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Glioblastoma (GBM) is the most common primary brain cancer, comprising half of all malignant brain tumors. Patients with GBM have a poor prognosis, with a median survival of 14–15 months. Current therapies for GBM, including chemotherapy, radiotherapy, and surgical resection, remain inadequate. Novel therapies are required to extend patient survival. Although immunotherapy has shown promise in other cancers, including melanoma and non-small lung cancer, its efficacy in GBM has been limited to subsets of patients. Identifying biomarkers of immunotherapy response in GBM could help stratify patients, identify new therapeutic targets, and develop more effective treatments. This article reviews existing and emerging biomarkers of clinical response to immunotherapy in GBM. The scope of this review includes immune checkpoint inhibitor and antitumoral vaccination approaches, summarizing the variety of molecular, cellular, and computational methodologies that have been explored in the setting of anti-GBM immunotherapies.

IMPORTANCE: O6-methylguanine-DNA methyltransferase (MGMT [OMIM 156569]) promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy for glioblastomas and is routinely used to guide treatment decisions. However, the utility of MGMT promoter status for low-grade and anaplastic gliomas remains unclear due to molecular heterogeneity and the lack of sufficiently large data sets. OBJECTIVE: To evaluate the association of mMGMT for low-grade and anaplastic gliomas with chemotherapy response. DESIGN, SETTING, AND PARTICIPANTS: This cohort study aggregated grade II and III primary glioma data from 3 prospective cohort studies with patient data collected from August 13, 1995, to August 3, 2022, comprising 411 patients: MSK-IMPACT, EORTC (European Organization of Research and Treatment of Cancer) 26951, and Columbia University. Statistical analysis was performed from April 2022 to January 2023. EXPOSURE: MGMT promoter methylation status. MAIN OUTCOMES AND MEASURES: Multivariable Cox proportional hazards regression modeling was used to assess the association of mMGMT status with progression-free survival (PFS) and overall survival (OS) after adjusting for age, sex, molecular class, grade, chemotherapy, and radiotherapy. Subgroups were stratified by treatment status and World Health Organization 2016 molecular classification. RESULTS: A total of 411 patients (mean [SD] age, 44.1 [14.5] years; 283 men [58%]) met the inclusion criteria, 288 of whom received alkylating chemotherapy. MGMT promoter methylation was observed in 42% of isocitrate dehydrogenase (IDH)–wild-type gliomas (56 of 135), 53% of IDH-mutant and non-codeleted gliomas (79 of 149), and 74% of IDH-mutant and 1p/19q-codeleted gliomas (94 of 127). Among patients who received chemotherapy, mMGMT was associated with improved PFS (median, 68 months [95% CI, 54-132 months] vs 30 months [95% CI, 15-54 months]; log-rank P < .001; adjusted hazard ratio [aHR] for unmethylated MGMT, 1.95 [95% CI, 1.39-2.75]; P < .001) and OS (median, 137 months [95% CI, 104 months to not reached] vs 61 months [95% CI, 47-97 months]; log-rank P < .001; aHR, 1.65 [95% CI, 1.11-2.46]; P = .01). After adjusting for clinical factors, MGMT promoter status was associated with chemotherapy response in IDH–wild-type gliomas (aHR for PFS, 2.15 [95% CI, 1.26-3.66]; P = .005; aHR for OS, 1.69 [95% CI, 0.98-2.91]; P = .06) and IDH-mutant and codeleted gliomas (aHR for PFS, 2.99 [95% CI, 1.44-6.21]; P = .003; aHR for OS, 4.21 [95% CI, 1.25-14.2]; P = .02), but not IDH-mutant and non-codeleted gliomas (aHR for PFS, 1.19 [95% CI, 0.67-2.12]; P = .56; aHR for OS, 1.07 [95% CI, 0.54-2.12]; P = .85). Among patients who did not receive chemotherapy, mMGMT status was not associated with PFS or OS. CONCLUSIONS AND RELEVANCE: This study suggests that mMGMT is associated with response to alkylating chemotherapy for low-grade and anaplastic gliomas and may be considered as a stratification factor in future clinical trials of patients with IDH–wild-type and IDH-mutant and codeleted tumors.

Resected lesions from the pineal region are rare specimens encountered by surgical pathologists, and their heterogeneity can pose significant diagnostic challenges. Here, we reviewed 221 pineal region lesions resected at New York-Presbyterian Hospital/Columbia University Irving Medical Center from 1994 to 2019 and found the most common entities to be pineal parenchymal tumors (25.3%), glial neoplasms (18.6%), and germ cell tumors (17.6%) in this predominantly adult cohort of patients. Six cases of a rare midline entity usually found exclusively in the fourth ventricle, the rosette-forming glioneuronal tumor, were identified. These tumors exhibit biphasic morphology, with a component resembling pilocytic astrocytoma admixed with variable numbers of small cells forming compact rosettes and perivascular pseudorosettes. Targeted sequencing revealed a 100% co-occurrence of novel and previously described genetic alterations in the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathways, suggesting a synergistic role in tumor formation. The most common recurrent mutation, PIK3CA H1047R, was identified in tumor cells forming rosettes and perivascular pseudorosettes. A review of the literature revealed 16 additional cases of rosette-forming glioneuronal tumors in the pineal region. Although rare, this distinctive low-grade tumor warrants consideration in the differential diagnosis of pineal region lesions.

The Wee1 (WEE1hu) inhibitor adavosertib and gemcitabine have shown preclinical synergy and promising activity in early phase clinical trials. We aimed to determine the efficacy of this combination in patients with ovarian cancer.

Graphical Abstract

Although radiation is widely used to treat cancers, resistance mechanisms often develop and involve activation of DNA repair and inhibition of apoptosis. Therefore, compounds that sensitize cancer cells to radiation via alternative cell death pathways are valuable. We report here that ferroptosis, a form of nonapoptotic cell death driven by lipid peroxidation, is partly responsible for radiation-induced cancer cell death. Moreover, we found that small molecules activating ferroptosis through system xc–inhibition or GPX4 inhibition synergize with radiation to induce ferroptosis in several cancer types by enhancing cytoplasmic lipid peroxidation but not increasing DNA damage or caspase activation. Ferroptosis inducers synergized with cytoplasmic irradiation, but not nuclear irradiation. Finally, administration of ferroptosis inducers enhanced the antitumor effect of radiation in a murine xenograft model and in human patient-derived models of lung adenocarcinoma and glioma. These results suggest that ferroptosis inducers may be effective radiosensitizers that can expand the efficacy and range of indications for radiation therapy.

Intraoperative diagnosis is essential for providing safe and effective care during cancer surgery1. The existing workflow for intraoperative diagnosis based on hematoxylin and eosin staining of processed tissue is time, resource and labor intensive2,3. Moreover, interpretation of intraoperative histologic images is dependent on a contracting, unevenly distributed, pathology workforce4. In the present study, we report a parallel workflow that combines stimulated Raman histology (SRH)5–7, a label-free optical imaging method and deep convolutional neural networks (CNNs) to predict diagnosis at the bedside in near real-time in an automated fashion. Specifically, our CNNs, trained on over 2.5 million SRH images, predict brain tumor diagnosis in the operating room in under 150 s, an order of magnitude faster than conventional techniques (for example, 20–30 min)2. In a multicenter, prospective clinical trial (n= 278), we demonstrated that CNN-based diagnosis of SRH images was noninferior to pathologist-based interpretation of conventional histologic images (overall accuracy, 94.6% versus 93.9%). Our CNNs learned a hierarchy of recognizable histologic feature representations to classify the major histopathologic classes of brain tumors. In addition, we implemented a semantic segmentation method to identify tumor-infiltrated diagnostic regions within SRH images. These results demonstrate how intraoperative cancer diagnosis can be streamlined, creating a complementary pathway for tissue diagnosis that is independent of a traditional pathology laboratory.

GH activates agouti-related protein (AgRP) neurons, leading to orexigenic responses in mice. The relationship between serum GH and plasma AgRP, which has been shown to reflect hypothalamic AgRP, has not been evaluated in humans.

Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTENmutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor’s clonal evolution during treatment.

Glucocorticoids regulate energy balance, in part by stimulating the orexigenic neuropeptide agouti-related protein (AgRP). AgRP neurons express glucocorticoid receptors, and glucocorticoids have been shown to stimulate AgRP gene expression in rodents.

R132H mutation status is related to vascular dysregulation caused by diffuse glioma and the volume of residual disease after surgical resection.

Aim:The number of breast cancer brain metastases is a prognostic clinical variable in the modified graded prognostic assessment (GPA) Index for breast cancer. Patients & methods:We retrospectively gathered data from 127 breast cancer patients who underwent radiation therapy for brain metastasis. Patients were stratified by both breast GPA and modified breast GPA scores, and survival was determined using the Kaplan–Meier curves and Cox proportional hazards model. Results & Conclusion:The Kaplan–Meier curve for patients under the breast GPA classification were not significant, but were significant under the modified breast GPA classification. The inclusion of number of brain metastases into the modified breast GPA index improved prognosis, thus validating the use of the modified breast GPA in prognosticating patient outcome.

Aim:The number of breast cancer brain metastases is a prognostic clinical variable in the modified graded prognostic assessment (GPA) Index for breast cancer. Patients & methods:We retrospectively gathered data from 127 breast cancer patients who underwent radiation therapy for brain metastasis. Patients were stratified by both breast GPA and modified breast GPA scores, and survival was determined using the Kaplan–Meier curves and Cox proportional hazards model. Results & Conclusion:The Kaplan–Meier curve for patients under the breast GPA classification were not significant, but were significant under the modified breast GPA classification. The inclusion of number of brain metastases into the modified breast GPA index improved prognosis, thus validating the use of the modified breast GPA in prognosticating patient outcome.

BACKGROUND:Given the vagaries of published guidelines and the lack of high-quality evidence on the method, timing, and dose of venous thromboembolism (VTE) prophylaxis in neurological surgery, little is known about practice patterns regarding VTE prophylaxis in the United States.OBJECTIVE:To estimate the use of VTE prophylaxis in patients who underwent surgery for a cerebral neoplasm and to identify patient, physician, and hospital characteristics associated with prophylaxis.METHODS:Using the Premier Perspective database, we classified patients undergoing surgery for intracranial neoplasm between 2006 and 2012 on the basis of the type of VTE prophylaxis they received (mechanical, pharmacological, or combination). Generalized estimating equations were used to analyze the effects of pretreatment patient and system variables, including hospital and surgeon volume, on prophylaxis while controlling for hospital clustering.RESULTS:A total of 43 327 patients were identified. Venous thromboembolism prophylaxis was given to 70.2% of patients. Overall, 16 957 (39.2%) had only mechanical prophylaxis, 5628 (13%) received only pharmacological prophylaxis, and 7826 (18.1%) received combination prophylaxis. Patients with high-volume providers (odds ratio, 2.22; 95% confidence interval, 1.33-3.69) were more likely to receive prophylaxis.CONCLUSION:Nearly one-third of patients who underwent surgery for an intracranial tumor did not receive any VTE prophylaxis. We noted that the rate of overall VTE prophylaxis did not significantly change over the course of the 7 years analyzed despite an increasing focus on complication prevention. High-volume surgeons were more likely to provide VTE prophylaxis.

Schwannomas are common peripheral nerve sheath tumors that can cause debilitating morbidities. We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas. Exome sequence analysis with validation by targeted DNA sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A, ARID1B and DDR1. RNA sequencing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis demonstrated the mechanism as resulting from a balanced 19-Mb chromosomal inversion on chromosome 10q. The fusion was associated with male gender predominance, occurring in one out of every six men with schwannoma. Methylation profiling identified distinct molecular subgroups of schwannomas that were associated with anatomical location. Expression of the SH3PXD2A-HTRA1 fusion resulted in elevated phosphorylated ERK, increased proliferation, increased invasion and in vivo tumorigenesis. Targeting of the MEK-ERK pathway was effective in fusion-positive Schwann cells, suggesting a possible therapeutic approach for this subset of tumors.

Intra-arterial (IA) drug delivery has been proposed for the treatment of a wide range of brain diseases, including malignant brain tumors. However, pharmacokinetic optimization for IA drug delivery to the brain remains a challenge. In this report, we apply and expand the well-established Dedrick model of IA drug delivery to the brain and test the effects of modifying drug and delivery parameters. These simulations show that altering the properties of candidate drugs and physiological variables can have profound effects on regional deposition after IA injections. We show that drug and physiological optimization aimed at rapid drug extraction and sustained retention is necessary to maximize regional deposition after of IA injections.

Nanoparticles such as liposomes may be used as drug delivery vehicles for brain tumor therapy. Particle geometry and electrostatic properties have been hypothesized to be important determinants of effective tumor targeting after intraarterial injection. In this study, we investigate the combined roles of liposome size and surface charge on the effectiveness of delivery to gliomas after intraarterial injection. Intracarotid injection of liposomes was performed in separate cohorts of both healthy and C6 glioma-bearing Sprague Dawley rats after induction of transient cerebral hypoperfusion. Large (200 nm) and small (60–80 nm) fluorescent dye-loaded liposomes that were either cationic or neutral in surface charge were utilized. Delivery effectiveness was quantitatively measured both with real-time, in vivo and postmortem diffuse reflectance spectroscopy. Semi-quantitative multispectral fluorescence imaging was also utilized to assess the pattern and extent of liposome targeting within tumors. Large cationic liposomes demonstrated the most effective hemispheric and glioma targeting of all the liposomes tested. Selective large cationic liposome retention at the site of glioma growth was observed. The liposome deposition pattern within tumors after intraarterial injection was variable with both core penetration and peripheral deposition observed in specific tumors. This study provides evidence that liposome size and charge are important determinants of effective brain and glioma targeting after intraarterial injection. Our results support the future development of 200-nm cationic liposomal formulations of candidate intraarterial anti-glioma agents for further pre-clinical testing.

Mechanisms that maintain cancer stem cells are crucial to tumour progression. The ID2 protein supports cancer hallmarks including the cancer stem cell state. HIFα transcription factors, most notably HIF2α (also known as EPAS1), are expressed in and required for maintenance of cancer stem cells (CSCs). However, the pathways that are engaged by ID2 or drive HIF2α accumulation in CSCs have remained unclear. Here we report that DYRK1A and DYRK1B kinases phosphorylate ID2 on threonine 27 (Thr27). Hypoxia downregulates this phosphorylation via inactivation of DYRK1A and DYRK1B. The activity of these kinases is stimulated in normoxia by the oxygen-sensing prolyl hydroxylase PHD1 (also known as EGLN2). ID2 binds to the VHL ubiquitin ligase complex, displaces VHL-associated Cullin 2, and impairs HIF2α ubiquitylation and degradation. Phosphorylation of Thr27 of ID2 by DYRK1 blocks ID2–VHL interaction and preserves HIF2α ubiquitylation. In glioblastoma, ID2 positively modulates HIF2α activity. Conversely, elevated expression of DYRK1 phosphorylates Thr27 of ID2, leading to HIF2α destabilization, loss of glioma stemness, inhibition of tumour growth, and a more favourable outcome for patients with glioblastoma.

Context:GH and IGF-I have important roles in the maintenance of substrate metabolism and body composition. However, when in excess in acromegaly, the lipolytic and insulin antagonistic effects of GH may alter adipose tissue (AT) deposition.Objectives:The purpose of this study was to examine the effect of surgery for acromegaly on AT distribution and ectopic lipid deposition in liver and muscle.Design:This was a prospective study before and up to 2 years after pituitary surgery.Setting:The setting was an academic pituitary center.Patients:Participants were 23 patients with newly diagnosed, untreated acromegaly.Main Outcome Measures:We determined visceral (VAT), subcutaneous (SAT), and intermuscular adipose tissue (IMAT), and skeletal muscle compartments by total-body magnetic resonance imaging, intrahepatic and intramyocellular lipid by proton magnetic resonance spectroscopy, and serum endocrine, metabolic, and cardiovascular risk markers.Results:VAT and SAT masses were lower than predicted in active acromegaly, but increased after surgery in male and female subjects along with lowering of GH, IGF-I, and insulin resistance. VAT and SAT increased to a greater extent in men than in women. Skeletal muscle mass decreased in men. IMAT was higher in active acromegaly and decreased in women after surgery. Intrahepatic lipid increased, but intramyocellular lipid did not change after surgery.Conclusions:Acromegaly may present a unique type of lipodystrophy characterized by reduced storage of AT in central depots and a shift of excess lipid to IMAT. After surgery, this pattern partially reverses, but differentially in men and women. These findings have implications for understanding the role of GH in body composition and metabolic risk in acromegaly and other clinical settings of GH use.

SUMMARY Glioblastoma is the most common primary brain tumor in adults and carries a dismal prognosis despite advancements in treatment. Diffuse tumor infiltration precludes curative surgical resection and necessitates advancements in drug delivery mechanisms. Convection-enhanced delivery (CED) enables continuous local drug delivery for a diverse population of antitumor agents. Importantly, CED circumvents therapeutic challenges posed by the blood–brain barrier by facilitating concentrated local therapeutic drug delivery with limited systemic effects. Here, we present a concise review of properties essential for safe and efficient convection-enhanced drug delivery, as well as a focused review of clinical studies evaluating CED in the treatment of glioblastoma.

SUMMARY Glioblastoma is the most common primary brain tumor in adults and carries a dismal prognosis despite advancements in treatment. Diffuse tumor infiltration precludes curative surgical resection and necessitates advancements in drug delivery mechanisms. Convection-enhanced delivery (CED) enables continuous local drug delivery for a diverse population of antitumor agents. Importantly, CED circumvents therapeutic challenges posed by the blood–brain barrier by facilitating concentrated local therapeutic drug delivery with limited systemic effects. Here, we present a concise review of properties essential for safe and efficient convection-enhanced drug delivery, as well as a focused review of clinical studies evaluating CED in the treatment of glioblastoma.

Summary: Background: P-glycoprotein (Pgp) mediates, in part, resistance to natural product chemotherapy drugs which constitute over half of the available drugs for cancer treatment. Tamoxifen (TAM) enhances intracellular deposition of natural product chemotherapy in human cell lines by inhibition of Pgp. Pgp is highly expressed in the choroid plexus and is thought to be a key component of the blood–cerebrospinal fluid barrier (BCSFB). We conducted a prospective, randomized study to assess if Pgp inhibition by TAM alters deposition of paclitaxel in cerebrospinal fluid (CSF). Methods: Ten patients with either primary or metastatic brain tumors were randomized to: paclitaxel alone (175 mg/m2/IV) or a course of TAM (160 mg/m2 PO BID on Days 1–5) followed by paclitaxel (175 mg/m2/IV on Day 5). CSF and plasma samples were obtained following paclitaxel infusion; paclitaxel and TAM concentrations were measured by high-performance liquid chromatography assays. Results: Paclitaxel was detected in the CSF of six of the 10 patients. Peak CSF paclitaxel concentrations of the paclitaxel and paclitaxel–TAM groups ranged between 3.5–57.4 and 2.3–24.6 nM, respectively. Though there was a 2.4-fold higher mean CSF paclitaxel concentration and a 3.7-fold higher median peak CSF:plasma paclitaxel ratio for those who received paclitaxel alone as compared to combined paclitaxel–TAM, it was not statistically significant (P = 0.22). In one patient enrolled to both arms, higher CSF concentrations of paclitaxel and higher paclitaxel CSF: plasma ratios were observed when given paclitaxel alone. Conclusions: The trend towards lower paclitaxel CSF concentrations when given with TAM is consistent with the published finding that Pgp’s localization in the endothelial cells of the choroid plexus works in an opposite direction and keeps drugs in the CSF. Thus, agents which inhibit Pgp, such as TAM, may increase efflux of Pgp substrates out of the BCSFB and may paradoxically lower CSF concentrations of natural product chemotherapy drugs. Conceptually, this finding implies that the Pgp in the BBB and BCSFB keeps natural toxins such as paclitaxel, from entering the brain (BBB) and, if they do enter the brain, keeps them in the CSF (BCSFB) where they may be less harmful than if they re-entered the brain. Thus, our work supports this novel idea and adds to the understanding of the functions of the BCSFB.

Optimal management of pineal region tumors depends on securing an accurate histologic diagnosis to facilitate management customized to the nuances of specific pathologies. As an initial step, surgical intervention by either stereotactic biopsy or open surgery is necessary to obtain tissue for pathologic examination. Stereotactic biopsy has the benefit of relative ease and minimal morbidity but is associated with greater likelihood of diagnostic inaccuracy compared to open surgery where more extensive tissue sampling is possible. The role of surgical debulking in the management of pineal tumors is clearly defined for some tumors but is less evident for others. Among the one third of pineal tumors that are benign or low grade, complete surgical resection is achievable and constitutes optimal management with excellent long-term recurrence-free survival. The benefits of aggressive surgical resection among malignant tumors are less clear but several studies have correlated degree of tumor removal with improved outcome. Advances in technology, surgical technique, and post-operative care have minimized surgical complications, however all surgical procedures in the pineal region, including both stereotactic biopsy and open surgery, are potentially hazardous. Advanced judgment, experience, and expertise are necessary to achieve rates of success sufficient to justify aggressive management. Management strategies using stereotactic biopsy, endoscopy, and radiosurgery can also provide favorable outcomes in some cases. Selective incorporation of these innovations can be expected to improve the already highly favorable outcome for all pineal region tumors.

Purpose:This was an open-label, dose-escalation trial of intratumoral administration of IL-4 Pseudomonasexotoxin (NBI-3001) in patients with recurrent malignant glioma. Patients and methods:A total of 31 patients with histologically verified supratentorial grades 3 and 4 astrocytoma were studied. Of these, 25 patients were diagnosed with glioblastoma multiforme (GBM) while six were diagnosed with anaplastic astrocytoma. Patients were over 18 years of age and had Karnofsky performance scores ≥60. Patients were assigned to one of four dose groups in a dose-escalation fashion: 6µg/ml×40ml,9µg/ml×40ml,15µg/ml×40ml, or 9µug/ml×100ml of NBI-3001 administered via convection-enhanced delivery intratumorally using stereotactically placed catheters. Patients were followed with serial MRI scans and clinical assessments every four weeks for the first 16 weeks and then every eight weeks until week 26. Results:No drug-related systemic toxicity, as evident by lack of hematological or serum chemical changes, was apparent in any patients; treatment-related adverse effects were limited to the central nervous system. No deaths were attributable to treatment. Drug-related grade 3 or 4 toxicity was seen in 39% of patients in all dose groups and 22% of patients at the maximum tolerated dose of 6µug/ml×40ml. The overall median survival was 8.2 months with a median survival of 5.8 months for the GBM patients. Six-month survival was 52% and 48%, respectively. Gadolinium-enhanced magnetic resonance imaging of the brain showed areas of decreased signal intensity within the tumor consistent with tumor necrosis following treatment in many patients. Conclusions:NBI-3001 appears to have an acceptable safety and toxicity profile when administered intratumorally in patients with recurrent malignant glioma.

Objectives:Adjuvant-linked vaccines have been shown to induce anti-tumor immunity in patients with a variety of solid tumors. In this study we describe an in vitromodel of active immunotherapy using autologous fibroblasts as immunogen. Correlative results from glioma patients immunized with autologous fibroblasts are also described. Methods:Peripheral blood lymphocytes (PBLs) from normal subjects were immunized in vitroagainst autologous skin fibroblasts coupled to the adjuvant muramyl dipeptide. The lymphocytes developed cell-mediated cytotoxicity that was measured with a short-term chromium release assay. Results of in vitroexperiments were compared to data derived from glioma patients immunized with subcutaneous injection of an autologous adjuvant-linked fibroblast vaccine. Glioma target cells and fibroblast immunogens were derived from early passage primary tissue culture. Results:A comparison of autologous vs. homologous immunogen indicated that major histocompatibility complex matching was required at the sensitization stage of immunity (17.2 ± 3.4% specific lysis vs. 0.4 ± 3.1%, P< 0.01). Pre-treatment of fibroblast immunogen cells with interferon gamma (IFN-γ) was found to significantly increase immunity (42.2 ± 10.0%, P< 0.01), as did IFN-γ pre-treatment of tumor target cells (35.8 ± 9.0%, P< 0.01). The positive effect of IFN-γ was diminished by treatment of cells with IFN-α. These in vitroresults correlated well with in vivodata derived from glioma patients immunized with an autologous adjuvant-linked fibroblast vaccine. PBLs from patients developed direct cell-mediated cytotoxicity against autologous tumor cells. Lysis of tumor targets after in vivoimmunization increased over a three-week interval (from 1.2 ± 3.0% to 21.0 ± 3.4%, P< 0.01) while lysis of a non-MHC matched control cell line remained essentially unchanged. Conclusions:Specific lysis of glioma targets in vitrowas achieved after in vivosensitization with autologous adjuvant-linked fibroblasts. Collectively, the data indicate that biochemically modified autologous cells can stimulate anti-glioma immunity in humans. The degree of specific immunity seen in our patients compares favorably with other published series using glioma cells as an antigenic source. Accordingly, fibroblasts may represent a practical alternative to glioma cells for vaccine construction.

Purpose:This was an open-label, dose-escalation trial of intratumoral administration of IL-4Pseudomonasexotoxin (NBI-3001) in patients with recurrent malignant glioma. Patients and methods:A total of 31 patients with histologically verified supratentorial grades 3 and 4 astrocytoma were studied. Of these, 25 patients were diagnosed with glioblastoma multiforme (GBM) while six were diagnosed with anaplastic astrocytoma. Patients were over 18 years of age and had Karnofsky performance scores ≥60. Patients were assigned to one of four dose groups in a dose-escalation fashion: 6 µg/ml × 40 ml, 9 µg/ml × 40 ml, 15 µg/ml × 40 ml, or 9 µg/ml × 100 ml of NBI-3001 administered via convection-enhanced delivery intratumorally using stereotactically placed catheters. Patients were followed with serial MRI scans and clinical assessments every four weeks for the first 16 weeks and then every eight weeks until week 26. Results:No drug-related systemic toxicity, as evident by lack of hematological or serum chemical changes, was apparent in any patients; treatment-related adverse effects were limited to the central nervous system. No deaths were attributable to treatment. Drug-related grade 3 or 4 toxicity was seen in 39% of patients in all dose groups and 22% of patients at the maximum tolerated dose of 6 µg/ml × 40 ml. The overall median survival was 8.2 months with a median survival of 5.8 months for the GBM patients. Six-month survival was 52% and 48%, respectively. Gadolinium-enhanced magnetic resonance imaging of the brain showed areas of decreased signal intensity within the tumor consistent with tumor necrosis following treatment in many patients. Conclusions:NBI-3001 appears to have an acceptable safety and toxicity profile when administered intratumorally in patients with recurrent malignant glioma.

Objectives:Adjuvant-linked vaccines have been shown to induce anti-tumor immunity in patients with a variety of solid tumors. In this study we describe anin vitromodel of active immunotherapy using autologous fibroblasts as immunogen. Correlative results from glioma patients immunized with autologous fibroblasts are also described. Methods:Peripheral blood lymphocytes (PBLs) from normal subjects were immunizedin vitroagainst autologous skin fibroblasts coupled to the adjuvant muramyl dipeptide. The lymphocytes developed cell-mediated cytotoxicity that was measured with a short-term chromium release assay. Results ofin vitroexperiments were compared to data derived from glioma patients immunized with subcutaneous injection of an autologous adjuvantlinked fibroblast vaccine. Glioma target cells and fibroblast immunogens were derived from early passage primary tissue culture. Results:A comparison of autologous vs. homologous immunogen indicated that major histocompatibility complex matching was required at the sensitization stage of immunity (17.2±3.4% specific lysis vs. 0.4±3.1%,P<0.01). Pre-treatment of fibroblast immunogen cells with interferon gamma (IFN-γ) was found to significantly increase immunity (42.2±10.0%,P<0.01), as did IFN-γpre-treatment of tumor target cells (35.8±9.0%,P<0.01). The positive effect of IFN-γwas diminished by treatment of cells with IFN-α. Thesein vitroresults correlated well within vivodata derived from glioma patients immunized with an autologous adjuvant-linked fibroblast vaccine. PBLs from patients developed direct cell-mediated cytotoxicity against autologous tumor cells. Lysis of tumor targets afterin vivoimmunization increased over a three-week interval (from 1.2 ± 3.0% to 21.0 ± 3.4%,P< 0.01) while lysis of a non-MHC matched control cell line remained essentially unchanged. Conclusions:Specific lysis of glioma targetsin vitrowas achieved afterin vivosensitization with autologous adjuvant-linked fibroblasts. Collectively, the data indicate that biochemically modified autologous cells can stimulate anti-glioma immunity in humans. The degree of specific immunity seen in our patients compares favorably with other published series using glioma cells as an antigenic source. Accordingly, fibroblasts may represent a practical alternative to glioma cells for vaccine construction.

The advent of molecular biology has provided tools to delineate genetic mutations that cause disease. Recently, several genetic mutations have been associated with intramedullary spinal cord tumors. Concurrently, advances in micro-neurosurgical techniques have significantly decreased the morbidity of surgical resection. In this review, we describe the current understanding of genetic mutations in sporadic and familial intramedullary spinal cord tumors. The future success of innovative gene therapy protocols may depend upon establishing a cause and effect relationship between these genetic mutations and disease progression. Successful gene therapy will also depend upon increasing the efficiency of gene therapy vector delivery.

This phase I dose-escalation study was performed to determine the tolerability of three-drug combination high-dose BCNU (B) (450 mg/m2), escalating-dose thiotepa (500–800 mg/m2) and etoposide (1200 mg/m2) in divided doses over four days in 22 adults with malignant primary brain tumors. Patients received G-CSF and hematopoeitic support with peripheral blood progenitor cells (PBPC) (n=18) or both PBPC and marrow (n=4). The maximum tolerated dose of thiotepa with acceptable toxicity was determined as 800 mg/m2. The 100-day mortality rate was 9% (2/22). Grade III/IV toxicities included mucositis (71%), diarrhea (29%), nausea/vomiting (19%), and hepatic toxicity (14%). Neurological toxicities occurred in 24% and included seizures (two patients) and encephalopathy (three patients). Encephalopathy was transient in two patients and progressive in one patient. All patients had neutropenic fever. Median time to engraftment with absolute neutrophil count (ANC) >0.5×109/l was 10 days (range 8–30 days). Platelet engraftment >20×109/l occurred after 11 days (range 9–65 days). In the eighteen patients supported solely with PBPC, there was a significant inverse correlation between CD34+dose and days to ANC (rho=−0.78, p=0.001) and platelet engraftment (rho=−0.76, p=0.002). Overall, 11% of evaluable patients (2/18) had a complete response to BTE. Median time to tumor progression (TTP) was 9 months, with an overall median survival of 17 months. BCNU (450 mg/m2), thiotepa (800 mg/m2) and etoposide (1200 mg/m2) in divided doses over four days is a tolerable combination HDC regimen, the efficacy of which warrants further investigation in adults with optimally resected chemoresponsive brain tumors.

An aggressive surgical approach to pineal tumors is recommended for diagnostic and therapeutic purposes. Advances in surgical technique have significantly lowered mortality and morbidity in patients with pineal tumors while prolonging survival and increasing the likelihood of cure. Identification of tumor histology of unresectable tumors is essential for directing postoperative tumor-specific adjuvant therapy.

This study investigates the use of tissue-soldering techniques to substitute or reinforce traditional suture closure of dural incisions. Fresh human cadaveric dura was incised and subsequently closed by use of three techniques: (1) conventional interrupted suture with 4–0 silk (n= 25), (2) laser solder reinforced suture closure (n= 25), and (3) laser solder closure alone (n= 25). Anastomosis tensile strength and hydrostatic leak pressures were measured. Dural repair was also performed in 15 live Lewis rats. Dural closure was accomplished with 9–0 Prolene sutures (n= 5), laser-reinforced suture closure (n= 5), and laser solder closure alone (n= 5). Histologic examination of the closure immediately after soldering and 2 weeks later was performed. Suture closure alone had the lowest leak pressure, 9.4 ± 1.7 mm Hg, and an intermediate break point, 13.3 ± 2.1 Kgf/cm2. Measurements with laser solder alone revealed a mean leak pressure of 26.2 ± 3.7 mm Hg and a break point of 4.6 ± 1.4 Kgf/cm2. Solder-reinforced suture closure leak pressure measured 64.0 ± 6.7 mm Hg and 21.4 ± 2.4 Kgf/cm2. There was a statistically significant increase in leak pressure and tensile strength in the closures performed with laser weld reinforcement of traditional suture technique (p= 0.0001). Dural closure with laser tissue welding alone provided an immediate leak-free closure, but with poor tensile strength. Histologic examination of welded dura and underlying brain tissue showed no evidence of thermal injury in four of five animals studied. Laser welding may significantly decrease the incidence of cerebrospinal fluid leak after dural closure. In addition, laser tissue welding also makes dural closure possible where space constraints make traditional suture closure difficult.

Abstract: Red Pt(bpm)Cl2·dmf forms a stacked structure which has Pt…Pt separations of 3.423(2) A and 3.447(2) Å with Pt…Pt…Pt angles of 155.39(3)o. The unit cell isP-1, witha=6.712(4) A,b=10.0765(6) Å,c=11.551(3) Å, α=106.732(12)o, β=103.65(4)o, γ=90.46(3)o, andZ=2. The structure refined to anR(F) of 0.046 using 181 parameter and 2165 reflections withI>1σ(I). The yellow complex Pt(bpm)(dmso)(SO4)·H2O does not stack in the solid state: the shortest Pt…Pt separation is 4.638(2) Å. The unit cell is alsoP-1, witha=8.060(3) A,b=9.560(3) A,c=9.7534(18) Å, α=90.62(2)o, β=99.43(3)o, γ=90.66(3)o, andZ=2. The structure refined to anR(F) of 0.039 using 208 parameters and 3689 reflections withI>1σ(l).

Summary Treatment objectives for meningiomas of the cranial base include relief of neurologic disability and prevention of clinical progression or recurrence with the least morbidity. Recent advances in skull base surgical techniques, through an appreciation of skull base anatomy and institutional specialization, have contributed major improvements to the outlook for patients with these tumors, and previously inoperable cases may now often be removed completely with acceptable risk. Since significant morbidity may be incurred during surgical resection of these difficult lesions, especially in terms of cranial nerve dysfunction, the value of aggressive surgical resection must be weighed against the often indolent natural history of these lesions, and must be individualized in each patient. Completeness of resection is the major prognostic factor determining the out-come of patients with typical benign meningiomas in terms of length of survival, risk of recurrence, and neurological disability. Various means of prognosticating the growth potential of a given tumor are being investigated, though none have yet been confirmed for their predictive value in typical, histologically benign meningiomas. The role of external beam radiotherapy has not been subjected to adequately controlled, prospective studies, and there is currently insufficient followup to assess the risks and benefits of stereotactic radiosurgery.

This study investigates the use of tissue-soldering techniques to substitute or reinforce traditional suture closure of dural incisions. Fresh human cadaveric dura was incised and subsequently closed by use of three techniques: (1) conventional interrupted suture with 4-0 silk (n = 25), (2) laser solder reinforced suture closure (n = 25), and (3) laser solder closure alone (n = 25). Anastomosis tensile strength and hydrostatic leak pressures were measured. Dural repair was also performed in 15 live Lewis rats. Dural closure was accomplished with 9-0 Prolene sutures (n = 5), laser-reinforced suture closure (n = 5), and laser solder closure alone (n = 5). Histologic examination of the closure immediately after soldering and 2 weeks later was performed. Suture closure alone had the lowest leak pressure, 9.4 ± 1.7 mm Hg, and an intermediate break point, 13.3 ± 2.1 Kgf/cm2. Measurements with laser solder alone revealed a mean leak pressure of 26.2 ± 3.7 mm Hg and a break point of 4.6 ± 1.4 Kgf/cm2. Solder-reinforced suture closure leak pressure measured 64.0 ± 6.7 mm Hg and 21.4 ± 2.4 Kgf/cm2. There was a statistically significant increase in leak pressure and tensile strength in the closures performed with laser weld reinforcement of traditional suture technique (p = 0.0001). Dural closure with laser tissue welding alone provided an immediate leak-free closure, but with poor tensile strength. Histologic examination of welded dura and underlying brain tissue showed no evidence of thermal injury in four of five animals studied. Laser welding may significantly decrease the incidence of cerebrospinal fluid leak after dural closure. In addition, laser tissue welding also makes dural closure possible where space constraints make traditional suture closure difficult. (Otolaryngol Head Neck Surg 1996;115:513-8.)

This study investigates the use of tissue-soldering techniques to substitute or reinforce traditional suture closure of dural incisions. Fresh human cadaveric dura was incised and subsequently closed by use of three techniques: (1) conventional interrupted suture with 4–0 silk (n= 25), (2) laser solder reinforced suture closure (n= 25), and (3) laser solder closure alone (n= 25). Anastomosis tensile strength and hydrostatic leak pressures were measured. Dural repair was also performed in 15 live Lewis rats. Dural closure was accomplished with 9–0 Prolene sutures (n= 5), laser-reinforced suture closure (n= 5), and laser solder closure alone (n= 5). Histologic examination of the closure immediately after soldering and 2 weeks later was performed. Suture closure alone had the lowest leak pressure, 9.4 ± 1.7 mm Hg, and an intermediate break point, 13.3 ± 2.1 Kgf/cm2. Measurements with laser solder alone revealed a mean leak pressure of 26.2 ± 3.7 mm Hg and a break point of 4.6 ± 1.4 Kgf/cm2. Solder-reinforced suture closure leak pressure measured 64.0 ± 6.7 mm Hg and 21.4 ± 2.4 Kgf/cm2. There was a statistically significant increase in leak pressure and tensile strength in the closures performed with laser weld reinforcement of traditional suture technique (p= 0.0001). Dural closure with laser tissue welding alone provided an immediate leak-free closure, but with poor tensile strength. Histologic examination of welded dura and underlying brain tissue showed no evidence of thermal injury in four of five animals studied. Laser welding may significantly decrease the incidence of cerebrospinal fluid leak after dural closure. In addition, laser tissue welding also makes dural closure possible where space constraints make traditional suture closure difficult.

Comparative genomic hybridization serves as a screening test for regions of copy number changes in tumor genomes. We have applied the technique to map DNA gains and losses in 5 cell lines derived from glioblastoma multiforme, the most common primary neoplasm of the central nervous system. The most frequent losses occurred on chromosomes 10 and 13. The most common gains were observed on chromosomes 5, 6, 7 and 20. Some novel sites of genomic alterations were also observed. Analysis of common areas of loss and gain in these cell lines provides a basis for future attempts to more finely map these genetic changes and for elucidation of genes involved in tumor progression.