Glioblastoma (GBM) is a highly heterogeneous type of tumor characterized by genomic and signaling abnormalities affecting pathways involved in control of cell fate, including tumor-suppressor- and growth factor-regulated pathways. An aberrant miRNA expression has been observed in GBM, being associated with impaired cellular functions resulting in malignant transformation, proliferation and invasion. Here, we demonstrate for the first time that platelet-derived growth factor-B (PDGF-B), a potent angiogenic growth factor involved in GBM development and progression, promotes downregulation of pro-oncogenic (miR-21) and anti-oncogenic (miR-128) miRNAs, as well as upregulation/downregulation of several miRNAs involved in GBM pathology. Retrovirally mediated overexpression of PDGF-B in U87 human GBM cells or their prolonged exposure, as well as that of F98 rat glioma cells to this ligand, resulted in decreased miR-21 and miR-128 levels, which was associated with increased cell proliferation. Furthermore, siRNA-mediated PDGF-B silencing led to increased levels of miR-21 and miR-128, while miRNA modulation through overexpression of miR-21 did not alter the levels of PDGF-B. Finally, we demonstrate that modulation of tumor suppressors PTEN and p53 in U87 cells does not affect the decrease in miR-21 levels associated with PDGF-B overexpression. Overall, our findings suggest that, besides its role in inducing GBM tumorigenesis, PDGF-B may enhance tumor proliferation by modulating the expression of oncomiRs and tumor suppressor miRNAs in U87 human GBM cells.
Recent preclinical studies suggest that treating glioblastoma (GBM) with a combination of targeted chemotherapy and radiotherapy may enhance the anti-tumor effects of both therapies. However, the effects of these treatments on glioma growth and progression are poorly understood.
In this study we have tested the effects of combination therapy in a mouse glioma model that utilizes a PDGF-IRES-Cre-expressing retrovirus to infect adult glial progenitors in mice carrying conditional deletions of Pten and p53. This model produces tumors with the histological features of GBM with 100% penetrance, making it a powerful system to test novel treatments. Sunitinib is an orally active, small molecule inhibitor of multiple receptor tyrosine kinases (RTKs) critical for tumor growth and angiogenesis, including PDGF receptors. We investigate the addition of Sunitinib to radiotherapy, and use bioluminescence imaging to characterize the effects of treatment on glioma growth and progression.
Treating our PDGF-driven mouse model with either Sunitinib or high-dose radiation alone delayed tumor growth and had a modest but significant effect on survival, while treating with low-dose radiation alone failed to control glioma growth and progression. The addition of Sunitinib to low-dose radiation caused a modest, but significant delay in tumor growth. However, no significant survival benefit was seen as tumors progressed in 100% of animals. Histological analysis revealed a reduction in vascular proliferation and a marked increase in brain invasion. An additional study combining Sunitinib with high-dose radiation revealed a fatal toxicity despite individual monotherapies being well tolerated.
These results show that the addition of Sunitinib to radiotherapy fails to significantly alter survival in GBM despite enhancement of the effects of radiation. Furthermore, an enhanced risk of toxicity associated with combined therapy must be considered in the design of future clinical studies.
glioblastoma; PDGF; radiation; radiotherapy; sunitinib; sutent; SU1128; VEGF
Gliomas are the most common primary brain tumor in both children and adults. The prognosis for glioblastoma (GBM), the most common type of malignant glioma, has remained dismal, with median survival a little over one year despite maximal therapy with surgery, chemotherapy, and radiation. Although immunotherapy has become increasingly successful against many systemic tumors, clinical efficacy against brain tumors has been limited. One reason for this is an incomplete understanding of the local immunologic tumor microenvironment, particularly the function of large numbers of infiltrating myeloid derived cells. Monocytes/microglia are myeloid derived immunomodulatory cells, and they represent the predominant infiltrating immune cell population in gliomas. Our group has previously demonstrated using complementary in
vitro and in
vivo approaches that GBM tumor cells polarize tumor-associated myeloid cells (TAMs) and suppress their immunostimulatory function.
Methods and Results
To better understand the mechanisms responsible for this immunosuppression, we used gene expression profiling of stimulated monocytes in the presence or absence of GBM tumor cells. Our analysis identified caveolin-1 (CAV1), a plasma membrane molecule with pleiotropic functions, as significantly up-regulated in monocytes in the presence of GBMs. We validated these findings ex
vivo by confirming up-regulation of CAV1 in TAMs isolated from GBMs immediately after surgical resection. Finally, we demonstrate that siRNA inhibition of CAV1 restores myeloid cell function, as measured by TNF-alpha secretion, in the presence of GBMs.
Restoration of TAM function through pharmacologic blockage of CAV1 may facilitate more successful immunotherapeutic strategies directed against a variety of solid human tumors infiltrated by TAMs.
Craniopharyngioma is a rare primary central nervous system neoplasm. Our objective was to determine factors associated with incidence, treatment, and survival of craniopharyngiomas in the United States. We used the surveillance, epidemiology and end results program (SEER) database to identify patients who received a diagnosis of craniopharyngioma during 2004–2008. We analyzed clinical and demographic information, including age, race, sex, tumor histology, and treatment. Age-adjusted incidence rates and age, sex, and race-adjusted expected survival rates were calculated. We used Cox proportional hazards models to determine the association between covariates and overall survival. We identified 644 patients with a diagnosis of craniopharyngioma. Black race was associated with an age-adjusted relative risk for craniopharyngioma of 1.26 (95% confidence interval [CI], 0.98–1.59), compared with white race. One- and 3-year survival rates of 91.5% (95% CI, 88.9%–93.5%), and 86.2% (95% CI, 82.7%–89.0%) were observed for the cohort; relative survival rates were 92.1% (95% CI, 89.5%–94.0%) and 87.6% (95% CI, 84.1%–90.4%) for 1- and 3-years, respectively. In the multivariable model, factors associated with prolonged survival included younger age, smaller tumor size, subtotal resection, and radiation therapy. Black race, on the other hand, was associated with worse overall survival in the final model. We demonstrated that >85% of patients survived 3 years after diagnosis and that subtotal resection and radiation therapy were associated with prolonged survival. We also noted a higher incidence rate and worse 1- and 3-year survival rates in the black population. Future investigations should examine these racial disparities and focus on evaluating the efficacy of emerging treatment paradigms.
benign tumor; craniopharyngioma; epidemiology; racial disparity; SEER
Surgical resection of pituitary tumors is the treatment of choice for patients with hormone-secreting tumors or those that impair vision and other neurological functions. A recent study by Grossman et al., however, found transsphenoidal surgery to be associated with increased mortality and morbidities in elderly patients, which suggests the need for careful individualized decision-making in this vulnerable population.
In vivo tracking of gene therapy vectors challenges the investigation and improvement of biodistribution of these agents in the brain, a key feature for their targeting of infiltrative malignant gliomas. The glioma-targeting Ad5/3-cRGD gene therapy vector was covalently bound to super-paramagnetic iron oxide (Fe3O4) nanoparticles (SPION) to monitor its distribution by MRI. Transduction of labeled and unlabeled vectors was assessed on the U87 glioma cell line and normal human astrocytes (NHA), and was higher in U87 compared to NHA, but was similar between labeled and unlabeled virus. An in vivo study was performed by intracranial subcortical injection of labeled-Ad5/3-cRGD particles into a pig brain. The labeled vector appeared in vivo as a T2-weighted hyperintensity and a T2-gradient echo signal at the injection site, persisting up to 72 hours post-injection. We describe a glioma-targeting vector that is labeled with SPION, thereby allowing for MRI detection with no change in transduction capability.
Adenovirus; Gene therapy; Nanoparticle
Tumor-associated macrophages (TAMs) contribute substantially to the tumor mass of gliomas and have been shown to play a major role in the creation of a tumor microenvironment that promotes tumor progression. Shortcomings of attempts at antiglioma immunotherapy may result from a failure to adequately address these effects. Emerging evidence supports an independent categorization of glioma TAMs as alternatively activated M2-type macrophages, in contrast to classically activated proinflammatory M1-type macrophages. These M2-type macrophages exert glioma-supportive effects through reduced anti-tumor functions, increased expression of immunosuppressive mediators, and nonimmune tumor promotion through expression of trophic and invasion-facilitating substances. Much of our work has demonstrated these features of glioma TAMs, and together with the supporting literature will be reviewed here. Additionally, the dynamics of glioma cell-TAM interaction over the course of tumor development remain poorly understood; our efforts to elucidate glioma cell-TAM dynamics are summarized. Finally, the molecular pathways which underlie M2-type TAM polarization and gene expression similarly require further investigation, and may present the most potent targets for immunotherapeutic intervention. Highlighting recent evidence implicating the transcription factor STAT3 in immunosuppressive tumorigenic glioma TAMs, we advocate for gene array-based approaches to identify yet unappreciated expression regulators and effector molecules important to M2-type glioma TAMs polarization and function within the glioma tumor microenvironment.
Recent improvements in the understanding of glioblastoma (GBM) have allowed for increased ability to develop specific, targeted therapies. In parallel, however, there is a need for effective methods of delivery to circumvent the therapeutic obstacles presented by the blood-brain barrier and systemic side effects. The ideal delivery system should allow for adequate targeting of the tumor while minimizing systemic exposure, applicability across a wide range of potential therapies, and have existing safe and efficacious systems that allow for widespread application. Though many alternatives to systemic delivery have been developed, this paper will focus on our experience with convection-enhanced delivery (CED) and our focus on translating this technology from pre-clinical studies to the treatment of human GBM.
Vaccination against tumor-associated antigens is one promising approach to immunotherapy against malignant gliomas. While previous vaccine efforts have focused exclusively on HLA class I-restricted peptides, class II-restricted peptides are necessary to induce CD4+ helper T cells and sustain effective anti-tumor immunity. In this report we investigated the ability of five candidate peptide epitopes derived from glioma-associated antigens MAGE and IL-13 receptor α2 to detect and characterize CD4+ helper T cell responses in the peripheral blood of patients with malignant gliomas.
Primary T cell responses were determined by stimulating freshly isolated PBMCs from patients with primary glioblastoma (GBM) (n = 8), recurrent GBM (n = 5), meningioma (n = 7), and healthy controls (n = 6) with each candidate peptide, as well as anti-CD3 monoclonal antibody (mAb) and an immunodominant peptide epitope derived from myelin basic protein (MBP) serving as positive and negative controls, respectively. ELISA was used to measure IFN-γ and IL-5 levels, and the ratio of IFN-γ/IL-5 was used to determine whether the response had a predominant Th1 or Th2 bias.
We demonstrate that novel HLA Class-II restricted MAGE-A3 and IL-13Rα2 peptides can detect T cell responses in patients with GBMs as well as in healthy subjects. Stimulation with a variety of peptide antigens over-expressed by gliomas is associated with a profound reduction in the IFN-γ/IL-5 ratio in GBM patients relative to healthy subjects. This bias is more pronounced in patients with recurrent GBMs.
Therapeutic vaccine strategies to shift tumor antigen-specific T cell response to a more immunostimulatory Th1 bias may be needed for immunotherapeutic trials to be more successful clinically.
Intracerebral convection-enhanced delivery (CED) of chemotherapeutic agents currently requires an externalized catheter and infusion system, which limits its duration because of the need for hospitalization and the risk of infection. To evaluate the feasibility of prolonged topotecan administration by CED in a large animal brain with the use of a subcutaneous implantable pump. Medtronic Synchromed-II pumps were implanted subcutaneously for intracerebral CED in pigs. Gadodiamide (28.7 mg/mL), with or without topotecan (136 μM), was infused at 0.7 mL/24 h for 3 or 10 days. Pigs underwent magnetic resonance imaging before and at 6 times points after surgery. Enhancement and FLAIR+ volumes were calculated in a semi-automated fashion. Magnetic resonance spectroscopy-based topotecan signature was also investigated. Brain histology was analyzed by hematoxylin and eosin staining and with immunoperoxidase for a microglial antigen. CED of topotecan/gadolinium was well tolerated in all cases (n = 6). Maximum enhancement volume was reached at day 3 and remained stable if CED was continued for 10 days, but it decreased if CED was stopped at day 3. Magnetic resonance spectroscopy revealed a decrease in parenchymal metabolites in the presence of topotecan. Similarly, the combination of topotecan and gadolinium infusion led to a FLAIR+ volume that tended to be larger than that seen after the infusion of gadolinium alone. Histological analysis of the brains showed an area of macrophage infiltrate in the ipsilateral white matter upon infusion with topotecan/gadolinium. Intracerebral topotecan CED is well tolerated in a large animal brain for up to 10 days. Intracerebral long-term CED can be achieved with a subcutaneously implanted pump and provides a stable volume of distribution. This work constitutes a proof of principle for the safety and feasibility for prolonged CED, providing a means of continuous local drug delivery that is accessible to the practicing neuro-oncologist.
brain tumor; convection-enhanced delivery; glioma; infusion; local delivery; topotecan
The contribution of microenvironment to tumor growth has important implications for optimizing chemotherapeutic response and understanding the biology of recurrent tumors. In this study, we tested the effects of locally administered topotecan on a rat model of glioblastoma that is induced by intracerebral injection of PDGF-IRES-GFP-expressing retrovirus, we treated the tumors by convection-enhanced delivery (CED) of topotecan (136 μM) for 1, 4, or 7 days and then characterized the effects on both the retrovirus-transformed tumor cells (GFP+ cells) as well as the uninfected glial progenitor cells (GFP- cells) that are recruited to the tumor. Topotecan treatment reduced GFP+ cells ~10-fold and recruited progenitors by ~80-fold while providing a significant survival advantage that improved with greater treatment duration. Regions of glial progenitor ablation occurred corresponding to the anatomical distribution of topotecan as predicted by MRI of a surrogate tracer. Histopathologic changes in recurrent tumors point to a decrease in recruitment, most likely due to the chemotherapeutic ablation of the recruitable progenitor pool.
Glioma; Glioblastoma; Topotecan; Convection Enhanced Delivery; progenitor
While a tumour in or abutting primary motor cortex leads to motor weakness, how tumours elsewhere in the frontal or parietal lobes affect functional connectivity in a weak patient is less clear. We hypothesized that diminished functional connectivity in a distributed network of motor centres would correlate with motor weakness in subjects with brain masses. Furthermore, we hypothesized that interhemispheric connections would be most vulnerable to subtle disruptions in functional connectivity. We used task-free functional magnetic resonance imaging connectivity to probe motor networks in control subjects and patients with brain tumours (n = 22). Using a control dataset, we developed a method for automated detection of key nodes in the motor network, including the primary motor cortex, supplementary motor area, premotor area and superior parietal lobule, based on the anatomic location of the hand-motor knob in the primary motor cortex. We then calculated functional connectivity between motor network nodes in control subjects, as well as patients with and without brain masses. We used this information to construct weighted, undirected graphs, which were then compared to variables of interest, including performance on a motor task, the grooved pegboard. Strong connectivity was observed within the identified motor networks between all nodes bilaterally, and especially between the primary motor cortex and supplementary motor area. Reduced connectivity was observed in subjects with motor weakness versus subjects with normal strength (P < 0.001). This difference was driven mostly by decreases in interhemispheric connectivity between the primary motor cortices (P < 0.05) and between the left primary motor cortex and the right premotor area (P < 0.05), as well as other premotor area connections. In the subjects without motor weakness, however, performance on the grooved pegboard did not relate to interhemispheric connectivity, but rather was inversely correlated with connectivity between the left premotor area and left supplementary motor area, for both the left and the right hands (P < 0.01). Finally, two subjects who experienced severe weakness following surgery for their brain tumours were followed longitudinally, and the subject who recovered showed reconstitution of her motor network at follow-up. The subject who was persistently weak did not reconstitute his motor network. Motor weakness in subjects with brain tumours that do not involve primary motor structures is associated with decreased connectivity within motor functional networks, particularly interhemispheric connections. Motor networks become weaker as the subjects become weaker, and may become strong again during motor recovery.
resting-state functional MRI; brain tumour; resting-state; motor network; primary motor cortex; supplementary motor area; grooved pegboard
Somatosensory evoked potential (SSEP) monitoring is commonly used to detect changes in nerve conduction and prevent impending nerve injury. We present a case series of 2 patients who had SSEP monitoring for their surgical craniotomy procedure, and who, upon positioning supine with their head tilted 30–45 degrees, developed unilateral upper extremity SSEP changes. These SSEP changes were reversed when the patients were repositioned. These cases indicate the clinical usefulness of monitoring SSEPs while positioning the patient and adjusting position accordingly to prevent injury.
Malignant gliomas including glioblastoma multiforme (GBM) and anaplastic astrocytomas are the most common primary brain tumors. Despite multimodal treatment including surgery, chemotherapy and radiation, median survival for patients with GBMs is only 12–15 months. Identifying molecules critical for glioma progression is crucial for devising effective targeted therapy. In the present study, we investigated the potential contribution of Astrocyte Elevated Gene-1 (AEG-1) in gliomagenesis and explored the possibility of AEG-1 as a therapeutic target for malignant glioma. We analyzed the expression levels of AEG-1 in 9 normal brain tissues and 98 brain tumor patient samples by Western blot analysis and immunohistochemistry. AEG-1 expression was significantly elevated in > 90% of diverse human brain tumor samples including GBMs and astrocytic tumors, and also in human glioma cell lines as compared to normal brain tissues and normal astrocytes. Knockdown of AEG-1 by siRNA inhibited cell viability, cloning efficiency, invasive ability of U87 human glioma cells and 9L rat gliosarcoma cells. We also found that matrix metalloproteases (MMP-2 and MMP-9) are involved in AEG-1-mediated invasion of glioma cells. In an orthotopic nude mouse brain tumor model using primary human GBM12 tumor cells, AEG-1 siRNA significantly suppressed glioma cell growth in vivo. Taken together these provocative results indicate that AEG-1 may play a crucial role in the pathogenesis of glioma and that AEG-1 could represent a viable potential target for malignant glioma therapy.
AEG-1; brain tumor; glioma; invasion; angiogenesis
Tumor heterogeneity is a major obstacle for finding effective treatment of
Glioblastoma (GBM). Based on global expression analysis, GBM can be
classified into distinct subtypes: Proneural, Neural, Classical and
Mesenchymal. The signatures of these different tumor subtypes may reflect
the phenotypes of cells giving rise to them. However, the experimental
evidence connecting any specific subtype of GBM to particular cells of
origin is lacking. In addition, it is unclear how different genetic
alterations interact with cells of origin in determining tumor
heterogeneity. This issue cannot be addressed by studying end-stage human
To address this issue, we used retroviruses to deliver transforming genetic
lesions to glial progenitors in adult mouse brain. We compared the resulting
tumors to human GBM. We found that different initiating genetic lesions gave
rise to tumors with different growth rates. However all mouse tumors closely
resembled the human Proneural GBM. Comparative analysis of these mouse
tumors allowed us to identify a set of genes whose expression in humans with
Proneural GBM correlates with survival.
This study offers insights into the relationship between adult glial
progenitors and Proneural GBM, and allows us to identify molecular
alterations that lead to more aggressive tumor growth. In addition, we
present a new preclinical model that can be used to test treatments directed
at a specific type of GBM in future studies.
Traditionally, acromegaly evaded diagnosis until in its clinically obvious later stages when treatment is more difficult. Over the last 25 years diagnostic tests have improved, but whether clinical disease detection also improved was unknown so we tested if disease severity at diagnosis had changed from 1981 to 2006.
Data on 324 consecutive acromegaly patients presenting from 1981–2006 at two New York City hospitals were collected by retrospective review (n=324) and by interview (n=200). The main complaint, acromegaly-associated co-morbidities, signs, symptoms, healthcare providers visited, pre-operative growth hormone (GH) and insulin-like growth factor I (IGF-I) levels and pituitary tumor size at diagnosis were compared in patients presenting in the earlier vs. later halves of the time period.
Times from symptom onset to diagnosis were 5.9 yr. (early) vs. 5.2 yr. (late)(p=ns). At diagnosis, 96% of early and late groups had facial feature changes and/or hand/foot enlargement. Co-morbidities included hypertension (HTN) 37 % (early) vs. 36% (late), carpal tunnel syndrome (24 vs. 24%), sleep apnea (13 vs. 29%)(p <0.01), osteoarthritis (25 vs. 23%), and diabetes mellitus (DM) (18 vs.15%); each patient had 1.2 (early) vs. 1.3 (late) (p=0.53) co-morbidities. Groups were similar in signs, symptoms, tumor size, GH and IGF-I.
Clinical, biochemical and tumor size characteristics at diagnosis of acromegaly patients were unchanged from 1981–2006. Most patients still have marked manifestations of acromegaly at diagnosis suggesting that acromegaly remains clinically under-recognized. Healthcare professionals should more commonly consider acromegaly, which can lead to earlier diagnosis and better treatment outcome.
Acromegaly; pituitary tumor; growth hormone; insulin-like growth factor 1
Foramen magnum (FM) lesions represent some of the most complex cases for the modern neurosurgeon because of their location near vital brainstem structures, the vertebral arteries, and lower cranial nerves. In particular, anterior or anterolaterally located FM tumors have traditionally been most difficult to resect with high morbidity and mortality resulting from approaches through the posterior midline or transorally. For many neurosurgeons, the far lateral, extreme lateral approach, and more recently, endoscopic endonasal approaches have become the preferred modern methods for the resection of anterior or anterolateral FM tumors. In this review, we examine both operative and non-operative approaches to FM tumors, including surgical anatomy, surgical technique, and indications for operative intervention in these complex cases. In addition, we compared outcomes from prior series.
Foramen magnum; meningioma; extreme lateral approach: Cerebrospinal fluid; computed tomography; foramen magnum; karnofsky performance scale; magnetic resonance angiogram; magnetic resonance imaging; stereotactic radiosurgery; vertebral artery
Tumor progression and metastasis are complex processes involving intricate interplay among multiple gene products. Astrocyte Elevated Gene (AEG)-1 was cloned as an HIV-1- and tumor necrosis factor α (TNF-α)-inducible transcript in primary human fetal astrocytes by a rapid subtraction hybridization approach. AEG-1 downregulates the expression of the glutamate transporter EAAT2, thus it is implicated in glutamate-induced excitotoxic damage to neurons as evident in HIV-associated neurodegeneration. Interestingly, AEG-1 expression is elevated in subsets of breast cancer, glioblastoma multiforme and melanoma cells and AEG-1 cooperates with Ha-ras to augment the transformed phenotype of normal immortal cells. Moreover, AEG-1 is overexpressed in >95% of human malignant glioma samples when compared with normal human brain. Overexpression of AEG-1 increases and siRNA inhibition of AEG-1 decreases migration and invasion of human glioma cells, respectively. AEG-1 contains a lung-homing domain facilitating breast tumor metastasis to lungs. These findings indicate that AEG-1 might play a pivotal role in the pathogenesis, progression and metastasis of diverse cancers. Our recent observations indicate that AEG-1 exerts its effects by activating the NF-κB pathway and AEG-1 is a downstream target of Ha-ras and plays an important role in Ha-ras-mediated tumorigenesis. These provocative findings are intensifying interest in AEG-1 as a crucial regulator of tumor progression and metastasis and as a potential mediator of neurodegeneration. In this review, we discuss the cloning, structure and function(s) of AEG-1 and provide recent insights into the diverse actions and intriguing properties of this molecule.
AEG-1; Progression; Metastasis; Ha-ras oncogene; Glutamate excitotoxicity; AEG-1 promoter
Identifying the origin of gliomas carries important implications for advancing the treatment of these recalcitrant tumors. Recent research promotes the hypothesis of a subventricular zone (SVZ) origin for the stemlike gliomagenic cells identified within human glioma specimens. However, conflicting evidence suggests that SVZ-like cells are not uniquely gliomagenic but this capacity may be shared by cycling progenitors distributed throughout the subcortical white matter (SCWM).
To review radiological evidence in glioblastoma multiforme (GBM) patients to provide insight into the question of glioma ontogeny.
We explored whether GBMs at first diagnosis demonstrated a pattern of anatomic distribution consistent with origin at the SVZ through retrospective analysis of preoperative contrast-enhanced T1-weighted magnetic resonance images in 63 patients. We then examined the relationship of tumor volume, point of origin, and proximity to the ventricles using a computer model of glioma growth.
Fewer than half of the GBMs analyzed had contrast-enhancing portions that contacted the ventricle on preoperative imaging. A strong correlation was found between tumor volume and the distance between the contrast-enhancing edge of the tumor and the ventricle, demonstrating that tumors abutting the ventricle are significantly larger than those that do not. The lesions simulated by the computer model validated our assumption that tumors that are radiographically distant from the ventricles are unlikely to have originated in the SVZ and supported our hypothesis that as they grow, the edges of all tumors will near the ventricles, regardless of their point of origin.
This work offers further support for the hypothesis that the origins of GBMs are at sites distributed throughout the white matter and are not limited to the region of the SVZ.
Cancer stem cell; Glioblastoma; Glioma; Glioma ontogeny
Only rarely do corticotroph pituitary tumors become invasive leading to symptoms caused by compression of cranial nerves and other local structures. When aggressive pituitary neuroendocrine tumors do develop, conventional treatment options are of limited success. A 50-year-old man developed a giant invasive corticotroph pituitary tumor 2 years after initial presentation. His tumor and symptoms failed to respond to maximal surgical, radio-surgical, radiation and medical therapy and a bilateral adrenalectomy was done. He subsequently developed rapid growth of his tumor leading to multiple cranial nerve deficits. He was administered salvage chemotherapy with capecitabine and temozolomide (CAPTEM), a novel oral chemotherapy regimen developed at our institution for treatment of neuroendocrine tumors. After two cycles of CAPTEM, his tumor markedly decreased in size and ACTH levels fell by almost 90%. Despite further decreases in ACTH levels, his tumor recurred after 5 months with increased avidity on PET scan suggesting a transformation to a more aggressive phenotype. Temozolomide had been reported to be effective against other pituitary tumors and this case adds to this literature demonstrating its use along with capecitabine (CAPTEM) against a corticotroph tumor. Further evaluation of the CAPTEM regimen in patients with pituitary neuroendocrine tumors which fail to respond to classic treatments is warranted.
Giant pituitary adenomas of excessive size, fibrous consistency or unfavorable geometric configuration may be unresectable through conventional operative approaches. We present our select case series for operative resection and long-term follow-up for these unusual tumors, employing both a staged procedure and a combined transsphenoidal-transcranial above and below approach.
A retrospective chart review was performed on patients operated via the staged, and combined approaches by the senior author (J.N·B.). Pre-operative characteristics and postoperative outcomes were reviewed. A detailed description of the operative technique and perioperative management is provided.
Between 1993 and 1996, two patients harboring giant pituitary adenomas underwent an intentionally staged resection, and between 1997 and 2006, nine patients harboring giant pituitary adenomas underwent surgery via a single-stage above and below approach. Nine patients (82%) presented with non-secreting adenomas and two patients (18%) presented with prolactinomas refractory to medical management. Gross total resection was achieved in six patients (55%), near total resection in 1 (9%), and subtotal removal in 4 (36%). Seven patients (64%) experienced visual improvement postoperatively and no major complications occurred. Long-term follow-up averaged 51.6 months. Panhypopituitarism was observed in four patients, partial hypopituitarism in four, persistent DI in two, and persistent SIADH in one.
The addition of a transcranial component to the transsphenoidal approach offers additional visualization of critical neurovascular structures during giant pituitary adenoma resection. Complications rates are similar to other series in which complex pituitary adenomas are resected by other means. The above and below approach is both safe and effective and the immediate and long-term advantages of a single-stage approach justify its utility in this select group of patients.
Adenoma; Approach; Pituitary; Transsphenoidal; Treatment; Tumor
Immunosuppression by gliomas contributes to tumor progression and treatment resistance. It is not known when immunosuppression occurs during tumor development but it likely involves cross-talk among tumor cells, tumor-associated macrophages and microglia (TAMs), and peripheral as well as tumor-infiltrating lymphocytes (TILs).
We have performed a kinetic study of this immunomodulation, assessing the dynamics of immune infiltration and function, within the central nervous system (CNS) and peripherally. PDGF-driven murine glioma cells were injected into the white matter of 13 mice. Four mice were sacrificed 13 days post-injection (dpi), four mice at 26 dpi, and five mice at 40 dpi. Using multiparameter flow cytometry, splenic T cells were assessed for FoxP3 expression to identify regulatory T cells (Tregs) and production of IFN-γ and IL-10 after stimulation with PMA/ionomycin; within the CNS, CD4+ TILs were quantified, and TAMs were quantified and assessed for TNF-α and IL-10 production after stimulation with LPS. Peripheral changes associated with tumor development were noted prior to effects within the CNS. The percentage of FoxP3+ regulatory T cells (Tregs) increased by day 26, with elevated frequencies throughout the duration of the study. This early increase in Tregs was paralleled by an increase in IL-10 production from Tregs. At the final time points examined (tumor morbidity or 40 dpi), there was an increase in the frequency of TAMs with decreased capacity to secrete TNF-α. An increase in TIL frequency was also observed at these final time points.
These data provide insight into the kinetics of the immunosuppressive state associated with tumor growth in a murine model of human gliomas. Functional impairment of TAMs occurs relatively late in the course of GBM tumor growth, potentially providing a window of opportunity for therapeutic strategies directed towards preventing their functional impairment.