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Purpose: Pineal region tumors are surgically demanding tumors to resect. Long term neuro-oncologic outcomes following surgical excision of tumors from this region have been underreported. We sought to define the long term outcomes of patients undergoing resection of pineal region tumors., Methods: A retrospective analysis of a prospectively maintained database was performed on patients who underwent intended surgical excision of pineal region tumors. Overall survival (OS) and progression free survival (PFS) were the primary endpoints of this study. Factors associated with OS, PFS and the degree of resection were analyzed, along with 30-day complication rates and dependence on CSF diversion., Results: Sixty-eight patients with a mean age of 30.9 ± 15.3 years were analyzed. The median clinical and radiographic follow-up was 95.7 and 48.2 months, respectively. The supracerebellar infratentorial and the occipital transtentorial corridors were utilized in the majority of cases (80.9%). The gross total resection (GTR) rate was 52.9% (n=36). The 5-year OS and PFS rates were 70.2% and 58.5%, respectively. Achieving GTR was associated with improved OS (HR 0.39, p = 0.03) and PFS (HR 0.4, p = 0.006). The 30-day mortality rate was 5.9%. The need for CSF diversion was high with 77.9% of patients requiring a shunt or ETV by last follow-up., Conclusions: This is the first modern surgical series providing long term follow-up for patients undergoing surgical resection of pineal region tumors. Obtaining a GTR of these challenging tumors is beneficial with regards to PFS/OS. Higher grade tumors have diminished PFS/OS and are treated with adjuvant chemotherapy and/or radiotherapy., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Thalamic gliomas are rare neoplasms that pose significant surgical challenges. The literature is limited to single-institution retrospective case series. We systematically review the literature and describe the clinical characteristics, treatment strategies, and survival outcomes of adult thalamic gliomas., Methods: Relevant articles were identified on PubMed, Scopus, and Cochrane databases. Papers containing cases of adult thalamic gliomas with clinical outcome data were included. A comprehensive review of clinical characteristics and survival analysis was conducted., Results: We included 25 studies comprising 617 patients. The median age was 45 years (male = 58.6%). Glioblastoma was the most frequent histological type (47.2%), and 82 tumors were H3 K27M-mutant. Motor deficit was the most common presenting symptom (51.8%). Surgical resection was performed in 69.1% of cases while adjuvant chemotherapy and radiotherapy were administered in 56.3% and 72.6%, respectively. Other treatments included laser interstitial thermal therapy, which was performed in 15 patients (2.4%). The lesion laterality (P = 0.754) and the surgical approach (P = 0.111) did not correlate with overall survival. The median progression-free survival was 9 months, and the overall two-year survival rate was 19.7%. The two-year survival rates of low-grade and high-grade thalamic gliomas were 31.0% and 16.5%, respectively. H3 K27M-mutant gliomas showed worse overall survival (P = 0.017)., Conclusion: Adult thalamic gliomas are associated with poor survival. Complete surgical resection is associated with improved survival rates but is not always feasible. H3 K27M mutation is associated with worse survival and a more aggressive approach should be considered for mutant neoplasms., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The aim of the present study is to assess whether postoperative residual non-enhancing volume (PRNV) is correlated and predictive of overall survival (OS) in glioblastoma (GBM) patients., Methods: We retrospectively analyzed a total 134 GBM patients obtained from The University of Texas MD Anderson Cancer Center (training cohort, n = 97) and The Cancer Genome Atlas (validation cohort, n = 37). All patients had undergone postoperative magnetic resonance imaging immediately after surgery. We evaluated the survival outcomes with regard to PRNV. The role of possible prognostic factors that may affect survival after resection, including age, sex, preoperative Karnofsky performance status, postoperative nodular enhancement, surgically induced enhancement, and postoperative necrosis, was investigated using univariate and multivariate Cox proportional hazards regression analyses. Additionally, a recursive partitioning analysis (RPA) was used to identify prognostic groups., Results: Our analyses revealed that a high PRNV (HR 1.051; p-corrected = 0.046) and old age (HR 1.031; p-corrected = 0.006) were independent predictors of overall survival. This trend was also observed in the validation cohort (higher PRNV: HR 1.127, p-corrected  = 0.002; older age: HR 1.034, p-corrected  = 0.022). RPA analysis identified two prognostic risk groups: low-risk group (PRNV < 70.2 cm 3 ; n = 55) and high-risk group (PRNV ≥ 70.2 cm 3 ; n = 42). GBM patients with low PRNV had a significant survival benefit (5.6 months; p = 0.0037)., Conclusion: Our results demonstrate that high PRNV is associated with poor OS. Such results could be of great importance in a clinical setting, particularly in the postoperative management and monitoring of therapy.

Brain metastases (BM) are one of the most common types of brain tumors and are a relatively common event in the disease process for several high-incidence cancer types, including breast and lung cancers. Historically, information on metastases including BM have not been collected as part of national cancer registration in the US, but BM at time of primary cancer diagnosis (SBM), is now collected by the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) system. Using data from 18 SEER registries from 2010 to 2013, we assessed the frequency of SBM at time of primary diagnosis in the US by site, histology group, sex, race, age, and insurance status. There were 1,634,954 total primary cancer cases in SEER from 2010 to 2013, 1.7% of which presented with SBM. The cancer type with the highest proportion of SBM was lung cancer (10.8% of cases with SBM), followed by esophageal (1.5%), kidney (1.4%), and melanoma (1.2%). SBM varied by age, sex, race, and insurance status for most histologies. Our results reflect the high proportion of patients who are diagnosed with lung cancer at late stages and present with SBM, in contrast to other common cancers in the US where SBM is less common. Demographic variation in molecular subtype and risk behavior may influence variation in SBM. BM is a relatively common event in late stage cancer and cause significant morbidity and mortality, and assessment of accurate population-based data is critical to estimate total disease burden.

The goal of glioma surgery is maximal safe resection. These intrinsic brain neoplasms, however, lack a clear margin and frequently infiltrate eloquent areas of the brain thus making their surgical resection challenging. This review first focuses on discussion of preoperative investigations that aid in anatomical and functional tumor characterization that help define tumor extent and determine the feasibility of complete resection. The second part of this review outlines intraoperative adjuncts that help identify tumor infiltrated tissues during surgery to maximize the extent of resection. In addition, we discuss the principles of intraoperative functional cortical and subcortical mapping and monitoring that enable maximal tumor resection while minimizing the risk of postoperative neurological deficit. Combined use of different modalities before and during surgery is encouraged to meet surgical goals and to ensure best patient outcome.

The accurate grading of malignant astrocytomas has significant prognostic and therapeutic implications. Traditional histopathological grading can be challenging due to regional tumor heterogeneity, especially in scenarios where small amounts of tissue are available for pathologic review. Here, we hypothesized that a critical tumor resection volume is needed for correct grading of astrocytomas by histopathology. For insufficient tissue sampling, IDH1 molecular testing can act as a complementary marker to improve diagnostic accuracy. Volumetric analyses were obtained using preoperative and postoperative MRI images. Histological specimens were gathered from 403 patients with malignant astrocytoma who underwent craniotomy. IDH1 status was assessed by immunohistochemistry and sequencing. Patients with >20 cubic centimeters (cc) of the total tumor volume resected on MRI have higher rate of GBM diagnosis compared to <20 cc [odds ratio (OR) 2.57, 95% confidence interval (CI) 1.6-4.06, P < 0.0001]. The rate of IDH1 status remained constant regardless of the tumor volume resected (OR 0.81, 95% CI 0.48-1.36, P < 0.43). The rate of GBM diagnosis is twofold greater for individual surgical specimen >10 cc than those of lower volume (OR 2.48, 95% CI 1.88-3.28, P < 0.0001). Overall survival for AA patients with >20 cc tumor resection on MRI is significantly better than those with <20 cc tumor resected (P < 0.05). No volume-dependent differences were observed in patients with GBM (P < 0.4), IDH1 wild type (P < 0.1) or IDH1 mutation (P < 0.88). IDH1 status should be considered when total resection volume is <20 cc based on MRI analysis and for surgical specimen <10 cc to complement histopathologic diagnosis of malignant astrocytomas. In these specimens, under-diagnosis of GBM may occur when analysis is restricted to histopathology alone.

Understanding the mechanism underlying p53's ability to induce cell cycle arrest versus apoptosis is critical to treating human gliomas, 70% of which contain wild-type p53. Although N-terminal phosphorylation results in activation of p53, the role of N-terminal phosphorylation, particularly at serines 15 and 20, in p53's ability to induce cell cycle arrest versus apoptosis remains controversial. Here we test the hypothesis that phosphorylation of serine 15 and/or 20 is causally related to p53-mediated apoptosis in human gliomas. Introduction of p53 plasmids containing alanine mutations at serine 15 or/and serine 20 (which block phosphorylation) or aspartate mutations (which mimic phosphorylation) at the same sites, implicated simultaneous phosphorylation of both sites in the induction of apoptosis. When a double phosphorylation-mimicking adenoviral p53 vector (Ad-p53-15D20D) was compared with an unphosphorylated p53 vector (Ad-p53), treatment with Ad-p53 resulted in G1-arrest, whereas Ad-p53-15D20D induced apoptosis. These effects occurred independent of phosphorylation of other N-terminal serine (i.e., serines 6, 9, 33, 37, 46) indicating that phosphorylation of S15 and S20 is sufficient for inducing apoptosis. Mechanistically, Ad-p53 was capable only of increasing the expression of p21/CIP, whereas Ad-p53-15D20D increased the binding to and expression of the pro-apoptotic genes Fas, Puma and PIG3. However, Ad-p53-15D20D did not alter the expression of Noxa, Bid, IGFBP3, PERP and Killer/DR5, suggesting that phosphorylation of S15 and S20 resulted in the expression of specific pro-apoptotic gene. In conclusion, simultaneous phosphorylation of S15 and S20 is causally associated with apoptosis, resulting in increased expression of specific p53-responsive pro-apoptotic genes.

Brain metastases are the most common neurological complication of systemic cancer and carry a very poor prognosis. The management of patients with brain metastases has become more important recently because of the increased incidence of these tumors and the prolonged patient survival times that have accompanied increased control of systemic cancer. In this article, we review the current perspectives on surgical treatment of brain metastases in terms of patient selection criteria, intraoperative adjuncts, whole-brain radiation therapy (WBRT) as a postoperative adjuvant, reoperation for tumor recurrence, and resection of multiple and single metastases. Achieving the best outcome in treatment of brain metastasis requires the judicious and complementary use of surgical resection along with modalities such as whole-brain radiation therapy and stereotactic radiosurgery.

Tumors rarely metastasize to the cerebellopontine angle. We report the first instance of simultaneous metastasis of renal cell carcinoma to the cerebellopontine angle and the lateral ventricle. A 51-year-old man presented with anemia and fatigue owing to stomach metastases from renal cell carcinoma 8 years after undergoing partial left nephrectomy for grade II clear cell renal carcinoma and radical right nephrectomy for grade III clear cell renal carcinoma. He also suffered metastases to the lung, both adrenal glands, the L-3 vertebra, and the brain (asymptomatic, but revealed by magnetic resonance imaging): a 1-cm (maximum diameter) mass in the left medullary cistern and a 2-cm (maximum diameter) mass in the right lateral ventricle trigone. Both brain lesions were treated with stereotactic radiosurgery, followed by gross-total resection of the right trigonal mass 7 months later. Both tumors shrank significantly, but the patient died from progressive systemic cancer 1 year after diagnosis of brain metastasis.

Objective: The AANS/CNS Section on Tumors is involved in the education of practitioners managing patients with tumors involving the nervous system. We report the results of a survey commissioned by this body to investigate how neurosurgical residents are trained in the neurosurgical oncology subspecialty., Methods: One hundred six North American training centers were anonymously surveyed regarding faculty background; resident rotations, research opportunities, and caseload; and post-graduate neuro-oncology-related activities. Additionally, the AANS membership database was searched to quantify self-identified neuro-oncologists., Results: Forty-four of 106 (41.5%) programs responded to the survey. Over 90% of responding programs have a faculty member specializing in neurosurgical oncology. Neurosurgical oncology fellowships or dedicated neuro-oncology resident rotation were found only in a small number of programs. Most residency programs support resident research, including exposure to brain tumor clinical trials. Twenty-nine (66%) programs reported their residents are exposed to >100 surgical cases of primary brain tumors. Twenty (46%) programs reported their residents are exposed to <50 skull base tumors. Thirty (70%) programs reported their resident would be exposed to <50 spine and peripheral nerve tumor cases. Half of the responding programs indicated that graduates of their programs had taken faculty positions focusing on neurosurgical oncology. Fifty-two members of the tumor section are in leadership positions for their given residency programs., Conclusions: Neuro-surgical oncology training appears to be strong at the programs that responded to our survey. However, resident training in neurosurgical oncology can be improved and residents with interests in this subspecialty need support to further this field.

The development of neurosurgical oncology as a subspecialty is closely tied to the development of neurosurgery as a whole. Therefore, the progress that has taken place in the diagnosis and the surgical management of neurosurgical disorders has been widely applied to oncologic disorders affecting the nervous system. The challenges and opportunities that characterize the specialty are grouped into five general categories. These are issues that are related to (1) the management of a large and diverse patient population, (2) the proper training of neurosurgeons to develop the set of required technical skills, (3) the lack of disease curability and its associated opportunity for research endeavors, (4) the importance of the multidisciplinary coordination of care in a horizontal matrix model, and (5) the psychosocial dimensions that are a part of the complexity of human nature. Based on a current assessment of the subspecialty, a perspective on the unfolding future is obtained. This future can be characterized by a stronger workforce, a broader connectivity and representations, and an improved scientific inquiry.

Between January 1975 and April 2001, 8,225 patients with ovarian cancer were seen at The University of Texas M.D. Anderson Cancer Center. Brain metastases developed in 72 of these patients (0.9%). The medical records of these patients were reviewed to assess the incidence of these metastases and their correlates of survival, as well as to describe the various treatment modalities used against them and their respective outcomes. The mean age of patients at the time of brain metastasis diagnosis was 53.7 years. The median interval between the diagnosis of the primary cancer and brain metastasis was 1.84 years. Neurological deficit, headache, and seizure were the most common symptoms. The brain was the only site of metastasis in 43% of patients. Multiple metastases were seen in 65% of them, although this may be a slight underestimate, as brain metastases in 17% of patients were evaluated prior to the magnetic resonance imaging era. The median survival time after the diagnosis of brain metastases was 6.27 months (95% CI, 4.48-8.06 months). The combination of surgical resection and whole-brain radiation therapy (WBRT) resulted in a longer survival time (median, 23.07 months) than did WBRT alone (median, 5.33 months) or surgery alone (median, 6.90 months) (p < 0.01 in both instances, multivariate Cox proportional hazards model analysis). The prognosis for patients with brain metastases from ovarian cancer appears to be poor. The existence of systemic dissemination at the time of brain metastasis was associated with a worse survival trend. The only significant predictor of survival in our series was the treatment modality. In particular, the resection of brain metastasis from ovarian cancer followed by WBRT appeared to be superior to resection alone or WBRT alone.

The poor prognosis of patients with malignant brain tumors in spite of aggressive multimodality therapy has led to the search for novel therapeutic strategies. Among the targets for such treatment approaches, tumor angiogenesis has captured the attention of not only the medical field but also of the lay public because of its conceptual departure from traditional methods of cancer therapy. Angiogenesis and vascular proliferation are particularly important in the growth and progression of malignant gliomas and are used as indicators of the degree of malignancy. Recent studies have helped us gain a better understanding of the molecular mediators of this process. It is now evident that after the initial formation of malignancy the continued growth of a glioma is critically dependent on its angiogenic potential. Hence, several approaches to control angiogenesis are being developed and tested. In the present review, we examine some of these approaches from a therapeutic perspective and summarize the findings from early human trials of such agents.

Although progress is being made in the imaging and medical therapy of malignant gliomas, surgery continues to play a central role in the management of these tumors. Surgery remains necessary for histological diagnosis and relief of mass effect upon adjacent neurological structures. Surgery also achieves cytoreduction of tumor mass, allowing more effective treatment of residual tumor volume. Recent technical advances have made the goal of gross total tumor resection safer and more readily achieved. Surgical techniques and adjuncts that aid the aggressive surgical resection of malignant gliomas will be reviewed.

Residual tumor volume has been considered important in predicting survival following brain surgery. The purpose of this study was to develop a procedure for quantifying pre- and postsurgical brain tumor volumes that is less subjective than the traditional qualitative grading scale still used by surgeons and radiologists to assess extent of resection (such as gross total, subtotal, and partial resection). Pre- and postsurgical magnetic resonance (MR) imaging brain scans on GE Medical System optical disks were transferred to a Macintosh personal computer using a Pioneer optical disk drive subsystem, and the MedVision 1.41 computer software program was used to analyze regions of interest (ROIs) within them for computation of the volume of tumor tissue therein. Because this procedure puts the original MRI (or CT scan) data file for a patient directly into the personal computer, it bypasses the need for scanning and digitizing MR (or CT scan) film images. Between June 1993 and May 1996, pre- and postsurgical volumetric measurements were made in more than 1,000 brain tumor resection cases and 49 radiosurgery cases. The average intra-observer error was estimated to be 1.8%. This method should facilitate the examination of the effects of various therapies on extent of brain tumor resection. The method is fast, is more precise than intraoperative visual assessment of tumor removal or qualitative comparison of pre- and postoperative scans, and it allows the computation of pre- and postsurgical (three-dimensional) volumes of even irregularly shaped tumors.

The most common structural neurologic complication of systemic cancer is brain metastasis. For the most part, treatment is palliative because the majority of patients (> or = 50%) have uncontrollable systemic cancer. However, for patients in whom the only metastasis is to the brain, death is more likely to result from the metastasis than from the systemic disease; hence, treatment of the metastasis is vitally important. Although radiotherapy is generally considered the preferred treatment, surgical removal of the mass, whether single or multiple, may be the most effective palliation, especially for tumors from radio-resistant diseases such as melanoma, kidney and colon cancer. We review the information regarding therapeutic decision-making; advances in surgical procedures, namely computer-assisted stereotactic and/or intraoperative ultrasound and mapping techniques; the efficacy of postoperative WBRT; complications and benefits of surgery; our experience with reoperation for recurrent metastatic brain tumors, the results of which indicate that reoperation for recurrent brain metastasis can prolong survival and improve quality of life for most individuals; our results comparing surgery versus radiosurgery, which show that patients who undergo surgical treatment live longer and have better tumor control than those treated with radiosurgery; and the patient's prognosis. The conclusion is that surgery should remain the treatment of choice whenever possible.

Tumor necrosis, enhancement, and associated edema in patients with glioblastoma multiforme (GBM) represent biological variables that can be quantitated on preoperative MRI scans. We reviewed 48 highly selected patients, all of whom had supratentorial lesions, had undergone gross total tumor resection, and had received adjuvant treatments (radio- and chemotherapies). None of these patients had had surgery for recurrent tumor resection and none had harbored multifocal tumors. The median age was 50 years. The median Karnofsky performance score was 80. Multivariate analysis using the Cox regression model revealed that the strongest prognostic variable was the amount of tumor necrosis on preoperative scan (P < 0.001), with median survivals of 42, 24, 15, and 12 months for tumor necrosis grades of 0 (7 'pts'), I (11 'pts'), II (9 'pts'), and III (21 'pts'), respectively. The intensity of enhancement of the tumor nodule was another prognostic factor (P = 0.003), with median survivals of 35, 18, and 13.5 months for enhancement grades of 0 (2 'pts'), I (22 'pts'), and II (24 'pts'), respectively. The extent of peritumoral edema had a quadratic effect (P = 0.001), with grades I (19 'pts'), II (22 'pts'), and III (7 'pts') surviving for 24, 12, and 20 months respectively. Location and volume of tumors were not statistically significant predictors of survival (P < 0.05). In conclusion, in this highly selected group, GBM patients with little or no necrosis and with less tumor nodule enhancement on preoperative MRI survive longer than patients with greater amounts of necrosis and greater degrees of tumor enhancement. In addition, a moderate degree of peritumoral edema is associated with worse prognosis.

Radiation-induced damage to the central nervous system is believed to be targeted to glial or endothelial cells or both, although the pathophysiology of this process is still poorly understood. A series of experiments were, therefore, conducted, including irradiation to primary rat astrocytes (in vitro) and rat spinal cords (in vivo). The levels of plasminogen activators (uPA and tPA) and their inhibitors (PNI and PAI-1) were determined by fibrin zymography, ELISA, amidolytic activity assay, complex formation, and Western blot analysis. Fibrin zymography revealed the presence of M(r) 48,000 (uPA) and M(r) 68,000 (tPA) lytic bands that were increased in irradiated samples. Three- to four-fold higher levels of tPA and 8- to 10-fold higher levels of uPA were detected in irradiated samples. Western blot analysis confirmed the presence of a 51-kDa band (PAI-1) in irradiated samples. PAI-1 is undetectable in nonirradiated spinal cord. Serum-free medium and cell and spinal cord extracts of nonirradiated samples showed a 43-kDa band (PNI), the intensity of which is decreased in irradiated samples. Four- to five-fold decreased levels of PNI were detected in irradiated serum-free media and cell extracts, but no levels of PNI were detected in irradiated spinal cord extracts. This study provides additional information regarding the proposed roles of plasminogen activators and their inhibitors in the development of CNS damage after irradiation.

The plasminogen activation system consists of plasminogen activators and their inhibitors, serine proteases, and serpins. The proteases and inhibitors regulate a variety of processes in tissue morphogenesis, differentiation, cell migration, and cancer cell invasiveness and metastasis. One of the plasminogen activators, urokinase-type plasminogen activator (uPA), binds to a specific surface and provides a localized cell surface proteolytic activity required for the destruction of extracellular matrix, which is a vital step in tumor cell invasion. The proteolytic activity of uPA is modulated by its cell surface receptor, as well as by plasminogen activator inhibitor type-1 (PAI-1) and, to a lesser degree, by other inhibitors. The role of plasminogen activators and their inhibitors in cancer invasion can be demonstrated in the development and progression of malignant brain tumors. Our findings indicate that uPA and PAI-1 expression are dramatically upregulated in malignant brain tumors in parallel with the histological progression of the tumors. The results suggest that these molecules may contribute to tumor invasion in addition to their significant role in angiogenesis. An evaluation of the plasminogen activation system could add diagnostic and prognostic significance to the evaluation of individual patients.

Proteases and their inhibitors have been shown to play roles in tumor invasion and metastasis in a number of experimental models. Recently, relative increases in the amounts of urokinase type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in tumor samples have been correlated with poorer, pathological grade, shorter disease-free interval, and shorter survival. To date, all studies investigating the prognostic significance of proteases and their inhibitors have been limited to extracranial cancer. In this article, we review the literature and present our data on the prognostic significance of proteases in human brain tumors. High levels of uPA were seen in malignant glioma and metastatic tumors (n = 82), whereas normal levels of uPA were found in low-grade gliomas. Analysis with magnetic resonance imaging (MRI) demonstrated a significant correlation between high levels of uPA and necrosis and edema (n = 50; P < 0.05). Similarly, patients with high levels of uPA had shorter survival than did patients with low levels of uPA. Tissue-type plasminogen activator (tPA), which was virtually absent in glioblastoma multiforme (GBM), colon lung, and breast metastasis, was found in normal quantities in anaplastic astrocytoma (AA), low-grade glioma (LGG), and meningioma. Melanoma had significantly more tPA activity than normal brain did. A reverse correlation was found between tPA and MRI findings of necrosis, enhancement, and edema. Similarly, patients with no detectable tPA activity had shorter survival than did patients with detectable tPA activity. We conclude that high levels of uPA and absent tPA activity correlate with histologically malignant brain tumors, aggressive characteristics, and shorter survival.

The invasive nature of human gliomas represents a major factor in preventing their total resection. The exact nature of the underlying mechanisms of tumor cell invasion are still unclear. In this study, we have quantitatively assayed a glioblastoma cell line for its ability to migrate through a polycarbonate filter coated with matrigel which contains a complex of multiple basement membrane components. At 48 h the glioblastoma cell line (U251) showed a rate of invasiveness of 42% and also dependent on the concentration of matrigel. The U251 cell line produced a urokinase type plasminogen activator and a 92-KDa type IV collagenase. Both enzymes were inhibited by the addition of uPA and 92-KDa type IV collagenase antibodies. Those same antibodies reduced the invasion rate of U251 cells from 42% to 12 and 21%, respectively. Similarly, the addition of epsilon-aminocaproic acid (a plasmin inhibitor) or tissue inhibitor of metalloprotease (TIMP2, a collagenase inhibitor) reduced the invasiveness of U251 cells from 42% to 14% and 10%, respectively. Additionally, the other two glioblastoma cell lines (LG11, UWR1) and astrocytes showed a rate of invasiveness at 41%, 61% and 12%, respectively. Finally, the addition of hyaluronic acid to the matrigel, a constituent of brain extracellular matrix, enhanced the rate of invasion. These findings provide evidence for the role of serine proteases and metalloproteases in facilitating the invasion of extracellular matrix components by glioblastoma cell line and suggest a therapeutic role for protease inhibitors in attempting to minimize the invasive propensity of gliomas.

Considerable interest in the roles of serine proteases and serine protease inhibitors (serpins) in regulating physiologic and pathologic tissue remodeling has led to studies that indicate their critical participation in development and diseases of the brain. Plasminogen activator inhibitor-1 (PAI-1) is the most significant regulator of fibrinolysis in plasma, but little is known of the levels or activities of this important serpin in normal brain and brain tumors. For this reason, we estimated qualitative and quantitative levels of PAI-1 in normal human brain and various brain tumors. Western-blot results indicated that a 51 kDa band recognized with polyclonal anti-PAI-1 was more prominently in metastatic and glioblastoma than in meningiomas and low-grade gliomas; normal human brain lacked any detectable band. Reverse zymography also showed high levels of PAI-1 in malignant brain tumors. The complex formation with 125I-urokinase demonstrated that PAI-1 complex levels were increased in metastatic and glioblastoma when compared with low-grade gliomas and meningiomas. Since PAI-1 acts as a modulator of fibrinolysis, a better understanding of the balance between serine proteases and PAI-1 is likely to enhance our knowledge of brain tumor biology.

A practical radiation shielding cap has been constructed for use during 125I brain implants. The cap is comfortable enough to be worn continuously during a 6-day implant and provides complete shielding from the implanted radioactive sources.

Forty-six patients who underwent surgery for brain tumors were studied prospectively with 125I labeled Fibrinogen leg scans to detect postoperative venous thrombosis. The incidence of thrombosis was 72% for meningioma patients, 60% for glioblastoma patients, and 20% for brain metastasis patients. Correlation between the occurrence of venous thrombosis and the various clinical factors thought to be responsible for the high incidence of thrombosis generally failed to show statistical significance. This finding, along with the marked variation in the incidence of venous thrombosis between the different brain tumor groups, strongly suggests that biological factors play a more important role than clinical factors in determining which brain tumor patient will suffer a postoperative thrombotic event.

Preoperative hemostatic data were obtained on 42 brain tumor patients and correlated with the subsequent occurrence of venous thrombosis detected with 125I-labeled fibrinogen leg scans. The occurrence of thrombosis correlated significantly with an increased prothrombin time, plasminogen, and total fibrinolytic activity and a decreased fibrinogen level. This overall trend in the group of patients with postoperative thrombosis indicates that the hemostatic disorder noted in brain tumor patients is most closely related to a subclinical form of chronic disseminated intravascular coagulation syndrome. Differences in hemostatic parameters seen with the various types of brain tumors suggest that biological factors specific to each tumor are likely responsible for the described hemostatic disorder and support the need for further research directed at the tumor tissue level.

The plasminogen activator activity of 31 human brain tumor samples was assessed and the results correlated with clinical parameters and the postoperative occurrence of venous thrombosis. A significant negative correlation was found between plasminogen activator activity and venous thrombosis (P = 0.02), while positive correlations were observed between plasminogen activator activity and peritumoral brain edema (P = 0.03) and alpha 2 antiplasmin measured in the systemic circulation (P = 0.01). Tissue plasminogen activator was found in higher concentrations in meningioma tissue but did not correlate significantly with the occurrence of venous thrombosis. The results of this study suggest a local enzymatic degradation effect of plasminogen activator on thrombogenic substances present in the brain tumor and/or its environment.

We report a case of a third ventricular neuroblastoma (neurocytoma) in a 66 year old man. A stereotactic needly biopsy was performed to obtain a tissue diagnosis and was followed by total resection. We elected not to give radiation or chemotherapy and to follow the patient closely with serial CT scans. Presently, 48 months postoperatively, the patient is free of tumor by head CT scan and able to live independently. We reviewed the literature of primary cerebral neuroblastomas/neurocytomas occurring in adults (greater than or equal to 15 years of age) and found 32 cases. Our patient is the oldest of this group with a mean age of 32 +/- 14 years (S.D.). The location of the 33 neoplasms was intraventricular in 17 cases (52%) and intraparenchymal in 16 cases. The male to female ratio was 2:1. Of the 17 patients having a minimal follow-up period of 5 months (mean 51 months), five developed recurrences after 5 to 144 months (mean 50 months) compared to 12 patients without recurrence after a 6- to 72-month follow-up period (mean 52 months). Recurrences occurred statistically significantly more often in parenchymal neuroblastomas/neurocytomas than in intraventricular tumor locations.