increasing in incidence for the last 35 years. The median age at the time of diagnosis is 53 years. It is much more common in whites than in people of color. Five-year survival rates for melanoma of the skin have been increasing since 1976. There are four types of melanoma: superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lintiginous melanoma. Clinical signs indicating possible melanoma are asymmetry, border irregularity, color variation, increase in diameter, elevation, ulceration, and bleeding of pigmented lesions. Histopathologic findings (tumor thickness, tumor invasion), surface ulceration, spread to lymph nodes, and distant metastases are used to project patient prognosis. Treatment consists of surgical excision, lymph node dissection, limb perfusion, regional chemotherapy infusion, radiation, intralesional immunotherapy, systemic chemotherapy, and/or interferon-alpha, depending on the staging of the melanoma. Oral melanomas are rare; however, approximately 20% of all melanomas are found in the head and neck region. The role of the dentist is to be alert for changes in pigmented lesions of the oral mucosa and skin of the head and neck. Lesions suspected of melanoma must be biopsied, which usually involves referral of the patient.

Ethnicity↗
PubMed2006

[A case of pericardial tamponade caused by recurrent breast cancer treated with intrapericardial and intrapleural infusion of cisplatin (CDDP)].

Breast cancer rarely metastasizes to the pericardial cavity to cause cardiac tamponade. We have recently experienced a case of pericardial tamponade due to recurrent breast cancer. A 41-year-old woman who underwent modified radical mastectomy for a right breast cancer (T(1)N(3)M(0), Stage IIIA) 8 years and 8 months ago, was admitted for dyspnea and cough. Chest X-ray and CT scan revealed cardiomegaly and right pleural effusion, and cardiac echogram showed marked retention of pericardial effusion. A diagnosis of cardiac tamponade was made, and pericardiocentesis and thoracentesis were carried out immediately. Based on cytodiagnosis of pericardial and pleural effusion, the diagnosis was pericardial and intrapleural metastases of the breast cancer. Dyspnea was improved by pericardiocentesis and thocacentesis. Both intrapericardiac and intrathoracic instillation of CDDP prevented reaccumulation of pericardial and pleural effusion. After local chemotherapy with CDDP, systemic chemotherapy of CPT-11 was started. Thereafter the patient was discharged from the hospital and recovered her daily activities. This case indicates that intrapericardiac application of CDDP was effective for carcinomatous cardiac tamponade without serious side effects.

Adult↗
PubMed2006

Locoregional delivery of adenoviral vectors.

UNLABELLED: The overall median survival of patients with a malignant glioma is <1 y. Because malignant gliomas rarely metastasize outside the skull, locoregional treatment strategies, such as gene therapy, are under investigation. Recently, convection-enhanced delivery (CED) has been presented as a method to improve delivery of large molecules. The goal of this study was to evaluate whether CED improves intratumoral delivery of adenoviral vectors and compare it with single injection (SI) and multiple injection (4x, MI). METHODS: A replication-deficient adenoviral vector encoding the herpes simplex virus thymidine kinase (HSV-tk) and the human somatostatin receptor subtype 2 (sst(2)) was administered into nude mice bearing subcutaneous U87 xenografts. Tumors were injected with 1.5 x 10(9) plaque-forming units of Ad5.tk.sstr by CED, SI, or MI. Three days later, [(99m)Tc-N(4)(0-1),Asp(0),Tyr(3)]octreotate ((99m)Tc-Demotate 2) was injected intravenously to monitor the virus-induced sst(2) expression. gamma-Camera imaging was performed for in vivo imaging, and the tumor uptake of (99m)Tc-Demotate 2 was determined by gamma-counter. Furthermore, the tumor was sectioned and ex vivo autoradiography was performed. After decay of radioactivity, adjacent sections were submitted to in vitro autoradiography with (125)I-DOTA-Tyr(3)-octreotate, which was used to calculate the transduced areas. RESULTS: Transfected xenograft tissues showed high sst(2) expression and were clearly visualized with a gamma-camera. Accumulation of radioactivity was 2-fold higher in the tumors that were injected with MI compared with CED and SI (P = 0.01). CED and SI resulted in equal uptake of radioactivity in the tumors. The measured areas of transduction in ex vivo and in vitro autoradiographs showed a high concordance (r(2) = 0.89, P < 0.0001). The maximum area of transfection was significantly larger after MI than after CED (P < 0.05) or SI (P = 0.05). Also, the measured volume of distribution was twice as high after administration of Ad5.tk.sstr by MI (56.6 mm(3)) compared with SI (25.3 mm(3)) or CED (26.4 mm(3)). CONCLUSION: CED does not increase adenoviral vector distribution in a glioma xenograft model compared with SI. Therefore, in the clinic MI is probably the most effective delivery method for the large adenoviral particle (70 nm) in malignant gliomas.

Adenoviridae↗
PubMed2006

Local infusion therapy in the monkey brainstem: technical considerations.

This chapter assesses the safety of freehand placement of an infusion catheter (outer diameter, 0.3 mm) in brainstems of cynomolgus monkeys (Macaca fascicularis) for local infusion therapy. A posterior midline approach through the cerebellum and roof of the fourth ventricle was used to implant catheters into a pontine target area. Computer tomography (CT), magnetic resonance imaging (MRI), and histology were used to examine the position of the implants. The freehand placement of a catheter resulted in approximately 5-mm variations in anterior-posterior and dorsal-ventral locations of the targeted implantation site. No evidence of morbidity from the surgery, or from the infusion process was present. In conclusion, small-diameter catheters for chronic drug infusions can be implanted safely into the brainstem, an eloquent region that has been considered surgically inoperable. Infusion systems may offer a minimally invasive, generally applicable tool to provide chronic therapy for central nervous system (CNS) lesions.

Animals↗
PubMed1998

Intralesional cytokine therapy in cancer: a pilot study of GM-CSF infusion in mesothelioma.

Systemic cytokine therapy in cancer has major side effects, and we reasoned that the local infusion of cytokines into tumors could induce local immunologic responses with minimal toxicity and potentially strong systemic anticancer effects. This study investigated the toxicity and effectiveness of intralesional granulocyte/macrophage-colony-stimulating factor (GM-CSF) infusion in solid-tumor masses. We studied 14 patients (12 men, two women) with malignant mesothelioma (MM), aged 60 years (range, 46-70 years), with stage 2 disease, in whom the tumor was of sufficient size and accessibility for an intralesional catheter to be inserted. Recombinant human GM-CSF (Molgramostim; Schering Plough) was infused intralesionally for 8 weeks, by using a portable pump, at a dose of 2.5-10 micrograms/kg/day. One patient using GM-CSF developed histologically confirmed necrosis of tumor surrounding the distal catheter, one developed a marked lymphocytic infiltrate in the tumor and had a partial response measured by chest computed tomography (CT) scan, 10 progressed, and three had no response. Neutrophilia with morphologic evidence of neutrophil activation and clinical features suggestive of neutrophil plugging of blood vessels occurred at doses > 5 micrograms/kg/day. In vitro, GM-CSF doubled human neutrophil/CD11b/CD18 expression, suggesting that neutrophil clumping as seen in vivo might be due to integrin upregulation. Intralesional infusion of cytokines is feasible but can be associated with systemic toxicity and has considerable technical problems. It produces a localized immune reaction with tumor regression in a minority of patients.

Aged↗
PubMedDate not supplied

Local ablation procedures in primary liver tumors: Levovist US versus spiral CTto evaluate therapeutic results.

BACKGROUND: The objective of this study was to compare Levovist power Doppler ultrasound (Levovist US) with contrast-enhanced spiral computed tomography (spiral CT), in the evaluation of the efficacy of percutaneous local ablation procedures, in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Forty-six patients with 62 HCC were studied using Levovist US and triphasic spiral CT, after treatment by radiofrequency ablation (RFA) (32), percutaneous ethanol injection (PEI) (24), transarterial chemoembolization (TACE) (4), laser-therapy (LT) (1) and RFA plus TACE (1). RESULTS: Spiral CT scan showed contrast enhancement in 47% of the cases; at basal power Doppler ultrasound only 10% of the nodules showed to be vascular but, after Levovist infusion, 72.5% showed intralesional vascular spots. CONCLUSION: We detected that residual tumor vascularity in HCC, after treatment using percutaneous local ablation procedures, was significantly increased by Levovist. Levovist US could be proposed as a good alternative in patients unfit for CT scanning due to allergies to iodate contrast media, renal failure or cardiovascular disease and, moreover, could help to select those patients requiring a new treatment, without performing spiral CT, thereby reducing the cost of treatment and improving patient tolerance.

Adult↗
PubMed1997

Three-dimensional dosimetry for intralesional radionuclide therapy using mathematical modeling and multimodality imaging.

UNLABELLED: A method of dosimetry is described that quantifies the three-dimensional absorbed-dose distribution resulting from an intralesional administration of a radiolabeled monoclonal antibody, allowing for both spatial and temporal heterogeneity of distribution of the radionuclide and without the need for a calibration scan. METHODS: A mathematical model was developed to describe the distribution of activity as a function of time resulting from infusion at a single point within the solid component of a tumor. The parameters required for this model are either known directly or may be obtained from SPECT image data registered to computed tomography. Convolution of this distribution with a point-source dose kernel enabled the three-dimensional absorbed-dose distribution to be obtained. RESULTS: This method was applied to a set of patient data acquired in the course of a clinical study performed at our center, and dose profiles and dose-volume histograms were produced. It was shown that the three-dimensional distribution of dose was significantly nonuniform. CONCLUSION: Initial results suggest that this method offers a means of determining the absorbed dose distribution within a tumor resulting from intralesional infusion. This method extends the Medical Internal Radiation Dose computation, which, in these circumstances, would make erroneous assumptions. Furthermore, it will enable individual patient treatment planning and optimization of the parameters that are within the clinician's control.

Humans↗
PubMed1989

Strong anti-tumor effect of monosialoganglioside specific monoclonal antibody 202: a clinical trial in a cancer patient with melanoma.

Mab 202, a mouse monoclonal IgM antibody which recognizes sialic acid alpha 2----3 galactosyl residue in monosialogangliosides and reacts with human melanoma cells but not with normal cells, was administered to a melanoma patient by either intralesional injection or intravenous infusion. Mab 202 induced regressions of the metastatic tumors without side effects. Histopathologic examination showed remarkable degenerative and necrotic changes in the tumor, around which lymphocytes, eosinophils, plasma cells and macrophages infiltrated. Immunoperoxidase staining revealed Mab 202 binding to melanoma cells. Clinical and pathologic evidence suggested that Mab 202 has cytotoxic effects against melanoma cells. Mab 202 may therefore be useful in the treatment of human malignant melanoma.

Antibodies, Monoclonal↗
PubMed1987

[Evaluation of rIFN-gamma in the treatment of lymphoma and melanoma of the skin by systemic and intralesional administration].

This study evaluated the clinical effect of rIFN-gamma for the treatment of lymphoma and melanoma of the skin by systemic intravenous and intralesional administration. By intravenous drip infusion, one of two cases of mycosis fungoides (stage IV) showed CR of skin lesions by administration of a total of 160 X 10(6) units, 4 or 8 X 10(6) units, every other day for 3 months. The remaining case was, however, in a state of PD. Intralesional administration of rIFN-gamma to six cases of cutaneous lymphoma, including three cases of mycosis fungoides, two cases of cutaneous T cell lymphoma, and one case of adult T cell lymphoma, resulted in three cases of CR, two cases of MR and one case of PD. In contrast, four cases of malignant melanoma, two of which received systemic administration and two intralesional administration, did not show any obvious clinical response, one showing PR and the other three PD. Histopathological examination of skin lesions before and after administration of rIFN-gamma indicated that the cutaneous lymphoma lesions were initially infiltrated by lymphocytes and macrophages, and that later on, they were free from tumor cells. Our study indicates that rIFN-gamma appears to provide a new modality for the treatment of cutaneous lymphoma by systemic and intralesional administration.

Administration, Cutaneous↗
PubMed2000

Lattice intrahepatic doxorubicin with and without in-flow occlusion: a pharmacokinetic study of direct liver injection.

AIM: To assess possible improvements in drug delivery to unresectable liver tumours we investigated the pharmacokinetics of intrahepatic doxorubicin in the dog liver with and without inflow occlusion. METHODS: Using a lattice template, doxorubicin was injected into 16 sites (over a 9 cm2 area) in each of three lobes of the liver for a total of 48 sites. The total doses of doxorubicin used were 4.8 mg and 96 mg (0.1 and 2 mg/site). Dogs with intravenous and intra-arterial delivery of the same total doses of doxorubicin were used as controls. Experiments using intrahepatic injection were performed with and without a 30 min occlusion of the hepatic artery, common bile duct and portal vein (inflow occlusion). The studies with vascular stasis were performed to determine if drug clearance from the injection sites and their plasma levels were reduced. Also, it was observed that blood and drug loss along the needle tract was reduced when inflow occlusion was used. Plasma and liver samples were harvested over a 90-min period and analysed by high pressure liquid chromatography (HPLC). RESULTS: In plasma mean peak levels and mean area under the curve (AUC) were significantly lower with intrahepatic doxorubicin (P<0.05) than with intravenous or intra-atrial delivery. In the liver AUCintrahepatic/AUCintravenous ratios were 3.45 and 3.6 with 4.8 mg and 96 mg of doxorubicin respectively. The AUCintrahepatic/AUCintraarterial ratios were 1.97 and 1.65 respectively. The liver extraction ratio (AUCliver/AUCplasma) after intravenous administration with 4.8 mg and 96 mg of doxorubicin was 31.9 with both doses of doxorubicin. The corresponding extraction ratios were 107.6 and 51 for intra-arterial administration and 425.2 and 237.7 for intrahepatic administration for the two doses of doxorubicin. Intrahepatic injection with inflow occlusion minimized the leakage back along the needle-tracts. The liver visibly retained the injected drug more completely. However, there was a decrease in systemic clearance resulting in a reduction of the pharmacological advantage. CONCLUSION: These results indicate that lattice-intrahepatic administration of doxorubicin into the liver using a lattice template was associated with a significant increase in local and decrease in systemic exposure as compared to intravenous or intra-arterial administration of the same doses. Simultaneous occlusion of arterial and portal venous inflow was not shown to improve regional drug delivery. These pharmacokinetic studies may constitute a basis for palliative treatment of liver tumours by lattice intralesional injection when these cancers are found to be unresectable at the time of exploratory surgery.

Animals↗
PubMed1999

The inhibitory effects of bryostatin 1 administration on the growth of rabbit papillomas.

Bryostatin 1 is a protein kinase C modulator that shows antineoplastic activity in a variety of tumor systems. This study examined the effects of bryostatin 1 administration on papilloma growth in rabbits. Investigations of optimal route, dose, and schedule were performed. Several groups of rabbits were inoculated with cottontail rabbit papillomavirus (CRPV) DNA. Bryostatin 1 was administered i.v., both daily and weekly, and intralesionally both weekly and bi-weekly. Intralesionally dosed papillomas were examined histologically for immune cell infiltration. In weekly and daily i.v. trials, 2.5 and 1.0 microg/kg, respectively, showed the greatest overall reduction in tumor size. Bryostatin 1 administered intralesionally also slowed papilloma growth. Treated lesions had significantly higher numbers of heterophils and eosinophils.

Animals↗
PubMed1979

Umbilical metastasis as the presenting symptom of cecal carcinoma.

Umbilical metastases were encountered as the initial presentation of cecal adenocarcinoma in a 62-year-old woman. Intravenous infusion of 5-fluorouracil, along with intralesional injections of 10% 5-fluorouracil, resulted in regression of the tumor masses on the abdominal wall. Although umbilical metastasis is rare, its significance in diagnosing an otherwise silent colorectal cancer warrants the physician's awareness.

Adenocarcinoma, Mucinous↗
PubMed1992

Treatment of malignant glioma by a new therapeutic principle.

L-2, 4 diaminobutyric acid (DAB) is a non-physiological, cationic amino acid transported into cells by System A with potent antitumour activity in vitro against human glioma cells. This activity was the result of the pronounced concentrated uptake of DAB in glioma cells to the extent that a cellular lysis could occur due to osmotic reasons. We describe the treatment of 3 patients with inoperable malignant glioma by direct and continuous administration of DAB in tumour tissue employing a microdialysis technique. One to three microdialysis probes were implanted in the tumour tissue through small dural incisions in 3 patients with inoperable malignant glioma. Micropumps charged with 3 ml a day of a Tris-buffered 0.125 M DAB solution made isotonic at pH 7.55 were adapted to the input channel of the probe and a sampling tube to the output for continuous flowing into tumour tissue. The patients were treated in this way for a total of 14-21 days without side effects assignable to DAB. Massive tumour necrosis occurred as judged by comparison of computed tomography performed before and after DAB treatment. The yield of the dialysis procedure with regard to DAB was estimated to be 40-50%. The dialysate concentration of arginine (a cationic amino acid considered to be transported mainly by system A) was high and increased nearly 4-fold from day 3 to day 6 of treatment. DAB administered in this way into malignant brain tumour tissue was well tolerated and showed promising antitumour activity in the 3 patients with inoperable malignant glioma.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminobutyrates↗
PubMed1996

Local treatment with an antithrombotic drug reduces thrombus size in coronary and peripheral thrombosed arteries.

Since the treatment of thrombotic disease by antithrombotic drugs may be associated with bleeding complications, a local delivery technique for administration of the drug may be useful. The efficacy of low-dose local delivery of an antithrombotic drug on thrombosis was investigated in 73 dogs. The antithrombotic drug (heparin, 25 U/kg, antithrombin: argatroban, 0.05 mg/kg, or defibrinogenating agent: batroxobin, 0.05 U/kg) was infused locally to a 1-h-old thrombus, and no drug was given in controls. The effect of the local delivery on the thrombus was evaluated. Low- and high-dose systemic drug delivery was also evaluated. The mean reduction in thrombotic coronary stenosis observed by angiography was 30.3% with argatroban, 22% with heparin, and 20.8% with batroxobin (P < 0.005 vs controls). Systemic delivery of low-dose heparin or argatroban did not induce any change in thrombus size. With high-dose systemic drug delivery (heparin 250 U/kg, argatroban 0.5 mg/kg), the mean reduction of thrombotic stenosis was 15.2% with heparin and 32.8% with argatroban (P < 0.005 vs controls). In the iliac arterial thrombosis, after local delivery of the drugs, the mean reduction of thrombotic stenosis observed by angiography was 24.4% in the argatroban group, and 19.2% in the heparin group (P < 0.05 vs controls, respectively). With high-dose systemic heparin delivery, the mean reduction of the thrombotic stenosis was 13.2% (P < 0.01 vs control). Angioscopy also demonstrated a similar trend. The high-dose drug delivery reduced systemic coagulability. Thus, local delivery of an antithrombotic agent can reduce the thrombus size in the coronary and iliac arteries without having any significant influence on coagulability.

Angioscopy↗
PubMed2005

Effects of irradiated tumor vaccine and infusion of granulocyte-macrophage colony-stimulating factor and interleukin-12 on established gliomas in rats.

PURPOSE: We investigated granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-12 (IL-12) infused into the injection site of irradiated tumor vaccine (TV) as therapy for gliomas. METHODS: Rats with subcutaneous RT-2 gliomas were treated with irradiated TV and/or subcutaneous infusion of GM-CSF and/or IL-12 via osmotic minipump 5 days after tumor-cell inoculation. Cytotoxic T lymphocyte (CTL) and natural killer (NK) cell activity were analyzed to investigate immune responses. Rats with intracerebral gliomas were treated with irradiated TV and infused GM-CSF/IL-12 3 days after tumor-cell inoculation. Tumor growth rates and animal survival were followed. Survivors were re-challenged with wild-type RT-2 cells subcutaneously or intracerebrally to study long-term anti-tumor immunity. RESULTS: Rats with subcutaneous gliomas treated with GM-CSF and IL-12 or TV plus GM-CSF or IL-12 did not have increased survival rate (P>0.2), but did have prolonged survival time (P<0.05); in contrast, rats treated with TV plus GM-CSF/IL-12 had increased survival rate (P<0.05) and prolonged survival time (P<0.05) compared with controls. These treatment strategies showed enhanced CTL and NK cell activities. Rats with intra-cerebral gliomas treated with TV plus GM-CSF/IL-12 did not have increased survival rate (P=0.11), but did have prolonged survival time (P<0.0001). Survivors in each group were re-challenged with wild-type RT-2 cells, and all had long-term survival. CONCLUSIONS: Irradiated TV plus continuous localized infusion of GM-CSF/IL-12 may induce a tumor-specific anti-tumor immune response on established subcutaneous or intra-cerebral gliomas, and such a treatment strategy deserves consideration as adjuvant treatment for glioma.

Animals↗
PubMed1994

Thrombolysis with tissue-plasminogen activator: results with a high-dose transthrombus technique.

PURPOSE: Low-dose intraarterial tissue plasminogen activator (t-PA) is effective in peripheral thrombolysis but treatment time is prolonged. The aim of this study was to determine whether a transthrombus bolus of t-PA before low-dose infusion shortens lysis time. METHODS: Twenty-three patients with peripheral arterial or bypass graft occlusion were treated with an initial bolus of 20 mg t-PA followed by a continuous infusion of 1 mg/hr. RESULTS: Angiographic lysis was achieved in 16 patients (70%) with a mean time to complete lysis of 14.4 +/- 7.9 hours. Two patients had reocclusion on days 1 and 3, respectively. There were three deaths within the first week of treatment, one from cerebral hemorrhage and two from myocardial infarction. A clinically successful outcome was achieved in 11 patients (48%). Those patients with patency at 1 week maintained this response at a mean follow-up of 11.7 +/- 9.1 months. Thrombolysis was unsuccessful in seven instances. In three of these cases the infusion had to be discontinued prematurely because of serious hemorrhage. Of the seven unsuccessful cases, three patients subsequently underwent a femorodistal bypass, two were left with tolerable ischemic symptoms, and two required a major amputation. There were eight major bleeding complications (35%), four at or adjacent to the catheter entry site and four at a distance, including two cases of cerebral hemorrhage, one of which was fatal. CONCLUSIONS: Transthrombus bolus delivery of tissue plasminogen activator followed by a low-dose infusion shortens lysis time, but this technique appears to be associated with an increased risk of serious hemorrhage.

Adult↗