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Study on chemosensitivity of oral squamous cell carcinomas by histoculture drug response assay.

The aim of this study was to evaluate the reliability and utility of a histoculture drug response assay (HDRA) for treatment of squamous cell carcinoma in the oral cavity. Nineteen patients with squamous cell carcinoma of the oral cavity were assessed. Tumor tissue samples were histocultured on Gelfoam sponge gels in 24-well plates, followed by treatment with 5-fluorouracil (5-FU, 300 microg/ml), cisplatinum (CDDP, 20 microg/ml), 4-0-tetrahydropyranyl adriamycin (THP, 4.6 microg/ml), bleomycin (BLM, 20 microg/ml), adriamycin (ADM, 15 microg/ml) and docetaxel (TXT, 100 microg/ml). The controls were cultured without drug treatment. After completion of the culture, the relative cell survival in the tumors was determined using an MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide) assay. The inhibition rate was calculated, and sensitivity was defined as a tumor inhibition rate greater than 60% for 5-FU, 40% for TXT, and 50% for the other drugs. All cases were successfully evaluated by the HDRA, and no apparent relationships between the chemosensitivity test results and clinico-histopathological characteristics were seen. CDDP tended to be sensitive, whereas 5-FU, THP, and BLM tended to show resistance in many cases. A good correlation was obtained between the chemosensitivity test results and clinical response. In conclusion, HDRA is a useful method for selection of an anticancer agent for individual oral cancer patients, because of its ease of evaluation and high predictability.

Adult↗

Value of pre-operative embolization in surgery for nasopharyngeal angiofibroma.

The value of embolization in surgery for nasopharyngeal angiofibroma is a controversial matter. We analysed retrospectively the results of surgical treatment in ten patients with a nasopharyngeal angiofibroma, the last five of whom underwent pre-operative embolization with Gelfoam. Embolization reduced the intraoperative blood loss at primary surgery from an average of 1510 ml in the non-embolized patients to 510 ml in the embolized patients and transfusions from an average of 4.4 units to none. Seven reoperations were performed on four non-embolized patients on account of tumour recurrence, while no recurrences were diagnosed among the pre-operatively embolized patients. Blood loss in the reoperations averaged 4065 ml, and transfusions 7.1 units. The results indicate that embolization is effective in reducing intraoperative blood loss and contributes to improved surgical results. We recommend it as a routine pre-operative adjunct to surgery for nasopharyngeal angiofibroma.

Adolescent↗

Long-term observation after soft posterior meatal wall reconstruction in ears with cholesteatoma.

We performed tympanoplasty with reconstruction of the soft posterior meatal wall for the prevention of post-operative retraction pocket formation. Our method is characterized by the reconstruction of the soft posterior meatal wall, non-obliteration with permanent or temporary materials, including Gelfoam, no use of a Palva flap and the use of fibrin glue for attaching the fascia to the posterior meatal skin. None of the patients experienced post-operative narrow-neck retraction pocket formation, and whenever aeration of the middle ear was disturbed, a balloon-like retraction was observed. Not all the posterior meatal walls retracted. The final position of the posterior meatal wall varied among the subjects. No serious cavity or hearing problems have occurred since surgery. Due to the strong possibility of post-operative retraction pocket formation in cases with a large balloon-like retraction, we rejected adopting the canal wall up technique or hard posterior meatal wall reconstruction.

Cholesteatoma, Middle Ear↗

Visual callosal projections in the adult ferret.

The laminar and tangential organization of visual callosal projections of areas 17 and 18 were investigated in the adult ferret, using histochemical methods to visualize axonally transported horseradish peroxidase (HRP). Normal adult ferrets were given injections of HRP throughout one visual cortex or had gelfoam soaked in HRP applied to the transected corpus callosum. The ferret callosal cell distribution has a greater tangential extent in area 18 than in area 17. In addition, the radial organization of callosal cells in areas 17 and 18 differs: three times as many infragranular cells are present in area 18 than in area 17, although the number of supragranular cells is similar for both areas 17 and 18. Since the projections of alpha retinal ganglion cells are reported to be exclusively contralateral in the ferret (Vitek et al., 1985), callosal projections may make a major contribution to the binocularity of neurons in area 18.

Animals↗

Systemic delivery of insulin via an enhancer-free ocular device.

Sodium insulin and zinc insulin ocular devices are developed for the systemic delivery of insulin. The devices consist of Gelfoam (absorbable gelatin sponge, USP) as an insulin carrier and do not contain any surfactant or absorption enhancer. Sodium insulin was dissolved in either distilled water, 30% ethanol, or 10% acetic acid for either eyedrop or device preparations. Because of its low solubility in water and aqueous ethanol solution, zinc insulin was dissolved in 10% acetic acid-water solution for eye devices preparation. Commercially available Humulin R was selected as another source of zinc insulin and was used as an eyedrop as well as one device preparation. Only 10% acetic acid solution-treated insulin devices produce significant blood glucose reduction. The dose of insulin used in this study is < 50% of that used in the reported insulin devices.

Animals↗

Primary Ewing's sarcoma/peripheral primitive neuroectodermal tumor at the vertex of the skull with elevated serum carcinoembryonic antigen: case report.

A primary Ewing's sarcoma arising in the skull is relatively rare. Although a small number of case reports noted elevated carcinoembryonic antigen (CEA) in patients with primary central nervous system (CNS) neoplasms, there is no report of Ewing's sarcoma/peripheral primitive neuroectodermal tumor (PNET) with elevated serum levels of CEA. A 7-year-old boy who had episodes of headache and vomiting had noticed a solid mass in the vertex of the head. Imaging studies revealed a large intra- and extracranial tumor at the vertex of the skull. Hematological examination demonstrated high serum levels of CEA: 91.09 ng/ml. The patient initially underwent an embolization of the bilateral middle meningeal arteries with Gelfoam particles. One week later, the patient was operated on and a subtotal resection of the tumor was performed. On histopathological and molecular genetic examination, the tumor was diagnosed as a Ewing's sarcoma/peripheral PNET. Immunohistochemical study showed strongly positive staining for CEA in the tumor cells. The serum level of CEA was normalized at 0.83 ng/ml after the tumor was removed and the boy underwent radiotherapy and 3 courses of chemotherapy. This is the first reported case of a primary Ewing's sarcoma/peripheral PNET at the vertex of the skull with elevated serum CEA.

Carcinoembryonic Antigen↗

Testing bone substitutes in a small animal model of revision arthroplasty.

This study evaluated a modification of the rat-pin model to enable testing of bone substitute materials. The model was characterized using the ceramic, beta-tricalcium phosphate (betaTCP) as a filler. A 1 mm wide, 3.6 mm deep defect was created around a stainless steel (SS) implant in the proximal tibia of a rat. This defect was filled with a ceramic powder. Large particles (90-312microm) of betaTCP were mixed with Gelfoam to form a paste which was then molded around the proximal end of either an uncoated SS pin or a pin coated with hydroxyapatite (HA). The pin with its ceramic collar was then implanted into the proximal tibia of 16 male Sprague Dawley rats. Two animals with coated implants and two with uncoated implants were sacrificed at 3, 6, 14 and 26 weeks. Longitudinal sections of each tibia were stained with toluidine blue and labeled for tartrate resistant acid phosphatase (TRAP). There was initial fibrous tissue interposition around the implants which was completely remodeled around the HA coated pins but which persisted in apposition to the SS pins. The remodeling process peaked at 3 weeks around the HA coated pins and at 6 weeks around the uncoated implants. There was little remodeling around either implant by 26 weeks. There was considerable residual betaTCP present which was well tolerated as the particles were often encased in bone. The model has several characteristics of revision arthroplasty and the results demonstrate the suitability of this model for testing bone substitutes.

Journal Article↗

Evidence for the causal role of endogenous interferon-alpha/beta in the regulation of angiogenesis, tumorigenicity, and metastasis of cutaneous neoplasms.

Primary tumor growth and metastasis depend on angiogenesis, which is determined by the balance between proangiogenic and antiangiogenic molecules. Interferon (IFN)-alpha and -beta inhibit angiogenesis through downregulation of interleukin-8, matrix metalloproteinase-9, and basic fibroblast growth factor. To provide evidence for the causal role of IFN-alpha/beta in the induction of neoplasms, their angiogenesis, and hence, progressive growth, we carried out experiments using 129S6 IFN-alpha/beta receptor -/- mice back-crossed to BALB/c nude mice. Subcutaneous angiogenesis was determined following implantation of gelfoam sponges containing 0.4% agarose and several proangiogenic molecules. Tumorigenicity and production of lung metastasis were determined subsequent to subcutaneous and intravenous injections, respectively, of highly metastatic A375SM human melanoma cells. Carcinogenesis was induced by chronic exposure of mice to UVB radiation (5 kJ/m2, 3 times/week). Angiogenesis, tumorigenicity, and production of metastasis, as well as development of autochthonous skin tumors, were all accelerated in IFN-alpha/beta receptor -/- mice as compared to control mice. Collectively, the data show that inability to respond to endogenous IFN-alpha/beta (through a mutation in the IFN-alpha/beta receptor) leads to increased susceptibility to carcinogenesis, enhanced angiogenesis, tumorigenicity, and metastasis.

Angiogenesis Inhibitors↗

Nonsurgical therapies for hepatocellular and cholangiocellular carcinoma.

Surgical resection is the first choice of treatment for patients with hepatocellular (HCC) and cholangiocellular carcinomas. Prolongation of survival is, however, the only realistic goal for most patients, which can be often achieved by nonsurgical therapies. Inoperable patients with large or multiple HCCs are usually treated with transarterial chemoembolization (TACE) with lipiodol in combination with a chemotherapeutic drug and gelfoam. Three-year survival depends on the stage of the disease and is about 20%. Patients with earlier tumor stages (one or two tumor nodules less than 3 cm in size) are suitable for treatment with percutaneous ethanol injection (PEI) alone or in combination with TACE. Several studies have shown that in these early stages, the 3-year survival rate is approximately 55%-70% in the actively treated patients which is significantly higher than in untreated patients. In advanced stages of the disease, TACE and PEI have no effect on survival and should not be performed. Some of these patients have been successfully treated with octreotide. Patients with inoperable cholangiocellular carcinoma are treated by endoscopic or percutaneous stent placement. If stenting does not achieve adequate biliary drainage, multidisciplinary therapy including internal/external radiotherapy or photodynamic therapy should be considered in patients with potential long-term survival. In conclusion, nonresectional therapies play an essential role in the therapy of inoperable hepato- and cholangiocellular carcinomas as they lead to satisfactory survival. Multidisciplinary therapy appears to be the current trend of management.

Bile Duct Neoplasms↗

A selective retinoid X receptor agonist bexarotene (LGD1069, targretin) inhibits angiogenesis and metastasis in solid tumours.

The present study determined the influence of a retinoid X receptor agonist bexarotene on angiogenesis and metastasis in solid tumours. In the experimental lung metastasis xenograft models, treatment with bexarotene inhibited the development of the lung tumour nodule formation compared to control. In vivo angiogenesis assay utilising gelfoam sponges, bexarotene reduced angiogenesis in sponges containing vascular endothelial growth factor, epidermal growth factor and basic fibroblast growth factor to various extent. To determine the basis of these observations, human breast and non-small-cell lung cancer cells were subjected to migration and invasion assays in the presence of bexarotene. Our data showed that bexarotene decrease migration and invasiveness of tumour cells in a dose-dependent manner. Furthermore, bexarotene inhibited angiogenesis by directly inhibiting human umbilical vein endothelial cell growth and indirectly inhibiting tumour cell-mediated migration of human umbilical vein endothelial cells through Matrigel matrix. Analysis of tumour-conditioned medium indicated that bexarotene decreased the secretion of angiogenic factors and matrix metalloproteinases and increased the tissue inhibitor of matrix metalloproteinases. The ability of bexarotene to inhibit angiogenesis and metastasis was dependent on activation of its heterodimerisation partner peroxisome proliferator-activated receptor gamma. Collectively, our results suggest a role of bexarotene in treatment of angiogenesis and metastasis in solid tumours.

Animals↗

Highly selective embolization of bilateral cavernous arteries for post-traumatic penile arterial priapism.

High-flow priapism is characteristically diagnosed on clinical findings: a prolonged, non-painful erection with a delayed onset that develops after a penile or perineal trauma. If conservative measures fail arteriography is indicated, which shows a blush of extravasating contrast from an arterio-cavernous fistula (rarely, as in our case bilateral) that can be treated by embolization. The embolic agent is gelfoam or a microcoil. Bilateral embolization is indicated when unilateral treatment does not result in detumescence of the penis. When the embolization is done highly selective the risk of complications is low and the results on erectile function are good.

Adult↗

TIMP-3 deficiency in the host, but not in the tumor, enhances tumor growth and angiogenesis.

Tumor cells, stromal cell compartment and the extracellular matrix (ECM) together generate a multifaceted tumor microenvironment. Matrix metalloproteinases and their tissue inhibitors (TIMPs) provide a means for tumor-stromal interaction during tumorigenesis. Among TIMPs, TIMP-3 is uniquely localized to the ECM and is frequently silenced in human cancers. Here, we asked whether the absence of TIMP-3 in the tumor cell or the host affects the process of tumorigenesis. Timp-3(-/-) ES-cell clones were generated and used to develop teratomas in nude mice. Timp-3(-/-) teratomas showed similar tumor take, growth, and angiogenesis compared to timp-3(+/+) teratomas. To study the effect of TIMP-3 ablation in the host stroma, we measured the growth kinetics of subcutaneous B16F10 melanomas in timp-3(-/-) and wild-type littermates. Tumors grew significantly faster in timp-3(-/-) than in wild-type mice and their CD31 content was significantly higher indicating increased angiogenesis. Augmented angiogenesis in timp-3(-/-) mice was directly tested using Matrigel plug and Gelfoam assays. In response to FGF-2, timp-3(-/-) endothelial cells invaded more efficiently, leading to enhanced formation of functional blood vessels. Thus, TIMP-3 deficiency in the host, but not in the tumor per se, leads to enhanced tumor growth and angiogenesis. TIMP-3 located within the tumor microenvironment inhibits tumorigenesis.

Animals↗

Non-operative management of haemobilia.

BACKGROUND: The aim was to evaluate a non-operative approach to the management of haemobilia. METHODS: This was a retrospective analysis of patients presenting over 10 years with haemobilia. All patients had upper gastrointestinal endoscopy, abdominal ultrasonography and digital subtraction angiography. Superselective coil and/or Gelfoam embolization was done as close as possible to the bleeding site. Completion angiography was performed routinely to confirm adequate embolization. RESULTS: There were 23 patients with liver trauma and six with inflammatory conditions. All patients required resuscitation with fluids and blood transfusion, and had the haemobilia controlled successfully by angiographic embolization. There was one death from fulminant hepatic sepsis. CONCLUSION: This series attests to the efficacy of a non-operative approach to haemobilia using radiological diagnosis and intervention.

Adolescent↗

Bone marrow CD34 cells generate fewer T cells in vitro with increasing age and following chemotherapy.

To assess the influence of high-dose chemotherapy and age on the intrinsic capacity of stem cells to generate T cells, CD34+ cells derived from bone marrow used in clinical transplantation were evaluated in an in vitro T-cell assay using a mouse thymic microenvironment. CD34+ cells were sorted from healthy donor and autologous back-up bone marrow after density gradient centrifugation and depletion for CD1, 3, 4, 7, 8, 19 and glycophorin A using magnetic beads. CD34+ cells were then introduced in day 14-15 fetal SCII) mouse thymus lobes by incubation in hanging drops for 48 h. After transfer to gelfoam rafts they were cultured for variable time periods. The lobes were then homogenized in a tissue grinder for flow cytometric analysis gating on human cells. These were evaluated for CD4, CD8, CD3 and HLA-DR surface expression. 51 samples were analysed and three patterns of T-cell precursor development could be observed. In pattern A no human cells could be recovered, in pattern B maturation stopped at the CD4+ CD8- CD3- pre-T-cell stage, and in pattern C maturation to double-positive CD4+ CD8+ thymocytes was reached. In 25 healthy donors under age 40 three showed pattern A, 12 pattern B and 10 pattern C, whereas in 16 healthy donors over the age 40 there were respectively four with A, seven with B and only five with C (P=0.01). In 10 patients who had previously received chemotherapy, none developed pattern C, five pattern B and five pattern A, in contrast to 15/41 pattern C, 19/41 pattern B and 7/41 pattern A in healthy donors. These data suggest an intrinsic loss of T-cell generation capacity from adult bone marrow stem cells in comparison to reports on stem cells of fetal origin. This loss correlated weakly with age, irrespective of thymic involution, and may be further reduced by prior chemotherapy.

Adult↗

Emergency embolization of spontaneous ruptured hepatocellular carcinoma: correlation between survival and Child-Pugh classification.

From February 1994 to April 2000, 29 emergency gelfoam embolizations for spontaneous ruptured hepatocellular carcinoma (HCC) performed in 28 patients were retrospectively reviewed. There were 11 patients in Child's A, 11 in Child's B and six in Child's C classification of cirrhosis. The duration of the procedure, artery embolized and complications were reviewed, and the Child-Pugh classification of each patient was correlated with their mean survival period. Embolization was done in 12 right hepatic arteries, two left hepatic arteries and 15 proper hepatic arteries. In one patient, the left hepatic artery was embolized initially but the proper hepatic artery was also embolized because another subcapsular liver tumour was found after reviewing the preangiogram CT scan. The entire procedure took 40-170 min (mean = 86 min) with no periprocedural complication. Following embolization, the mean survival period for Child's A class was 218.3 days, Child's B class was 83.4 days and Child's C class was 11.0 days. Transcatheter embolization is an effective treatment to arrest bleeding in spontaneous ruptured HCC. Patients with Child's A class cirrhosis have the longest survival. Selective embolization of either the right or the left hepatic artery alone carries the potential risk of missing multifocal HCC that might not be easily appreciated during angiography.

Adult↗

Hepatocellular carcinoma and chemoembolization.

BACKGROUND: Chemoembolization is often used in the treatment of hepatocellular carcinoma; however, there are limited data on its efficacy in an Australian setting. AIMS: To review retrospectively the experience of 21 patients with hepatocellular carcinoma who collectively had 36 chemoembolizations performed between October 1995 and February 1999 in a teaching hospital and liver transplant centre in Victoria. METHODS: Selective catheterization of the right or left hepatic arteries was performed. A mixture of cisplatin 50 mg, epirubicin 50 mg, mitomycin C 10 mg, Lipiodol and gelfoam was injected. Computed tomography (CT) scans were performed at baseline and at 1-3 months after chemoembolization. Outcome measures included response rates, toxicity, progression-free and overall survival. RESULTS: CT response rates: partial response 19% (n = 7), median duration 11 months (range 2+ to 37+); minor response 17% (n = 6), median duration 7 months (1+ to 12+); stable disease 42% (n = 15), median duration 3 months (1+ to 15 months); and progressive disease 22% (n = 8). Major toxicities included one case each of acute renal failure, contrast encephalopathy, gastric ulceration and hepatorenal failure. Median progression-free survival was 3 months (range 0-37+). Median overall survival was 15 months (range 6-50+). CONCLUSION: Chemoembolization has a role in the palliative treatment of hepatocellular carcinoma. Our response rates and toxicity data are consistent with those in the published literature. However, new treatments are needed and prevention of disease by reduction in the prevalence of chronic hepatitis B and C will be required to significantly reduce mortality from this tumour.

Adult↗

BDNF and NT-3 applied in the whisker pad reverse cortical changes after peripheral deafferentation in neonatal rats.

It has been known for a long time that subcortical input drives the specification of cortical areas. Molecular signals mediating this instructive effect from the periphery are poorly understood. In foetal or neonatal rats, ablation of whisker follicles, transection of the infraorbital nerve, inhibition of axonal transport, but not impulse activity blockade, prevent formation of barrels in the primary somatosensory cortex (S1). These findings suggest that a chemical signal, possibly arising from the skin or the follicle, may be responsible for somatotopic pattern formation in S1. Neurotrophins promote survival and differentiation of primary sensory neurons, and are expressed in the whisker pad during development. Neonatal rats received gelfoam impregnated with NGF, BDNF or NT-3 under the whisker pad following surgical denervation of whisker rows D and E on P0. Barrel formation in S1 was assessed on P7 by acetylcholinesterase histochemistry and 5-HT-immunohistochemistry. BDNF and NT-3, but not NGF, promoted development of the cortical barrels corresponding to denervated whiskers. Furthermore, BDNF and NT-3 prevented the lesion-induced expansion of row C barrels, while NGF appeared to promote row C expansion. Our results suggest that BDNF and NT-3 arising from the whisker pad are involved in the formation and/or maintenance of the barrel pattern in S1. These findings are potentially relevant for the prevention of sensory disturbances possibly due to reorganization of central sensory circuits after peripheral nerve lesions in humans.

Acetylcholinesterase↗

Arteriovenous malformation of the uterus associated with a missed abortion.

Arteriovenous malformation of the uterus is a rare uterine abnormality. This entity is generally associated with the presence of molar disease, choriocarcinoma and uterine surgery, but may be congenitally acquired. The presence of an arteriovenous malformation generally leads to unexplained profuse uterine bleeding. The diagnosis of this entity has traditionally been made by arteriography, and the treatment is usually hysterectomy. We present a patient with an arteriovenous malformation of the uterus whose prior delivery was by Cesarean section. The patient experienced episodes of heavy vaginal bleeding in the first month following the procedure of suction curettage for a first-trimester pregnancy loss. Chorionic villus sampling performed prior to the procedure showed a chromosomally normal fetus. The diagnosis of an arteriovenous malformation was made by color Doppler velocimetry and confirmed with arteriography. The patient desired to maintain her fertility. Interventional radiological techniques were successfully utilized to obliterate the arteriovenous malformation with the use of polyvinyl alcohol particles (250 micro m) and gelfoam. Discussion includes the presenting signs and symptoms along with the method of both diagnosis and conservative management.

Journal Article↗