A novel brain metastases model developed in immunodeficient rats closely mimics the growth of metastatic brain tumours in patients.

AIMS: brain metastasis is a common cause of mortality in cancer patients, and associated with poor prognosis. Our objective was to develop a clinically relevant animal model by transplanting human biopsy spheroids derived from metastatic lesions into brains of immunodeficient rats. METHODS: nine different patient brain metastases from four different primary cancers were implanted into brains of immunodeficient rats. The xenografts were compared with patient tumours by magnetic resonance imaging, histochemistry, immunohistochemistry and DNA copy number analysis. RESULTS: after transplantation, tumour growth was achieved in seven out of nine human brain metastases. Spheroids derived from four of the metastases initiated in the rat brains were further serially transplanted into new animals and a 100% tumour take was observed during second passage. Three of the biopsies were implanted subcutaneously, where no tumour take was observed. The animal brain metastases exhibited similar radiological features as observed clinically. Histological comparisons between the primary tumours from the patients, the patient brain metastases and the derived xenografts showed striking similarities in histology and growth patterns. Also, immunohistochemistry showed a strong marker expression similarity between the patient tumours and the corresponding xenografts. DNA copy number analysis between the brain metastases, and the corresponding xenografts revealed strong similarities in gains and losses of chromosomal content. CONCLUSION: we have developed a representative in vivo model for studying the growth of human metastatic brain cancers. The model described represents an important tool to assess responses to new treatment modalities and for studying mechanisms behind metastatic growth in the central nervous system.

Evaluation of predicted patellofemoral joint kinematics with a moving-axis joint model.

The main objectives of this study were to expand the moving-axis joint model concept to the patellofemoral joint and evaluate the patellar motion against experimental patellofemoral kinematics. The experimental data was obtained through 2D-to-3D bone reconstruction of EOS images and segmented MRI data utilizing an iterative closest point optimization technique. Six knee model variations were developed using the AnyBody Modeling System and subject-specific bone geometries. These models consisted of various combinations of tibiofemoral (hinge, moving-axis, and interpolated) and patellofemoral (hinge and moving-axis) joint types. The newly introduced interpolated tibiofemoral joint is calibrated from the five EOS quasi-static lunge positions. The patellofemoral axis of the hinge model was defined by performing surface fits to the patellofemoral contact area; and the moving-axis model was defined based upon the position of the patellofemoral joint at 0° and 90° tibiofemoral-flexion. In between these angles, the patellofemoral axis moved linearly as a function of tibiofemoral-flexion, while outside these angles, the axis remained fixed. When using a moving-axis tibiofemoral joint, a hinge patellofemoral joint offers (-5.12 ± 1.23 mm, 5.81 ± 0.97 mm, 14.98 ± 2.30°, -4.35 ± 1.95°) mean differences (compared to EOS) while a moving-axis patellofemoral model provides (-2.69 ± 1.04 mm, 1.13 ± 0.80 mm, 12.63 ± 2.03°, 1.74 ± 1.46°) in terms of lateral-shift, superior translation, patellofemoral-flexion, and patellar-rotation, respectively. Furthermore, the model predictive capabilities increased as a direct result of adding more calibrated positions to the tibiofemoral model (hinge-1, moving-axis-2, and interpolated-5). Overall, a novel subject-specific moving-axis patellofemoral model has been established; that produces realistic patellar motion and is computationally fast enough for clinical applications.

Development and validation of a subject-specific moving-axis tibiofemoral joint model using MRI and EOS imaging during a quasi-static lunge.

The aims of this study were to introduce and validate a novel computationally-efficient subject-specific tibiofemoral joint model. Subjects performed a quasi-static lunge while micro-dose radiation bi-planar X-rays (EOS Imaging, Paris, France) were captured at roughly 0°, 20°, 45°, 60°, and 90° of tibiofemoral flexion. Joint translations and rotations were extracted from this experimental data through 2D-to-3D bone reconstructions, using an iterative closest point optimization technique, and employed during model calibration and validation. Subject-specific moving-axis and hinge models for comparisons were constructed in the AnyBody Modeling System (AMS) from Magnetic Resonance Imaging (MRI)-extracted anatomical surfaces and compared against the experimental data. The tibiofemoral axis of the hinge model was defined between the epicondyles while the moving-axis model was defined based on two tibiofemoral flexion angles (0° and 90°) and the articulation modeled such that the tibiofemoral joint axis moved linearly between these two positions as a function of the tibiofemoral flexion. Outside this range, the joint axis was assumed to remain stationary. Overall, the secondary joint kinematics (ML: medial-lateral, AP: anterior-posterior, SI: superior-inferior, IE: internal-external, AA: adduction-abduction) were better approximated by the moving-axis model with mean differences and standard errors of (ML: -1.98 ±â€¯0.37 mm, AP: 6.50 ±â€¯0.82 mm, SI: 0.05 ±â€¯0.20 mm, IE: 0.59 ±â€¯0.36°, AA: 1.90 ±â€¯0.79°) and higher coefficients of determination (R2) for each clinical measure. While the hinge model achieved mean differences and standard errors of (ML: -0.84 ±â€¯0.45 mm, AP: 10.11 ±â€¯0.88 mm, SI: 0.66 ±â€¯0.62 mm, IE: -3.17 ±â€¯0.86°, AA: 11.60 ±â€¯1.51°).

Leptomeningeal tissue: a barrier against brain tumor cell invasion.

BACKGROUND: Primary brain tumors are characterized by an extensive infiltrative growth into the surrounding brain tissue. This process is confined to the central nervous system, and tumor cell metastasis to other organs is rare. However, other tumors of non-neural origin may frequently metastasize to the central nervous system. PURPOSE: The purpose of the present study was to examine the invasive behavior of different glioma cells into tissues of neural (brain aggregates) as well as non-neural origin (leptomeningeal tissue). Using the same target tissues, the invasive characteristics of two neural metastatic tumors (one malignant melanoma and one small-cell lung carcinoma) were also studied. This direct comparison of the invasive behavior between tumors of neural and non-neural origin provides valuable information regarding the mechanisms of glioma cell dissemination in the central nervous system. METHODS: The in vitro invasive behavior of human tumors of the central nervous system into human leptomeningeal tissue as well as into normal rat brain tissue was studied. For this purpose, a co-culture system consisting of tumor biopsy specimens, human leptomeningeal cell aggregates, and brain cell aggregates was established. Three glioblastomas, one oligodendroglioma, one meningioma, one small-cell lung carcinoma, and one malignant melanoma were studied. RESULTS: In co-cultures of gliomas and leptomeningeal cell aggregates, a well-defined border between the two tissues was observed. The brain cell aggregates, in contrast, were consistently invaded by the glioma cells. The brain metastases showed a different invasion pattern. The metastatic cells invaded and progressively destroyed leptomeningeal cell aggregates, whereas they did not invade the brain cell aggregates. Upon confrontation of the leptomeningeal tissue with the meningioma, a fusion of the two tissues was observed. Immunostaining of the leptomeningeal tissue showed a strong expression of the basement membrane components fibronectin, collagen type IV, and laminin with no expression of glial fibrillary acidic protein, neuron-specific enolase, or S-100 protein. CONCLUSIONS: The present study indicates that there may be important biologic differences between the invasive behavior of gliomas and non-neuroepithelial tumors. Our co-culture experiments suggest that leptomeningeal cells and associated acellular components may constitute a barrier against glioma cell invasion. However, this barrier may not be functional for metastatic tumors to the brain. The presence of glioma cells within the leptomeninges should not necessarily be taken as evidence of aggressive growth or as an indicator of malignancy.

Migratory pattern of fetal rat brain cells and human glioma cells in the adult rat brain.

The migratory behavior of two human glioma cell lines (D-54MG and GaMG) and fetal rat brain cells grafted into the adult rat brain was studied. To trace the implanted cells, they were stained with the carbocyanine vital dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate before injecting them into the white matter above the corpus callosum. The animals were sacrificed 2 h and 7 and 21 days after injection, and the brains were removed and cryosectioned. Fluorescence microscopy showed that both the 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate-stained fetal and tumor cells had the same migratory pattern. Implanted cells were found along myelinated fibers in the corpus callosum and in the perivascular space. After immunostaining for several extracellular matrix (ECM) components (laminin, fibronectin, collagen type IV, and chondroitin sulfate), laminin deposits were observed in the border zone between the host tissue and implanted tumor cells as well as fetal cells. By using two different types of antibodies against fibronectin, it is shown that the fibronectin expression observed in the tumor matrix may be host derived. This was further supported by the fact that tumor spheroids obtained from the two glioma cell lines were negative when immunostained for these ECM components. Several of the ECM components may be host derived. This can be caused by neovascularization and repair synthesis or by a local production of guiding substrates which are important for tumor cell locomotion. The present data suggest that the migratory patterns of fetal and glioma cells are indistinguishable when transplanted into the adult rat brain. Thus, glioma cells may be routed by the same ECM components that play a major role during brain development.

Drug repurposing: sulfasalazine sensitizes gliomas to gamma knife radiosurgery by blocking cystine uptake through system Xc-, leading to glutathione depletion.

Glioblastomas (GBMs) are aggressive brain tumors that always recur after radiotherapy. Cystine, mainly provided by the system X(c)(-) antiporter, is a requirement for glioma cell synthesis of glutathione (GSH) which has a critical role in scavenging free radicals, for example, after radiotherapy. Thus, we hypothesized that the X(c)(-)-inhibitor sulfasalazine (SAS) could potentiate the efficacy of radiotherapy against gliomas. Here, we show that the catalytic subunit of system X(c)(-), xCT, was uniformly expressed in a panel of 30 human GBM biopsies. SAS treatment significantly reduced cystine uptake and GSH levels, whereas it significantly increased the levels of reactive oxygen species (ROS) in glioma cells in vitro. Furthermore, SAS and radiation synergistically increased DNA double-strand breaks and increased glioma cell death, whereas adding the antioxidant N-acetyl-L-cysteine (NAC) reversed cell death. Moreover, SAS and gamma knife radiosurgery (GKRS) synergistically prolonged survival in nude rats harboring human GBM xenografts, compared with controls or either treatment alone. In conclusion, SAS effectively blocks cystine uptake in glioma cells in vitro, leading to GSH depletion and increased ROS levels, DNA damage and cell death. Moreover, it potentiates the anti-tumor efficacy of GKRS in rats with human GBM xenografts, providing a survival benefit. Thus, SAS may have a role as a radiosensitizer to enhance the efficacy of current radiotherapies for glioma patients.

Benign intracerebral cysts treated with internal shunts: review and report of two patients.

Two elderly women with symptomatic benign intracerebral cysts are reported. Before treatment, they both had developed moderate, but slowly increasing, symptoms from a cyst in the left hemisphere, which included epileptic seizures and right hemiparesis. During local anesthesia, an internal cystosubarachnoid shunt was inserted. After the operation, the cyst size was reduced markedly, with a corresponding improvement in the symptoms. A review of reported cases of benign intracerebral cysts is given. The average age of these patients is surprisingly high for a presumed congenital condition. There is a female preponderance, but the previously reported overrepresentation of left-sided lesions is not found in cases described after the introduction of computerized tomographic imaging.

Spinal cord damage caused by rotation of a T-drain in a patient with syringoperitoneal shunt.

We report on a severe complication to the use of intramedullary T-drain in syringoperitoneal shunting procedures: rotational forces in the shunt system causing the arms of the T-drain to gradually compress spinal cord tissue and damage it. Further rotation/destruction was prevented by removing the distal part of the drain system, and by separating the two arms of the T-drain, thus changing it into a syringosubarachnoidal shunt. The syrinx remained collapsed throughout all procedures.

[CFC gases in medicinal sprays]. / CFC-gasser i medicinske spray.

In 1987, approximately 1.18 million aerosol dispensers for medicinal use were sold in Denmark. These contained approximately 29 tons of completely halogenized CFC gases ("Freon") and the preparations were employed for the treatment of bronchial asthma and rhinitis. The possibilities of substitutes are discussed in this article. Preparations are already available which do not contain CFC. Producers of CFC are also attempting to develop new aerosol gases which do not damage the environment. Perhaps these will be found in medicinal preparations in the future.

[Induced abortion after the 12th week of pregnancy employing prostaglandin F2alpha administered extra-amnially]. / Abortfremkaldelse efter 12. gravidittetsuge med prostaglandin F2alpha indgivet ekstra-amnialt

PIP: (PGF2alpha) Prostaglandin F2alpha was administered to 34 patients in clinical trials to produce abortion later than the 12th week of pregnancy. The preparation was instilled extraamnially via a Foley catheter with balloon. The concentration of the fluid instilled was 250 mcg/ml. In group 1 (10 patients), the maximum was a single dose of 750 mcg; 50% of these aborted within 36 hours. The catheters were then removed and the remaining 5 patients were treated with oxytocin. After 52 hours, all of the patients had completed abortions. In group 2 (24 patients), the maximal single dose was increased to 1500 mcg. 15 of the patients aborted within 24 hours (63%) and 1 patient aborted immediately after the 24 hours had elapsed. In the remaining patients, treatment was continued after 24 hours with a combination of PGF2alpha and oxytocin. All of these patients had aborted within 36 hours. The average time for abortion for patients in group 2 was 21.6 hours and the average dose of PGF2alpha was 13.3 mg. The side effects were mild and it did not prove necessary to interrupt treatment on account of side effects in any of the cases. 4 patients (12%) developed febrile reactions without accompanying symptoms and reevacuation of the uterus proved necessary in 1 case. The therapeutic regime for patients in group 2 may be recommended for provocation of late abortion. It is discussed whether PGs should be administered intraamnially after the 16th week of pregnancy. Similarly, it is discussed whether the combined treatment with PG-oxytocin should be initiated early to further reduce the duration of abortion. (author's)^ieng

[Prostaglandin F 2 as an oxytocic agent in the second and third trimesters]. / Prostaglandin F 2 som vefremkaldende middel i andet og tredje trimester.

PIP: Prostaglandin F2alpha (PGF2alpha) was submitted to trial for induction of labor in a total of 44 patients of whom 39 were delivered in connection with the infusion (89%). An infusion fluid with 15 mg PGF2alpha in 1000 ml isotonic glucose (15 mcg/ml) was employed for patients with living nonanencephalic fetuses. In cases where the fetus was dead or suffered from anencephaly, a solution of 25 mg PGF2alpha in 500 ml isotonic glucose (50 mcg/ml) was employed. All of the patients who were treated with the concentrated infusion fluid were delivered. The duration of the infusion varied from 3 3/4-23 hours with an average duration of 10 1/2 hours for all of the cases, regardless of whether a dilute or a concentrated solution was employed. The dosage also varied considerably between 3 and 27.5 mg (average 12.9 mg) in the group with the normal living fetuses and between 5 and 100 mg (average 45 mg) in the groups with dead or anencephalic fetuses. The side effects were slight and did not necessitate withdrawal of treatment in any case. More than 1/2 of the patients did not experience any side effects. No damage to the fetuses were observed. PGF2alpha appears to be well-suited as a labor-inducing agent in cases of intrauterine fetal death and anencephaly. On the other hand, PGF2alpha presents no advantages over oxytocin in cases with normal living fetuses as long as the only method of administration is in the form of intravenous infusion. (author's)^ieng

[Atypical endometrial hyperplasia. Prognosis and course]. / Atypisk hyperplasi i endometriet. Prognose og forløb.

The treatment of patients with the diagnosis atypical endometrial hyperplasia has been disputed during the last decades. The aim of the study was to evaluate the treatment of these patients and analyse the progression rate to invasive carcinoma of the endometrium. Fifty-seven patients with atypical hyperplasia were examined and treated from 1976 through 1991. The medical records were examined retrospectively and the pathology slides were revised by one pathologist in accordance with the 1975 WHO recommendations. Thirty-one (54%) patients were on oestrogen treatment as monotherapy at the time of diagnosis. Forty-two patients had a hysterectomy performed within five months, and five patients had a hysterectomy performed 10 to 61 months after diagnosis. A total of 18 out of 57 patients (31.6%) had or developed endometrial carcinoma all with myometrial invasion: 14 stage I with < or = 50% myometrial invasion, three stage I with > 50% myometrial invasion, and one stage IV. There was no significant difference in age, body mass index, parity or hormone replacement treatment between the group with endometrial carcinoma and the group without endometrial carcinoma. We conclude that unopposed oestrogen treatment and nulliparity are the main risk factors for atypical hyperplasia and that hysterectomy is the appropriate treatment for patients with atypical hyperplasia of the endometrium.

[Patients with early stages of endometrial cancer should be spared adjuvant radiotherapy. Danish Endometrial Cancer Group]. / Patienter med tidlige stadier af endometriecancer bør skånes for adjuverende strålebehandling.

In an attempt to create uniform nationwide guidelines for the management of all stages of endometrial carcinoma, and to limit the use of adjuvant radiation therapy in stage I disease to high-risk patients only, a protocol was developed by the Danish Endometrial Cancer group (DEMCA). From September 1986 through August 1988, 1214 women in Denmark with newly diagnosed carcinoma of the endometrium have been treated according to this protocol. This figure represents all endometrial carcinomas diagnosed in Denmark during this two-year period. The primary treatment was total abdominal hysterectomy and bilateral salpingo-oophorectomy, no preoperative radiation therapy was delivered. In 1039 cases no macroscopic residual tumour and/or microscopic tumor tissue in the resection margins was found following surgery. Based on surgery and histopathology, these patients were classified as: P-stage I low risk (n = 641), P-stage I high risk (n = 235), P-stage II (n = 105) and P-stage III, Group 1 (n = 58). No postoperative radiation therapy was given to P-I low risk cases. P-I high risk, P-II, and P-III (Group 1) cases received external radiation therapy. Recurrence rate at 68-92 months follow-up was 45/641 (7%) in P-I low risk, 36/235 (15%) in P-I high risk, 30/105 (29%) in P-II, and 27/58 (47%) in P-III (Group 1) cases. Fifteen of 17 vaginal recurrences in P-I low risk cases were salvaged (mean observation time 61 months). In this population-based investigation it has been shown that P-stage low-risk patients are adequately treated by total abdominal hysterectomy and bilateral salpingo-oophorectomy, and that no pre- or postoperative radiation therapy is necessary.

Gamma knife surgery of meningiomas involving the cavernous sinus: long-term follow-up of 100 patients.

OBJECTIVE: Resection of meningiomas involving the cavernous sinus often is incomplete and associated with considerable morbidity. As a result, an increasing number of patients with such tumors have been treated with gamma knife surgery (GKS). However, few studies have investigated the long-term outcome for this group of patients. METHODS: 100 patients (23 male/77 female) with meningiomas involving the cavernous sinus received GKS at the Department of Neurosurgery at Haukeland University Hospital, Bergen, Norway, between November 1988 and July 2006. They were followed for a mean of 82.0 (range, 0-243) months. Only 2 patients were lost to long-term follow-up. Sixty patients underwent craniotomy before radiosurgery, whereas radiosurgery was the primary treatment for 40 patients. RESULTS: Tumor growth control was achieved in 84.0% of patients. Twelve patients required re-treatment: craniotomy (7), radiosurgery (1), or both (4). Three out of 5 patients with repeated radiosurgery demonstrated secondary tumor growth control. Excluding atypical meningiomas, the growth control rate was 90.4%. The 1-, 5-, and 10-year actuarial tumor growth control rates are 98.9%, 94.2%, and 91.6%, respectively. Treatment failure was preceded by clinical symptoms in 14 of 15 patients. Most tumor growths appeared within 2.5 years. Only one third grew later (range, 6-20 yr). The complication rate was 6.0%: optic neuropathy (2), pituitary dysfunction (3), worsening of diplopia (1), and radiation edema (1). Mortality was 0. At last follow-up, 88.0% were able to live independent lives. CONCLUSION: GKS gives long-term growth control and has a low complication rate. Most tumor growths manifest within 3 years following treatment. However, some appear late, emphasizing the need for long-term follow-up.