The presence of foetal ganglioside antigens 3′-IsoLM1 and 3′6′-IsoLD1 in both glioma tissue and surrounding areas from human brain

Summary Glioma-associated gangliosides, in particular the expression of foetal gangliosides 3′-isoLM1 and 3′6′-isoLD1, have been investigated in biopsies from 44 patients with astrocytoma grade II, anaplastic astrocytoma, anaplastic oligodendrogliomas, oligodendrogliomas, and glioblastoma multiforme. The total ganglioside content decreased in proportion to the estimated number of tumour cells present in the biopsy. Ganglioside GD3 was increased in 17 of the tumour tissues and in 6 of the surrounding area specimens. In agreement with our previous studies, tumour specimens contained the lactoseries ganglioside 3′-isoLM1 and, as demonstrated for the first time, the disialylated form of the ganglioside, 3′6′-isoLD1. These gangliosides are in normal brain tissue restricted to the developmental period. Most frequent was the expression of ganglioside 3′-isoLM1 which was detected in 92% of the tumour specimens in concentrations varying between just detectable amounts to 13 nmol/g wet weight. In the area surrounding the macroscopic tumour tissue 78% of the specimens expressed 3′-isoLM1 and the values varied between just detectable amounts to 24 nmol/g wet weight. Ganglioside 3′6′-isoLD1 was found in 47% of the tumour biopsies and in only 17% of the specimens taken outside macroscopic tumour tissue. The values varied between non-detectable amounts to 40 nmol/g wet weight of tissue. The expression of 3′-isoLM1 correlated significantly (p<0.01) to malignancy grade. For 3′6′-isoLD1 a significant (p<0.05) difference was found between tomour and surrounding tissue. Likewise, 3′6′-isoLD1 correlated significantly (p<0.05) to malignancy grade. The correlation between 3′-isoLM1 and 3′6′-isoLD1 to malignancy grade and the frequent expression of these gangliosides both in the tumour itself and in its surrounding area should encourage additional studies concerning their biological role in tumour disease.     

An assay to measure adriamycin binding in osteosarcoma cells

Adjuvant chemotherapy is currently employed in the treatment of patients with osteosarcoma, but the drug regiments, although effective in improving disease-free survival, are unsuccessful in 20–40% of patients and very toxic. It would be useful to know whether tumor cells are sensitive to a given drug prior to its use. To this end, we developed a method of assessing Adriamycin (doxorubicin) binding to tumor nuclei as a possible means of detecting sensitivity to the drug. Adriamycin-sensitive murine osteosarcoma cells were used to develop the assay. The in vitro conditions (drug concentration, duration of incubation, and temperature) were optimized with use of the murine osteosarcoma cells in culture. After the cells had been incubated with Adriamycin, cell viability was determined and Adriamycin fluorescence intensity was measured with a cytofluorometer. The optimal parameters for Adriamycin binding were found to be a 30-minute incubation in a 10 μg/ml concentration of Adriamycin at 37°C the frequency of cells that emitted Adriamycin fluorescence from the nucleus compared with the total number of livin cells reached 100% under these conditions. In a murine leukemia cell line with known sensitivity to Adriamycin, the cells emitted red fluorescence from the nucleus and cytoplasm, whereas in a resistant line the cells emitted Adriamycin fluorescence from only the cytoplasm. We demonstrated that it is possible to differentiate nuclear from cytoplasmic concentration of Adriamycin in a tumor cell with use of a fluorescent microscope and that resistant cell lines can be distinguished from sensitive cell lines by this method. Since Adriamycin acts by intercalating to DNA, its absence in the nucleus probably indicates a resistant cell. This is a rapid technique that may allow prediction of drug sensitivity at the time of diagnosis or relapse.     

Prognostic value of perfusion-weighted imaging in brain glioma: a prospective study

Summary Object. Biopsy targeting based on MR imaging alone may fail to identify malignant areas in brain gliomas. Considering the differences in relative Cerebral Blood Volume (rCBV) ratios reported among tumour grades, we evaluated whether perfusion-weighted MR imaging (PWI) could usefully implement the routine preoperative imaging by detecting those areas bearing a higher yield for malignancy to guide the stereotactic biopsy or the surgical removal. Clinical material and methods. We studied a series of 55 consecutive patients with newly diagnosed brain glioma using both conventional MR imaging and PWI in the preoperative assessment. The pathological diagnosis was established by stereotactic biopsy in 29 cases and by craniotomy in 24 cases. We evaluated the patient survival to detect undergrading. Discussion. Independent from contrast-enhancement, perfusion-weighted MR imaging improved the target selection in stereotactic biopsy guidance and the removal of malignant areas in tumours amenable to surgery. Particularly sensitive to the perfused part of the tumour as to small regional changes, rCBV maps allowed a better detection of malignant areas. The rCBV ratios correlated significantly to the tumour grade and the final outcome (p < 0.01). Conclusions. We found PWI valuable in the preoperative assessment of brain gliomas, discriminating high from low-grade gliomas. PWI can easily be performed on widely available MR imaging systems as part of the routine imaging of gliomas.     

阿霉素异体脱钙骨基质骨粒骨水泥缓释体的制备及相关研究

目的：研制阿霉素异体脱钙骨基质骨粒骨水泥缓释体，分析其缓释性能及对骨肉瘤细胞OS－9901的抑制能力。方法：按Urist法制备异体脱钙骨基质骨粒，经冻干、真空吸附等处理，载入阿霉素与骨水泥按1：1复合，制得阿霉素异体脱钙骨基质骨粒骨水泥缓释体。对该缓释体行体内外药物释放及其浸出液的体外抑瘤试验。结果：缓释体体外第1d释放量为总的19．23％，其后在较低水平维持相对稳定的缓慢释放，持续释放70d以上；其第1、20、40、70d的浸出液对骨肉瘤细胞OS－9901的抑制率分别为64．27％，41．68％、28．71％及24．32％。体内释药时，局部骨组织浓度高于血浆中浓度；局部骨组织早期浓度高，以后为稳定的低浓度释放。结论：该缓释体具有良好的缓释功能，在70d内对骨肉瘤细胞OS－9901维持良好有效的抑制率。     

南瓜蛋白对人胰腺癌细胞系PANC-1的细胞毒性及化疗增敏作用

目的：观察南瓜蛋白（CUS）对人胰腺癌细胞系PANC-1的细胞毒性和化疗增敏作用。方法：采用四甲基偶氮唑蓝（MTT）比色法,观察不同浓度（量效）的CUS及作用不同时间（时效）对胰腺癌细胞PANC-1的细胞毒性;采用 Chou Talalay 联合指数法判断CUS增加胰腺癌细胞对吉西他滨(GEM)的化疗敏感性。结果：CUS对胰腺癌PANC-1细胞具有显著的增殖抑制作用,0.3125, 0.625, 1.25, 2.5, 5.0, 10.0, 20.0, 40.0, 80.0 μg/mL的CUS作用于胰腺癌细胞24 h,其抑制率分别为9.16％,11.9％,14.4％,20.2％,32.0％,36.4％,44.1％,50.3％和58.6％,呈现明显的剂量依赖性;随着作用时间的延长,其抑制率明显增加, 24,48,72 h的半数抑制浓度（IC 50）分别为40.24,8.24,1.17 μg/mL,呈现明显的时间依赖性。两药在不同效应时各自所需浓度之间相互作用均为协同作用（CI<1）, 单吉西他滨用于胰腺癌细胞的IC 50为36.76 nmol/L, CUS与其合用时的IC 50为12.14 nmol/L,合用比单用时吉西他滨的剂量减少67.0%。结论：CUS对胰腺癌的细胞毒性作用呈明显的剂量依赖性和时间依赖性,与吉西他滨联合使用可增加其细胞毒作用,起到化疗增敏效应。     

111Indium (DTPA-octreotide) scintigraphy in patients with cerebral gliomas

Summary Somatostatin receptors (SR) have been identified in vitro in normal brain tissue, in neuro-endocrine tumours and in cerebral gliomas WHO grade 1 or 2 by autoradiography or using somatostatin-gold conjugates. In vivo, SR detection has become possible by scintigraphy applying the somatostatin analogue octreotide, radio-labelled with¹¹¹Indium. It was supposed that expression of SR in cerebral gliomas corresponds to low grade tumour malignancy and that, in vivo, somatostatin receptor scintigraphy (SRS) could refine and improve the WHO grading system for cerebral gliomas.Nineteen patients with cerebral gliomas (grade 2: n=8, grade 3: n=3, grade4: n=8) were examined with¹¹¹In (DTPA-octreotide) to evaluate, whether SRS could improve the pre-operative estimation of tumour biology and the postoperative management. The results of SRS were related with the histological findings and with the in vitro demonstration of somatostatin-binding sites on cultured tumour cells incubated with a somatostatin-gold conjugate.In vivo, none of the patients with glioma grade 2 showed enhanced tracer uptake in the SRS, whereas in vitro SR were detected in cultured tumour tissue in 5 out of 5 cases. Every patient with glioma grade 3 or 4 demonstrated a high focal uptake of¹¹¹In (DTPA-octreotide), as shown by SRS. Three patients with glioma grade 4, additionally examined with 99mTc-DTPA, showed an increased tracer uptake within the tumour area when compared with results of SRS. In vitro, SR were detected on tumour cell surface in 5 out of 6 tissue samples from patients with gliomas grade 3 or 4. One patient harbouring a cerebral abscess presented with a high focal tracer uptake in the SRS but with absence of somatostatinbinding sites in vitro.We concluded, that in glioma patients enhanced tracer uptake in receptor scintigraphy with¹¹¹In (DTPA-octreotide) does not depend on the presence of SR in tumour tissue but on the dysfunction of the blood-brain barrier. Thus, SRS does not improve the preoperative glioma grading or postoperative management in patients with cerebral tumours of glial origin.The article is dedicated to Prof. H. Leonhardt on the occasion of his 75th birthday.     

Histological examination of false positive tissue resection using 5-aminolevulinic acid-induced fluorescence guidance

Intraoperative 5-aminolevulinic acid (5-ALA)-induced fluorescence guidance for resection of malignant brain tumors was correlated with histological examination to investigate false positive findings in 42 patients with malignant glioma and six patients with metastatic brain tumor. Patients received a single 1 g oral dose of 5-ALA 2 hours before surgery. The tumor site was illuminated with a laser with a peak wavelength of 405 +/- 1 nm and output of 40 mW. Samples with strong fluorescence were obtained from the tumor bulk and samples with weak fluorescence from the tumor cavity. Fluorescence was observed in 36 of the 42 malignant gliomas and four of the six metastatic brain tumors. No tumor cells were found in fluorescent samples from six of the 36 malignant gliomas and all four metastatic brain tumors. Five of the six malignant gliomas were recurrent cases. Fluorescence was found in areas of peritumoral edema or inflammatory cell and reactive astrocyte infiltration. Intraoperative 5-ALA-induced fluorescence guidance is useful for the resection of initial malignant glioma since false positive results are rare, but only non-eloquent weak positive areas should be resected. In contrast, all weak positive areas of recurrent malignant gliomas must be resected. Weak positive areas of the peritumoral edema surrounding metastatic brain tumors should be removed carefully as false positive results are common.     

Difference in DNA index of seminomas and nonseminomas

Summary. Flow cytometric examinations were performed consecutively on fresh tumour tissue of 90 patients with testicular germ cell tumours. Measured parameters were the DNA index, the stem-cell shoulder fraction (SSF) as an expression of mitotic activity, and the incidence of tumour populations above 5c (5c-exceeding events). The results were correlated with the type of tumour, as determined histologically, the local and clinical stage of the tumour, and clinical outcome. In 94.5% of the cases, flow cytometry detected malignant testicular tumour tissue. The mediam DNA index in the 53 nonseminoma patients was 1.53, in the 37 seminoma patients, 1.82 ( P < 0.01). Four out of 42 patients with nonseminomas had progressive disease. These few patients were more likely to have an increase in the S-phase fraction or a positive 5c-ee index than patients without progressive disease. In 24 patients with nonseminoma, it was also possible to examine lymph node tissue. Lymph node metastases were detected in 92.8% of these cases through aneuploidy: the median DNA index was 1.57, which corresponded to that of the primary tumours. This study confirmed the value of flow cytometry for rapid, automatic diagnosis of malignancy in testicular tumours. The method could aid in discriminating between seminomas and nonseminomas.     

2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) in a nude rat glioma model: implications for photodynamic therapy

BACKGROUND AND OBJECTIVE: In this study, we evaluated 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-alpha (HPPH or Photochlor) as a photosensitizer for the treatment of malignant gliomas by photodynamic therapy (PDT). STUDY DESIGN/MATERIALS AND METHODS: We performed in vivo reflection spectroscopy in athymic rats to measure the attenuation of light in normal brain tissue. We also studied HPPH pharmacokinetics and PDT effects in nude rats with brain tumors derived from stereotactically implanted U87 human glioma cells. Rats implanted with tumors were sacrificed at designated time points to determine the pharmacokinetics of HPPH in serum, tumor, normal brain, and brain adjacent to tumor (BAT). HPPH concentrations in normal brain, BAT and tumor were determined using fluorescence spectroscopy. Twenty-four hours after intravenous injection of HPPH, we administered interstitial PDT treatment at a wavelength of 665 nm. Light was given in doses of 3.5, 7.5 or 15 J/cm at the tumor site and at a rate of 50 mW/cm. RESULTS: In vivo spectroscopy of normal brain tissue showed that the attenuation depth of 665 nm light is approximately 30% greater than that of 630 nm light used to activate Photofrin, which is currently being evaluated for PDT as an adjuvant to surgery for malignant gliomas. The t1/2 of disappearance of drug from serum and tumor was 25 and 30 hours, respectively. CONCLUSION: Twenty-four hours after injection of 0.5 mg/kg HPPH, tumor-to-brain drug ratios ranged from 5:1 to 15:1. Enhanced survival was observed in each of the HPPH/PDT-treated animal groups. These data suggest that HPPH may be a useful adjuvant for the treatment of malignant gliomas.     

Doxorubicin pharmacokinetics—The effects of protein deprivation

Recent studies suggest that protein-calorie malnutrition decreases tumor response to chemotherapy. This study was designed to evaluate the effects of dietary protein deprivation on the pharmacokinetics and distribution of Adriamycin. Male Sprague-Dawley rats were assigned randomly to receive either in a regular diet or a high-carbohydrate, protein-free diet for the duration of the experiment. Ten days after the initiation of the designated diet, all animals received a single dose (5.0 mg/kg) of Adriamycin intravenously. Animals were sacrificed at 0.5, 1.2, 6, 24, and 48 hr following drug administration, and the concentration of Adriamycin in serum, urine, and tissue was determined by fluorometric assay. Animals maintained on the regular diet continued to gain weight during the study interval, while animals provided the protein-free diet lost an average of 21% of their initial study weight (P < 0.01). Serum Adriamycin concentration was significantly lower in the protein-free diet animals at 0.5, 1, 2, 24, and 48 hr following administration: Adriamycin was not detectable in the serum of the protein-free diet animals at 48 hr, but was still present in the serum of the regular diet group (P < 0.01). The cumulative urinary excretion of Adriamycin, expressed as a percentage of the administered dose, was identical in both dietary groups during the initial 24 hr, but was significantly higher in the protein-free diet group by 48 hr after administration (P < 0.05). Significant differences were observed when liver, kidney, lung, and heart Adriamycin concentrations were compared. The elevated concentration of Adriamycin in the kidneys of the protein-free diet animals correlated with the increased urinary drug excretion, and indicated that accelerated renal clearance of Adriamycin was one possible mechanism for the more rapid serum elimination of the drug in the protein-free diet animals.     

Expression of cALLa/NEP on gliomas: A possible marker of malignancy

Summary First described on pre-B leukemia cells, the common acute lymphoblastic leukemia antigen (cALLa) is also expressed on glioma cellsin vitro. Its identity to neutral endopeptidase (NEP) (E.C.3.24.11) was corroborated by our finding that cALLa positive glioma cells had NEP activity. To study cALLa/NEP distribution on glial tumours in vivo, we examined 76 brain tumour biopsies by immunostaining techniques on frozen tissue sections using anticALLa (FAH99) and anti-NEP (135 A 3) monoclonal antibodies. We found that 96% of grade 4 gliomas (25/26) expressed NEP. Whereas only 45% (4/9) of grade 3 or anaplastic astrocytomas did. In low grade gliomas, we found 2 positive tumours out of 21 tested (10%). Double immunostaining procedures revealed that NEP was co-expressed with GFAP. However no NEP could be detected on non-glial brain tumours nor on reactive astrocytes. These results suggest that cALLa/NEP expression could be linked to malignant progression of gliomas.     

Comparison of regional versus systemic chemotherapy with adriamycin

To achieve the high drug concentrations in a target tissue (tumor) with minimal drug levels in organs not involved by cancer, thereby avoiding serious systemic side effects, three methods of Adriamycin administration: 1) Isolation perfusion, 2) Intra-arterial infusion, and 3) Intravenous infusion were studied in 22 dogs. Latter two methods were studied in several patients with soft tissue sarcoma of the extremities. Isolation perfusion of the hind extremity was done through the femoral vessels; intra-arterial and intravenous infusions were done through the femoral artery and cephalic vein, respectively. Adriamycin levels in tissues of the hind extremity and blood were determined. The highest Adriamycin levels in tissues could safely be achieved by isolation perfusion. Drug concentrations in regional tissues were not significantly different after intra-arterial infusion as compared to those after intravenous infusion. Much of the drug went into systemic circulation after intra-arterial infusion and almost none after isolation perfusion. Hematologic and histologic evidence of lethal systemic toxicity was noted only in dogs receiving Adriamycin by infusions. Edema, patchy muscle necrosis, hemorrhages, and skin ulcerations were observed in the perfused extremities only. In human studies, drug levels in blood were comparable to those in animal study when Adriamycin was administered by the latter two methods.     

光动力诊断和荧光指导切除脑恶性胶质瘤15例

目的研究光动力诊断(PDD)和荧光指导的肿瘤切除在脑恶性胶质瘤治疗中的作用。方法对手术治疗的原发和复发的15例恶性脑胶质瘤患者,在手术中进行荧光波谱诊断及其指导下的肿瘤切除。光敏剂为血卟啉衍生物,剂量为2mg/kg体重。应用激光电子波谱分析系统,光纤尖端激发激光波长632．5nm。手术前48h静脉注射光敏剂,注射后患者进行避光。手术为常规开颅手术,显微镜下切除肿瘤,在手术医师认为肿瘤完全切除后用光纤探头在瘤腔各壁进行多于4个点的光动力诊断,同时取该点样本送常规病理。如光动力诊断发现肉眼未发现的肿瘤则进一步切除。直至瘤腔各壁均确认为正常脑组织。分别记录肉眼辨别,光动力诊断和病理诊断结果,计算光动力诊断的敏感率,特异率和准确率。术后复查CT或MRI确定切除程度,记录手术死亡率和致残率。结果15例肿瘤标本均表现特异肿瘤波谱图形,其中有2例患者在光动力诊断后发现肿瘤,继续切除肿瘤。有1例显微镜下可疑肿瘤组织,经光动力诊断为脑组织,未切除,取病理证实为脑组织。2例(胶质肉瘤和胶质母细胞瘤)离体肿瘤组织和正常脑组织进行光动力诊断,均获得和术后病理诊断相一致的诊断。在瘤腔各壁取样标本106份,根据病理诊断,光动力诊断的敏感率90．60%,特异率96．8％,准确率94．3％。15例患者无手术死亡,1例术后偏瘫失语加重。9例患者肿瘤全切,6例患者肿瘤未全切,其中5例患者因肿瘤位于功能区,为保护功能未能全切肿瘤,并被手术后．MRI或CT证实。有1例术中肉眼辨认和PDD均未提示肿瘤,但样本病理提示仍为肿瘤边缘组织。结论荧光波谱分析的光动力诊断具有比较快速准确、简单客观等特点,对于提高脑恶性胶质瘤的切除程度和减少手术损伤具有积极意义。     

Pharmacokinetics of a new water-soluble nitrosourea derivative (ACNU) in human gliomas

The pharmacokinetics of a newly developed water-soluble nitrosourea derivative (ACNU) following a single intravenous injection was investigated in 11 patients with gliomas. A major portion of ACNU was excreted within 2 hours. The distribution rate was very fast, and the elimination rate tended to be slow. More than 50% of ACNU moves into the tissue compartment. ACNU tended to move into glioma tissue well. The ACNU level in glioma tissue was above 1.0 microgram/gm 30 to 60 minutes ater injections. ACNU was detected at a higher concentration in malignant gliomas than in benign gliomas. These results suggest that ACNU is taken up by tumor tissue relatively rapidly and eliminated slowly, which leads to effective manifestation of its antitumor activity.     

Local concentrations of gentamicin obtained by microdialysis after a controlled application of a GentaColl sponge in a porcine model

Local treatment with gentamicin may be an important tool in the prevention and treatment of surgical site infections in high-risk procedures and patients. The aim of this study was to evaluate the pharmacokinetic profile of gentamicin in bone and surrounding tissue, released from a controlled application of a GentaColl sponge in a porcine model. In eight female pigs, a GentaColl sponge of 10 × 10 cm (1.3 mg gentamicin/cm²) was placed in a cancellous bone cavity in the proximal tibia. Microdialysis was used for sampling of gentamicin concentrations over 48 hours from the cavity with the implanted GentaColl sponge, cancellous bone parallel to the cavity over and under the epiphyseal plate, cortical bone, the intramedullary canal, subcutaneous tissue, and the joint cavity of the knee. Venous blood samples were obtained as reference. The main finding was a mean peak drug concentration (95% CI) of gentamicin in the cancellous bone cavity containing the implanted GentaColl sponge of 11 315 (9049-13 581) μg/mL, persisting above 1000 μg/mL until approximately 40 hours after application. Moreover, the concentrations were low (<1 μg/mL) in the surrounding tissues as well as in plasma. The mean peak gentamicin concentration from the cancellous bone cavity after a controlled application of a GentaColl sponge was high and may be adequate for the prevention of biofilm formation. However, high MIC strains and uncontrolled application of the GentaColl sponge may jeopardize this conclusion.     

Platinum distribution in malignant glioma following intraoperative intravenous infusion of carboplatin

The objective of this paper was to determine the time course and extent of platinum uptake into human malignant glioma tissue. An intraoperative, intravenous infusion of carboplatin was given to nine patients (seven glioblastoma and two anaplastic glioma) undergoing tumour excision. Carboplatin dosage was calculated individually to achieve a target systemic free carboplatin exposure. Tumour and peritumoural tissue was harvested at timed intervals following carboplatin administration. Plasma and tumour platinum concentrations were measured by graphite furnace flameless atomic absorption spectrophotometry. Histological examination was also performed on a piece of each tissue sample. The mean carboplatin dose administered was 783, SEM 56 mg (range 485-903). Plasma pharmacokinetics showed a typical elimination curve. The mean peak plasma platinum concentration was 44, SEM 5 micrograms/ml (range 27-74). The mean total elemental plasma platinum area under the curve (AUC) was 9.0, SEM 1.4 mg/ml/min. Platinum was detected in 61 tumour samples, the mean peak concentration being 13 SEM 2 micrograms/g (range 5-21). Platinum was also detected in peritumoural brain and necrotic tumour. No correlation was apparent between the degree of necrosis in each tumour specimen and tumour platinum concentration. Platinum concentrations achieved in tumour were similar to levels that would be cytotoxic for glioma cells in vitro. The results of this study have implications for future studies using capillary permeability modifying agents as adjuncts to brain tumour chemotherapy.     

The Thermal Activity of Normal and Malignant Tissues

The usefulness of metabolic heat measurements in quantifying the response of a solid tumour to anticancer treatment was evaluated. The heat production characteristic of malignant tissues, as measured from human stomach, breast and liver cancer samples, was observed to be inconsistent, and its value could be higher or lower than that of its normal tissue of origin. The various thermal activity responses of an experimental rat hepatoma to hepatic artery ligation, cryotherapy, intra-arterial (i.a) Adriamycin (2.4 mg/ kg), i.a. Norcantharidin (0.5 mg/kg) were next studied. The tumour/liver (T/L) ratio of untreated tumour-bearing rats was 0.83 but this fell to a minimum at 24 h in both the hepatic artery ligation and the cryosurgery groups. In these two groups marked fluctuations in the heat production of normal liver occurred with poor recovery of the T/ L ratio even at 2--3 weeks. In the Adriamycin group, the T/L ratio dropped to a minimum at 5 days, and in the Norcantharidin group, at 3 days. Minimal disturbances in the thermal activity of liver tissue occured in these two chemotherapy groups and the T/L ratio recovered by 3 weeks. Norcantharidin appeared as efficacious as Adriamycin in the treatment of hepatoma when evaluated in terms of thermal activity.     

Increased activity of lysosomal glycohydrolases in glioma tissue and surrounding areas from human brain

Summary Increased metabolic activity represented by an increase in both anabolism and catabolism in tumours, including gliomas, is a well known phenomenon and utilised in positron emission tomography imaging of tumours. In this study lysosomal enzyme activities of some glycohydrolases were investigated in glioma tissue from human brain. Tumour tissue (ten cases) and brain tissue surrounding the tumour tissue (seven cases) from patients with a histopathological diagnosis of glioblastoma multiforme or anaplastic astrocytoma were analysed for activity of the lysosomal enzymes galactosylceramidase, glucosylceramidase, β-galactosidase, β-N-acetylglucosaminidase, β-glucuronidase, and acid phosphatase. All of the investigated lysosomal enzymes except galactosylceramidase showed increased activity compared with that in normal brain tissue. Moreover, despite sparsity of tumour cells the specimens taken from surrounding areas showed elevated activities of the same enzymes. The findings indicate an upregulation of the activity not only in tumour but also in normal cells of the surrounding area.     

Monte Carlo Simulations of Light Distributions in an Embedded Tumour Model: Studies of Selectivity in Photodynamic Therapy

. It is well known that photosensitisers in photodynamic therapy (PDT) tend to localise in greater concentrations in tumours. This attractive feature may help confer on PDT the potential to selectivity destroy tumours while sparing the surrounding normal tissue. In this paper Monte Carlo simulations were used to study light distributions in a simple model consisting of tumour embedded in surrounding normal tissue subjected to superficial irradiance. The Monte Carlo model was coded to allow modelling of arbitrary geometries and multiple tissue types. This permitted the use of different optical properties for tumour and normal tissue. Two simulations were run using optical coefficients appropriate to breast carcinoma in adipose tissue and liver tumour in liver. Contours of equal fluence were plotted against depth for both simulations. Contours of equal photodynamic dose (fluence×drug concentration) were plotted for various tumour/normal drug ratios. By assuming a threshold for necrosis it was possible to estimate the depth of damage in the normal tissue and tumour simultaneously. A greater depth of selective tumour damage was observed in the breast tissue simulation for a given drug ratio due to the higher penetration of light compared to the liver. For a tumour to normal ratio of 4:1 selective damage to a depth greater than 4 mm was observed in the breast simulation compared to almost 3 mm in the case of the liver model. Paper received 1 December 1998; accepted after revision 13 July 1999.     

The disposition of TCNU (tauromustine) in human malignant glioma: pharmacokinetic studies and clinical implications

Tauromustine (TCNU), 130 mg/sq m, was administered intraoperatively by nasogastric tube to 10 patients with malignant glioma (seven glioblastomas and three anaplastic astrocytomas). High-performance liquid chromatography analysis of 32 tumor specimens for TCNU revealed that tissue concentrations ranged from 0 to 554 ng/gm: TCNU was not detected in necrotic regions of the tumor. Levels of TCNU in brain adjacent to tumor were similar to those recorded within the gliomas (range 0 to 635 ng/gm). The variability in the tissue level of TCNU was partly attributable to variable absorption of the drug, since peak plasma TCNU levels ranged from 164 to 3333 ng/ml. There were close quantitative and temporal relationships between the times of peak plasma levels (median 456 ng/ml at 45 minutes after administration), peak tumor levels (median 250 ng/gm tissue at 55 minutes), and brain adjacent to tumor levels (median 256 ng/gm tissue at 50 minutes). Linear regression analysis of the ratio between tissue and plasma TCNU levels at particular times after drug administration suggest that plasma concentrations can be used to estimate tissue concentrations. This study demonstrates that TCNU enters malignant glioma. In view of the activity of TCNU against a range of tumors, a full clinical evaluation of this new nitrosourea in malignant glioma seems justified.