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1.  Vascular alterations in schwannoma 
Schwannomas or neurilemmoma are benign peripheral nerve sheath tumors, which most frequently occur at the cerebellopontine angle. This morphologic study examines vascular alterations in these tumors, comparing them to other benign spindle cell neoplasms of the nervous system, while correlating these findings with evidence of vascular permeability. Thirty-four nervous system spindle cell neoplasms, sixteen schwannomas, nine fibroblastic/transitional meningiomas and nine peripheral neurofibromas were stained with H&E, Prussian-blue stain, and immunoreacted for factor VIII-related antigen and interstitial albumin. Schwannomas had focal clusters of vascular proliferation including groups of small thin-walled vessels, as well as larger vessels with extensive hyalinization. Neurofibromas and meningiomas almost uniformly had modest numbers of well-defined, thin walled individual vessels. Free hemosiderin and hemosiderin-laden macrophages were frequently identified in schwannomas. Prussian-blue stain for iron revealed focal or fairly widespread positivity in almost all schwannomas, only one meningioma and none of the neurofibromas. Immunoreaction for albumin demonstrated leakage of vascular proteins into the interstitium confirming tumor vessel permeability in schwannomas. Neither neurofibromas nor meningiomas displayed any detectable interstitial albumin. The above findings confirm a degree of reactive proliferation of vessels in schwannoma along with functional deficits in their vascular integrity with permeability to protein and blood. The presence of hyalinized vessels, hemosiderin, both free and within macrophages, and more readily evident Prussian blue staining, may provide an additional diagnostic clue in discriminating between histologically similar spindle cell lesions. The study however raises the possibility that these changes likely precede or facilitate the degenerative ‘ancient change’ seen in some schwannoma.
PMCID: PMC4129016  PMID: 25120781
Schwannoma; vascular hyalinization; hemosiderin; vascular permeability
2.  Tumor-to-tumor metastasis: pathology and neuroimaging considerations 
The phenomenon of tumor-to-tumor metastasis has been reported in the literature for over a century. However, it remains fairly uncommon, with fewer than 100 cases being described during that time. Virtually any benign or malignant tumor can be a recipient, but meningiomas have been implicated as the most common intracranial neoplasm to harbor metastasis. The donor neoplasm is most frequently lung or breast carcinoma, while rare cases of metastasis from other primary tumors have been reported. We report here three examples of such rare metastases. This case series reports the first documented instance involving rectal adenocarcinoma. In addition, we report two cases of metastatic prostate adenocarcinoma to a meningioma; to date of which only three cases have been published. The terms “tumor-to-tumor metastasis” and “collision tumor” are addressed, as are details of the pathology. The limitations of standard radiological imaging techniques, such as standard CT and MR, which cannot reliably identify the presence of metastasis within a meningioma are compared with physiology-based neuroimaging methods, such as perfusion MR and MR spectroscopy, which may be more useful in noninvasively differentiating tumor histology.
PMCID: PMC3365818  PMID: 22670183
Tumor-to-tumor metastasis; meningioma; adenocarcinoma; neuroimaging; pathology
3.  Expression of MMP-2 correlates with increased angiogenesis in CNS metastasis of lung carcinoma 
Matrix metalloproteinases (MMP) have been implicated in increased invasive and metastatic potential of tumors, possibly via interactions with the extracellular matrix and angiogenesis. This study investigates the relationship between MMP-2 immunoexpression and angiogenesis in a series of lung carcinomas metastatic to the central nervous system (CNS). Twenty eight metastatic carcinoma cases with adequate brain-tumor interface were identified from the archives at the Moffitt Cancer Center. MMP-2 expression was determined by immunohistochemistry using an antibody directed against pro and active forms (NeoMarkers). Similarly, microvessels were identified on parallel sections with anti-CD34 antibody (Biogenix). Angiogenesis profiles within the tumor and at the CNS/tumor interface were morphometrically assessed by the Image Pro Plus image analysis system. Briefly, CD34 positive vessels were quantitated and correlated with presence or absence of MMP-2 expression in the tumor. Mean microvessel area (MMVA) and mean microvessel number (MMVN) were assessed within areas of brain-tumor interface and within the tumor and expressed as a ratio relative to the tumor. Sixteen (57.14%) metastatic tumors were strongly immunoreac-tive for MMP-2, while 12 (42.86%) were negative. MMP-2 positive tumors had a higher MMVA and MMVN ratio at the CNS/tumor interface in comparison to MMP-2 negative neoplasms. MMP-2 expression thus appears to confer enhanced vascular proliferation particularly at the brain-tumor interface which would support the contention of enhanced capability of growth and invasion within the CNS, possibly modulated by MMP2. The relationship between MMP-2 expression and angiogenesis has been previously reported and its biological and therapeutic implications remain the focus of investigations.
PMCID: PMC2993228  PMID: 21151391
Matrix metalloproteinases (MMP); angiogenesis; lung cancer; CNS metastasis
4.  CD44 and p53 immunoexpression patterns in NF1 neoplasms - indicators of malignancy and infiltration 
Neurofibromatosis type 1 (NF1) provides a unique system to evaluate the complete range of neoplastic expressions, from encapsulated benignity to invasiveness and malignancy. This study was aimed at determining whether CD44 and p53 may serve as indicators of malignant progression of neurofibroma. CD44, a transmembrane glycoprotein receptor for hyaluronic acid, and participates in cell-extracellular matrix interactions and migration. CD44 may play a vital role, either through under or overexpression, with invasion and metastases of tumors, altering their ability to infiltrate the adjacent tissue. The tumor suppressor gene, p53, has also been implicated in malignant progression of various human tumors including malignant peripheral nerve sheath tumors (MPNST). A total of 44 tumors from 33 patients with NF1 were evaluated with an anti-human CD44H, CD44 splice variant v6 and anti-p53 monoclonal antibodies. Morphologic expression patterns of expression were evaluated for CD44 while semiquantitative criteria were applied to assess, p53 nuclear positivity. Immunoexpression of p53 was markedly higher in 12 of 16 MPNST (75%). Thirteen of 28 (46%) benign neurofibroma also had some expression of p53 above ‘normal level', although much lower than the MPNST. Plexiform neurofibroma did not differ from other benign lesions in their expression of p53. Our results suggest that p53 mutation as evidenced by immunohistochemical overexpression is a factor in malignant transformation and progression of neurofibroma. 70% of benign neurofibroma demonstrated some, usually focal, CD44 positivity. The pattern of CD44 expression in plexiform neurofibroma was revealing, as it was maximal in the ‘nonencapsulated’ portions of the tumors. Eight of 11 (72%) locally infiltrative cutaneous neurofibroma and 13 of 16 (81%) MPNST exhibited diffuse CD44 positivity. CD44v6 expression was positive in control tissues but was not identified in any of tumor samples. Also, within the confines of encapsulated tumors CD44 expression is limited, while in poorly circumscribed neurofibroma CD44 expression is upregulated. This is interpreted as a reflection of the interaction of CD44+ tumor cells with extracellular matrix, hence facilitating infiltrative behavior.
PMCID: PMC2897111  PMID: 20606732
Neurofibromatosis type 1 (NF1); CD44; p53; tumor markers; infiltration; immunohistochemistry
5.  RTOG 0913: A Phase I Study of Daily Everolimus (RAD001) In Combination with Radiation Therapy and Temozolomide in Patients with Newly Diagnosed Glioblastoma 
To determine the safety of the mTOR inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients.
Methods and Materials
Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (75 mg/m2/day). Everolimus was escalated from 2.5 (Dose Level 1), to 5 (Dose Level 2), to 10 mg/day (Dose Level 3). Adjuvant temozolomide was delivered at 150-200 mg/m2 on days 1 to 5 every 28 days for up to 12 cycles with concurrent everolimus at the previously established daily dose of 10 mg/day. Dose escalation continued if a dose level produced DLTs in ≤ 2 of the first 6 evaluable patients.
Between October 28, 2010 and July 2, 2012, the Radiation Therapy Oncology Group (RTOG) 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria receiving drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined MTD of 10 mg/day. Two of the first 6 eligible patients experienced a DLT at each dose level. DLTs included: gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were Grade 1/2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was one death reported, which was attributed to tumor progression.
Daily oral everolimus (10 mg) combined with both concurrent radiation and temozolomide followed by adjuvant temozolomide, is well tolerated, with an acceptable toxicity profile. A phase II randomized clinical trial with mandatory correlative biomarker analysis is currently underway, designed to both determine the efficacy of this regimen and identify molecular determinants of response.
PMCID: PMC3766839  PMID: 23725999
6.  The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma 
Indoleamine 2,3-dioxygenase (IDO) is an enzyme with immune-suppressive properties that is commonly exploited by tumors to evade immune destruction. Anti-tumor T cell responses can be initiated in solid tumors, but are immediately suppressed by compensatory upregulation of immunological checkpoints, including IDO. In addition to these known effects on the adaptive immune system, we previously showed widespread, T cell-dependent complement deposition during allogeneic fetal rejection upon maternal treatment with IDO-blockade. We hypothesized that IDO protects glioblastoma from the full effects of chemo-radiation therapy by preventing vascular activation and complement-dependent tumor destruction.
To test this hypothesis, we utilized a syngeneic orthotopic glioblastoma model in which GL261 glioblastoma tumor cells were stereotactically implanted into the right frontal lobes of syngeneic mice. These mice were treated with IDO-blocking drugs in combination with chemotherapy and radiation therapy.
Pharmacologic inhibition of IDO synergized with chemo-radiation therapy to prolong survival in mice bearing intracranial glioblastoma tumors. We now show that pharmacologic or genetic inhibition of IDO allowed chemo-radiation to trigger widespread complement deposition at sites of tumor growth. Chemotherapy treatment alone resulted in collections of perivascular leukocytes within tumors, but no complement deposition. Adding IDO-blockade led to upregulation of VCAM-1 on vascular endothelium within the tumor microenvironment, and further adding radiation in the presence of IDO-blockade led to widespread deposition of complement. Mice genetically deficient in complement component C3 lost all of the synergistic effects of IDO-blockade on chemo-radiation-induced survival.
Together these findings identify a novel mechanistic link between IDO and complement, and implicate complement as a major downstream effector mechanism for the beneficial effect of IDO-blockade after chemo-radiation therapy. We speculate that this represents a fundamental pathway by which the tumor regulates intratumoral vascular activation and protects itself from immune-mediated tumor destruction.
PMCID: PMC4105871  PMID: 25054064
IDO; Indoleamine; Complement; Tumor; Immunotherapy; Chemotherapy; Radiation therapy; Indoximod; Glioblastoma; NLG919
7.  6p22.3 amplification as a biomarker and potential therapeutic target of advanced stage bladder cancer 
Oncotarget  2013;4(11):2124-2134.
Genetic and epigenetic alterations have been identified as to contribute directly or indirectly to the generation of transitional cell carcinoma of the urinary bladder (TCC-UB). In a comparative fashion much less is known about copy number alterations in TCC-UB, but it appears that amplification of chromosome 6p22 is one of the most frequent changes. Using fluorescence in situ hybridization (FISH) analyses, we evaluated chromosomal 6p22 amplification in a large cohort of bladder cancer patients with complete surgical staging and outcome data. We have also used shRNA knockdown candidate oncogenes in the cell based study. We found that amplification of chromosome 6p22.3 is significantly associated with the muscle-invasive transitional cell carcinoma of the urinary bladder (TCC-UB) (22%) in contrast to superficial TCC-UB (9%) (p=7.2-04). The rate of 6p22.3 amplification in pN>1 patients (32%) is more than twice that in pN0 (16%) patients (p=0.05). Interestingly, we found that 6p22.3 amplification is as twice as high (p=0.0201) in African American (AA) than European American (EA) TCC-UB patients. Moreover, we showed that the expression of some candidate genes (E2F3, CDKAL1 and Sox4) in the 6p22.3 region is highly correlated with the chromosomal amplification. In particular, knockdown of E2F3 inhibits cell proliferation in a 6p22.3-dependent manner, whereas knockdown of CDKAL1 and Sox4 has no effect on cell proliferation. Using gene expression profiling, we further identified some common as well as distinctive subset targets of the E2F3 family members. In summary, our data indicate that E2F3 is a key regulator of cell proliferation in a subset of bladder cancer and the 6p22.3 amplicon is a biomarker of aggressive phenotype in this tumor type.
PMCID: PMC3875774  PMID: 24231253
bladder cancer; chromosome 6p22; FISH; outcome; survival
8.  Vascular development in mouse lung metastases 
Dissemination of cancer cells is strongly associated with reduction in quality of life, worsening of prognosis, and remains the primary cause of therapeutic failure and high mortality in cancer. A crucial factor in the progression of metastases is the ability to establish a functioning blood vessel network. Consequently therapeutic strategies which selectively target tumor vasculature may hold promise for the treatment of metastatic disease. A complicating factor in the assessment of the efficacy of vascular targeting therapies is that the metastatic process can result in multiple neoplastic lesions at various stages of growth and vascularity in a single organ. The goal of this project was to utilize a rodent squamous cell carcinoma (SCCVII) model to characterize the development of metastatic lung lesions and their associated vasculature. Mice were injected with tumor cells via the tail vein to introduce a reproducible number of lung metastases. At various times after cell injection, lungs were removed and serial sections were taken throughout the lobes for morphometric analysis. Tumor volumes were calculated for each nodule using 2 hematoxylin and eosin (H&E) stained sections that were a known distance apart. Sections adjacent to those used for size determination were reserved for immunohistochemical staining with CD31 to identify blood vessels associated with each nodule. The results showed that although the median tumor volume increased from 0.006 to 0.51 mm3 between 7 and 18 days post SCCVII cell injection, a range of tumor sizes existed at all-times. Irrespective of the time of assessment, nodules with volumes ≤ 0.5 mm3 had a constant vessel density while those with volumes >0.5 mm3 showed increasing vessel densities with increasing size. These findings indicate that the methodology outlined in this study can identify metastases in various stages of vascular development and could therefore be applied to evaluate and distinguish therapeutic interventions that seek to prevent the initiation of blood vessel networks and those targeting already established expanding tumor vasculature. Examining the efficacy of such approaches, alone or in combination, in the treatment of metastases in a preclinical model could lead to the development of more effective therapeutic strategies for metastatic disease.
PMCID: PMC3433106  PMID: 22957309
Metastasis; vascular development; carcinoma
9.  Support of a Free Radical Mechanism for Enhanced Antitumor Efficacy of the Microtubule Disruptor OXi4503 
Microvascular research  2010;81(1):44-51.
Unlike normal blood vessels, the unique characteristics of an expanding, disorganized and leaky tumor vascular network can be targeted for therapeutic gain by vascular disrupting agents (VDAs), which promote rapid and selective collapse of tumor vessels, causing extensive secondary cancer cell death. A hallmark observation following VDA treatment is the survival of neoplastic cells at the tumor periphery. However, comparative studies with the second generation tubulin-binding VDA OXi4503 indicate that the viable rim of tumor tissue remaining following treatment with this agent is significantly smaller than that seen for the lead VDA, combretastatin. OXi4503 is the cis-isomer of CA1P and it has been speculated that this agent's increased antitumor efficacy may be due to its reported metabolism to orthoquinone intermediates leading to the formation of cytotoxic free radicals. To examine this possibility in situ, KHT sarcoma-bearing mice were treated with either the cis- or trans-isomer of CA1P. Since both isomers can form quinone intermediates but only the cis-isomer binds tubulin, such a comparison allows the effects of vascular collapse to be evaluated independently from those caused by the reactive hydroxyl groups. The results showed that the cis-isomer (OXi4503) significantly impaired tumor blood flow leading to secondary tumor cell death and >95% tumor necrosis 24 h post drug exposure. Treatment with the trans-isomer had no effect on these parameters. However, the combination of the trans-isomer with combretastatin increased the antitumor efficacy of the latter agent to near that of OXi4503. These findings indicate that while the predominant in vivo effect of OXi4503 is clearly due to microtubule collapse and vascular shut-down, the formation of toxic free radicals likely contributes to its enhanced potency.
PMCID: PMC3021177  PMID: 20974154
OXi4503; combretastatin; vascular disrupting agents; endothelial cells; magnetic resonance imaging; viable rim; tubulin-binding agents
10.  Alzheimer’s presenilin 1 causes chromosome missegregation and aneuploidy 
Neurobiology of aging  2006;29(3):319-328.
Mutations in the presenilin 1 gene cause most early-onset familial Alzheimer’s disease (FAD). Here we report that a defect in the cell cycle—improper chromosome segregation—can be caused by abnormal presenilin function and therefore may contribute to AD pathogenesis. Specifically we find that either over-expression or FAD mutation in presenilin 1 (M146L and M146V) leads to chromosome missegregation and aneuploidy in vivo and in vitro: 1) Up to 20% of lymphocytes and neurons of FAD-PS-1 transgenic and knockin mice are aneuploid by metaphase chromosome analysis and in situ hybridization, 2) Transiently transfected human cells over-expressing normal or mutant PS-1 develop similar aneuploidy within 48 hours, including trisomy 21. 3) Mitotic spindles in the PS-1 transfected cells contain abnormal microtubule arrays and lagging chromosomes. Several mechanisms by which chromosome missegregation induced by presenilin may contribute to Alzheimer’s disease are discussed.
PMCID: PMC2692942  PMID: 17169464
Alzheimer’s disease; mitosis; chromosome segregation; microtubules; presenilin; trisomy 21; Down syndrome
11.  The prognostic value of nestin expression in newly diagnosed glioblastoma: Report from the Radiation Therapy Oncology Group 
Nestin is an intermediate filament protein that has been implicated in early stages of neuronal lineage commitment. Based on the heterogeneous expression of nestin in GBM and its potential to serve as a marker for a dedifferentiated, and perhaps more aggressive phenotype, the Radiation Therapy Oncology Group (RTOG) sought to determine the prognostic value of nestin expression in newly diagnosed GBM patients treated on prior prospective RTOG clinical trials.
Tissue microarrays were prepared from 156 patients enrolled in these trials. These specimens were stained using a mouse monoclonal antibody specific for nestin and expression was measured by computerized quantitative image analysis using the Ariol SL-50 system. The parameters measured included both staining intensity and the relative area of expression within a specimen. This resulted into 3 categories: low, intermediate, and high nestin expression, which was then correlated with clinical outcome.
A total of 153 of the 156 samples were evaluable for this study. There were no statistically significant differences between pretreatment patient characteristics and nestin expression. There was no statistically significant difference in either overall survival or progression-free survival (PFS) demonstrated, although a trend in decreased PFS was observed with high nestin expression (p = 0.06).
Although the correlation of nestin expression and histologic grade in glioma is of considerable interest, the presented data does not support its prognostic value in newly diagnosed GBM. Further studies evaluating nestin expression may be more informative when studied in lower grade glioma, in the context of markers more specific to tumor stem cells, and using more recent specimens from patients treated with temozolomide in conjunction with radiation.
PMCID: PMC2563009  PMID: 18817556

Results 1-11 (11)