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Background: Meningioma is the most common extra-axial primary intracranial tumor in adults that rarely metastasizes outside of the central nervous system (CNS). Among recognized sites of metastases, the lung is the most common, but the importance of lung metastases relative to prognosis is unknown. ¹¹¹Indium (¹¹¹In)-octreotide scintigraphy (octreotide scanning) is a valuable imaging modality with which to evaluate intracranial meningiomas and their response to treatment with somatostatin analogues and has the potential to identify extracranial metastatic disease. Methods: In this retrospective multicenter study, adult patients treated for recurrent meningioma were identified. These patients underwent ¹¹¹In-octreotide positron emission tomography/computed tomography imaging (octreotide scintigraphy) and were found to have positive octreotide uptake in their lungs. Results: Six cases were identified with recurrent meningioma (after surgery, radiotherapy, and at least 1 chemotherapy agent) and pulmonary lesions by octreotide scintigraphy. Biopsy of a pulmonary lesion in 1 patient confirmed the diagnosis of metastatic meningioma. Patients with metastatic pulmonary involvement identified by ¹¹¹In-octreotide scintigraphy in this case series had an overall survival of 6 months, which is less than that reported from previously published series of patients with unknown systemic disease status. Conclusions: ¹¹¹In-octreotide scintigraphy is useful for assessing both CNS disease and extracranial metastases. The presence of pulmonary metastases appears to negatively affect survival in patients with recurrent meningioma. The usefulness of ¹¹¹In-octreotide scintigraphy should be considered in staging patients with recurrent meningioma who are considered for further treatment. A prospective study to confirm this finding is warranted [ABSTRACT FROM AUTHOR]

Background: High-grade gliomas (HGGs) are the most aggressive type of gliomas and have the poorest outcomes. Chromatin remodeling (CR) genes have been implicated in multiple oncogenic pathways in numerous cancer types. In gliomagenesis, CR genes have been implicated in regulating the stemness of glioma cells, the tumor microenvironment (TME), and resistance to therapies., Methods: We performed molecular profiling of 4244 HGGs and evaluated associations of CR mutations with other cancer-related biomarkers, infiltration by immune cells, and immune gene expression. We also evaluated the association between CR mutations and survival in wild-type IDH HGG patients., Results: Nearly 10% of HGGs carry mutations in CR genes, with a higher prevalence (15%) in HGGs with IDH mutations. Analysis of cooccurrence with other biomarkers revealed that CR-mutated HGGs possess favorable genetic alterations which may have prognostic value. CR-mutated HGGs with wild-type IDH demonstrated colder TME and worse OS overall compared to the CR-wild-type HGGs., Conclusions: Our study reveals the prognostic effects of CR mutations in HGG and points to several biomarker candidates that could suggest sensitivity to emerging therapeutic strategies., Competing Interests: A.S. discloses a conflict of interest as a consultant with Tempus and speakers’ bureau for Novocure; J.X, A.H., and D.S. are employed at Caris Life Sciences; S.D. discloses honoraria from OncoLens, BostonGene and advisory role at Bayer; M.J.D. discloses advisory roles at Bayer, Loxo/Lilly, OnCusp Therapeutics, Orphagen Pharmaceuticals, Pfizer, TD2, Crinetics, and Theralink; S.S. discloses advisory roles at Novocure and Data and Safety Monitoring Board (DSMB) at Bexion; S.K. discloses stock and other ownership Interests in xcures; S.K. discloses honoraria from Jubilant Biosys and Pyramid Biosciences; S.K. discloses advisory roles at Biocept, iCAD, and xcures; S.K. discloses research funding from AIVITA Biomedical, Inc., Bayer, Biocept, Blue Earth Diagnostics, Boehringer Ingelheim, Boston Biomedical, Caris MPI, CNS pharmaceuticals, EpicentRx, Lilly, Oblato, and Orbus therapeutics; D.M.A. discloses stock and other ownership Interests in Diverse Biotech and MAIA Biotechnology; D.M.A. discloses advisory roles at Jackson Laboratory for Genomic Medicine and MAIA Biotechnology; D.M.A discloses patents, royalties, and other Intellectual Property - Methods for predicting tumor response to immunotherapy, U.S. Provisional application no. 62/787,508 filed January 2, 2019 Methods for predicting tumor response to immunotherapy, U.S. Provisional application no. 62/620,577 filed January 23, 2018; A.L.S. discloses stock and other ownership Interests in Novocure; A.L.S. discloses honoraria from Cardinal Health, Curio Science, and Gerson Lehrman Group; A.L.S. discloses advisory roles at Abbvie, Amgen, Athenex, Bayer, Exelixis, Merck, and Novocure; A.L.S. discloses speaker’s bureau at Abbvie; Bayer; Bristol-Myers Squibb; Exelixis; Merck; Novocure; Prime Oncology; A.L.S. discloses research funding from Bristol-Myers Squibb, Exelixis, Kura Oncology, Novocure, and Oncoceutics; A.L.S. discloses travel and accommodation expenses from American Association of Neurological Surgeons, Bristol-Myers Squibb, Novocure, and Xcenda; M.J.G. discloses advisory role at Biocept; M.J.G. discloses research funding from cns pharmaceuticals, Denovo Biopharma, European Organization for Research and Treatment of Cancer (EORTC), Five Prime Therapeutics, Genentech, ImmunoCellular Therapeutics, Ono Pharmaceutical, RTOG, Sunovion, Triphase Accelerator Corp, and Vascular Biogenics; The rest of the authors have no conflicts of interest to disclose., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Necrosis in solid tumors is commonly associated with poor prognostic but how these lesions expand remains unclear. Studies have found that neutrophils associate with and contribute to necrosis development in glioblastoma by inducing tumor cell ferroptosis through transferring myeloperoxidase-containing granules. However, the mechanism of neutrophilic granule transfer remains elusive. We performed an unbiased small molecule screen and found that statins inhibit neutrophil-induced tumor cell death by blocking the neutrophilic granule transfer. Further, we identified a novel process wherein neutrophils are engulfed by tumor cells before releasing myeloperoxidase-containing contents into tumor cells. This neutrophil engulfment is initiated by integrin-mediated adhesion, and further mediated by LC3-associated phagocytosis (LAP), which can be blocked by inhibiting the Vps34-UVRAG-RUBCN-containing PI3K complex. Myeloperoxidase inhibition or Vps34 depletion resulted in reduced necrosis formation and prolonged mouse survival in an orthotopic glioblastoma mouse model. Thus, our study unveils a critical role for LAP-mediated neutrophil internalization in facilitating the transfer of neutrophilic granules, which in turn triggers tumor cell death and necrosis expansion. Targeting this process holds promise for improving glioblastoma prognosis., (© 2024. The Author(s).)

Triple-negative breast cancer (TNBC) is the most aggressive subtype with high metastasis and mortality rates. Given the lack of actionable targets such as ER and HER2, TNBC still remains an unmet therapeutic challenge. Despite harboring high CDK4/6 expression levels, the efficacy of CDK4/6 inhibition in TNBC has been limited due to the emergence of resistance. The resistance to CDK4/6 inhibition is mainly mediated by RB1 inactivation. Since our aim is to overcome resistance to CDK4/6 inhibition, in this study, we primarily used the cell lines that do not express RB1 . Following a screening for activated receptor tyrosine kinases (RTKs) upon CDK4/6 inhibition, we identified the TAM (Tyro3, Axl, and MerTK) RTKs as a crucial therapeutic vulnerability in TNBC. We show that targeting the TAM receptors with a novel inhibitor, sitravatinib, significantly sensitizes TNBC to CDK4/6 inhibitors. Upon prolonged HER2 inhibitor treatment, HER2+ breast cancers suppress HER2 expression, physiologically transforming into TNBC-like cells. We further show that the combined treatment is highly effective against drug-resistant HER2+ breast cancer as well. Following quantitative proteomics and RNA-seq data analysis, we extended our study into the immunophenotyping of TNBC. Given the roles of the TAM receptors in promoting the creation of an immunosuppressive tumor microenvironment (TME), we further demonstrate that the combination of CDK4/6 inhibitor abemaciclib and sitravatinib modifies the immune landscape of TNBC to favor immune checkpoint blockade. Overall, our study offers a novel and highly effective combination therapy against TNBC and potentially treatment-resistant HER2+ breast cancer that can be rapidly moved to the clinic.

Purpose: Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often associated with poorer GBM patient survival, the predominant source(s) of maladaptive aging effects remains to be established. Here, we studied intratumoral and extratumoral relationships between adult patients with GBM and mice with brain tumors across the lifespan., Experimental Design: Electronic health records at Northwestern Medicine and the NCI SEER databases were evaluated for GBM patient age and overall survival. The commercial Tempus and Caris databases, as well as The Cancer Genome Atlas were profiled for gene expression, DNA methylation, and mutational changes with varying GBM patient age. In addition, gene expression analysis was performed on the extratumoral brain of younger and older adult mice with or without a brain tumor. The survival of young and old wild-type or transgenic (INK-ATTAC) mice with a brain tumor was evaluated after treatment with or without senolytics and/or immunotherapy., Results: Human patients with GBM ≥65 years of age had a significantly decreased survival compared with their younger counterparts. While the intra-GBM molecular profiles were similar between younger and older patients with GBM, non-tumor brain tissue had a significantly different gene expression profile between young and old mice with a brain tumor and the eradication of senescent cells improved immunotherapy-dependent survival of old but not young mice., Conclusions: This work suggests a potential benefit for combining senolytics with immunotherapy in older patients with GBM., (©2023 The Authors; Published by the American Association for Cancer Research.)

Therapy-resistant cancer stem cells (CSCs) contribute to the poor clinical outcomes of patients with recurrent glioblastoma (rGBM) who fail standard of care (SOC) therapy. ChemoID is a clinically validated assay for identifying CSC-targeted cytotoxic therapies in solid tumors. In a randomized clinical trial (NCT03632135), the ChemoID assay, a personalized approach for selecting the most effective treatment from FDA-approved chemotherapies, improves the survival of patients with rGBM (2016 WHO classification) over physician-chosen chemotherapy. In the ChemoID assay-guided group, median survival is 12.5 months (95% confidence interval [CI], 10.2-14.7) compared with 9 months (95% CI, 4.2-13.8) in the physician-choice group (p = 0.010) as per interim efficacy analysis. The ChemoID assay-guided group has a significantly lower risk of death (hazard ratio [HR] = 0.44; 95% CI, 0.24-0.81; p = 0.008). Results of this study offer a promising way to provide more affordable treatment for patients with rGBM in lower socioeconomic groups in the US and around the world., Competing Interests: Declaration of interests P.P.C. and J.V. report ownership of intellectual property rights on the CSC platform technology licensed to Cordgenics, LLC., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Tumor necrosis is a poor prognostic marker in glioblastoma (GBM) and a variety of other solid cancers. Accumulating evidence supports that necrosis could facilitate tumor progression and resistance to therapeutics. GBM necrosis is typically first detected by magnetic resonance imaging (MRI), after prominent necrosis has already formed. Therefore, radiological appearances of early necrosis formation and the temporal-spatial development of necrosis alongside tumor progression remain poorly understood. This knowledge gap leads to a lack of reliable radiographic diagnostic/prognostic markers in early GBM progression to detect necrosis. Recently, we reported an orthotopic xenograft GBM murine model driven by hyperactivation of the Hippo pathway transcriptional coactivator with PDZ-binding motif (TAZ) which recapitulates the extent of GBM necrosis seen among patients. In this study, we utilized this model to perform a temporal radiographic and histological study of necrosis development. We observed tumor tissue actively undergoing necrosis first appears more brightly enhancing in the early stages of progression in comparison to the rest of the tumor tissue. Later stages of tumor progression lead to loss of enhancement and unenhancing signals in the necrotic central portion of tumors on T1-weighted post-contrast MRI. This central unenhancing portion coincides with the radiographic and clinical definition of necrosis among GBM patients. Moreover, as necrosis evolves, two relatively more contrast-enhancing rims are observed in relationship to the solid enhancing tumor surrounding the central necrosis in the later stages. The outer more prominently enhancing rim at the tumor border probably represents the infiltrating tumor edge, and the inner enhancing rim at the peri-necrotic region may represent locally infiltrating immune cells. The associated inflammation at the peri-necrotic region was further confirmed by immunohistochemical study of the temporal development of tumor necrosis. Neutrophils appear to be the predominant immune cell population in this region as necrosis evolves. This study shows central, brightly enhancing areas associated with inflammation in the tumor microenvironment may represent an early indication of necrosis development in GBM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yee, Wang, Chih, Aregawi, Glantz, Zacharia, Thamburaj and Li.)

Background: Clonal immunoglobulin and T-cell receptor rearrangements serve as tumor-specific markers that have become mainstays of the diagnosis and monitoring of lymphoid malignancy. Next-generation sequencing (NGS) techniques targeting these loci have been successfully applied to lymphoblastic leukemia and multiple myeloma for minimal residual disease detection. However, adoption of NGS for primary diagnosis remains limited., Methods: We addressed the bioinformatics challenges associated with immune cell sequencing and clone detection by designing a novel web tool, CloneRetriever (CR), which uses machine-learning principles to generate clone classification schemes that are customizable, and can be applied to large datasets. CR has 2 applications-a "validation" mode to derive a clonality classifier, and a "live" mode to screen for clones by applying a validated and/or customized classifier. In this study, CR-generated multiple classifiers using 2 datasets comprising 106 annotated patient samples. A custom classifier was then applied to 36 unannotated samples., Results: The optimal classifier for clonality required clonal dominance ≥4.5× above background, read representation ≥8% of all reads, and technical replicate agreement. Depending on the dataset and analysis step, the optimal algorithm yielded sensitivities of 81%-90%, specificities of 97%-100%, areas under the curve of 91%-94%, positive predictive values of 92-100%, and negative predictive values of 88%-98%. Customization of the algorithms yielded 95%-100% concordance with gold-standard clonality determination, including rescue of indeterminate samples. Application to a set of unknowns showed concordance rates of 83%-96%., Conclusions: CR is an out-of-the-box ready and user-friendly software designed to identify clonal rearrangements in large NGS datasets for the diagnosis of lymphoid malignancies., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Tumor necrosis commonly exists and predicts poor prognoses in many cancers. Although it is thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscure. Here, we show that necrosis in glioblastoma (GBM) involves neutrophil-triggered ferroptosis. In a hyperactivated transcriptional coactivator with PDZ-binding motif-driven GBM mouse model, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse brain tumors kill cocultured tumor cells. Mechanistically, neutrophils induce iron-dependent accumulation of lipid peroxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibition or depletion of myeloperoxidase suppresses neutrophil-induced tumor cell cytotoxicity. Intratumoral glutathione peroxidase 4 overexpression or acyl-CoA synthetase long chain family member 4 depletion diminishes necrosis and aggressiveness of tumors. Furthermore, analyses of human GBMs support that neutrophils and ferroptosis are associated with necrosis and predict poor survival. Thus, our study identifies ferroptosis as the underlying nature of necrosis in GBMs and reveals a pro-tumorigenic role of ferroptosis. Together, we propose that certain tumor damage(s) occurring during early tumor progression (i.e. ischemia) recruits neutrophils to the site of tissue damage and thereby results in a positive feedback loop, amplifying GBM necrosis development to its fullest extent.

Background: Numerous studies have examined the impact of initiating an external ventricular drain (EVD) placement and handling protocol on the infection rate dating back to the early 2000s., Methods: We report a quantitative systematic review of the published literature, described our own protocol (including a mandatory checklist), and present our single institution experience. Search terms "external ventricular drain protocol" or "external ventricular drain placement protocol" or "preventing infections in external ventricular drains" or "external ventricular drain infections" were entered into standard search engines in a systematic fashion. Articles were reviewed and graded independently for class of evidence. There were 10 relevant class IV articles and no discrepancies among article ratings (i.e., κ = 1). The published evidence was reviewed and evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria., Results: Our meta-analysis revealed a statistically significant drop in rates of EVD infection after initiation of the protocol, although the overall quality of the body of evidence according to the GRADE criteria was "very poor". Preimplementation and postimplementation infection rates were collected and analyzed in combination with the results from our literature review. The EVD infection rate in our institution was 12% in the 8 months before protocol initiation (January 2015 to August 2015), and dropped to 0% in the 7 months after initiation., Conclusions: Although the quality of the literature supporting EVD placement protocols is poor, all published studies show a consistent and substantial benefit, and this effect was recapitulated in our own meta-analysis-based prospective EVD protocol experience., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cadmium selenide (CdSe) based quantum dots modified with polyethylene glycol and chemically linked to interleukin-13 (IL13) were prepared with the aim of identifying the high affinity receptor (IL13Rα2) which is expressed in glioma stem cells and exosomes secreted by these cancer stem cells. IL13 conjugated quantum dots (IL13QD) were thoroughly characterized for their physicochemical properties including particle size and surface morphology. Furthermore, the specific binding of the IL13QD to glioma cells and to glioma stem cells (GSC) was verified using a competitive binding study. The exosomes were isolated from the GSC conditioned medium and the expression of IL13Rα2 in the GSC and exosomes was verified. The binding property of IL13QD to the tumor associated exosomes was initially confirmed by transmission electron microscopy. The force of attraction between the quantum dots and U251 glioma cells and the exosomes was investigated by atomic force microscopy, which indicated a higher force of binding interaction between the IL13QD and IL13Rα2 expressing glioma cells and exosomes secreted by glioma stem cells. Flow cytometry of the IL13QD and exosomes from the culture media and cerebrospinal fluid (CSF) of patients with glioma tumors indicated a distinctly populated complex pattern different from that of non-targeted quantum dots and bovine serum albumin (BSA) conjugated quantum dots confirming specific binding potential of the IL13QD to the tumor associated exosomes. The results of this study demonstrate that IL13QD can serve as an ex vivo marker for glioma stem cells and exosomes that can inform diagnosis and prognosis of patients harboring malignant disease., Statement of Significance: Functionalized quantum dots are flexible semiconductor nanomaterials which have an immense application in biomedical research. In particular, when they are functionalized with biomolecules like proteins or antibodies, they have the specialized ability to detect the expression of receptors and antigens in cells and tissues. In this study we designed a cytokine (interleukin-13) functionalized quantum dot to detect a cancer associated receptor expressed in cancer stem cells and the extracellular vesicles (exosomes) secreted by the cancer cells themselves. The binding pattern of these cytokine modified quantum dots to the cancer stem cells and exosomes alters the physical properties of the complex in the fixed and suspended form. This altered binding pattern can be monitored by a variety of techniques, including transmission electron microscopy, atomic force microscopy and flow cytometry, and subsequent characterization of this quantum dot binding profile provides useful data that can be utilized as a fingerprint to detect cancer disease progression. This type of functionalized quantum dot fingerprint is especially useful for invasive cancers including brain and other metastatic cancers and may allow for earlier detection of disease progression or recurrence, thus saving the lives of patients suffering from this devastating disease., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The positive results of recent clinical trials examining endovascular treatment of acute stroke were the culmination of nearly two decades of studies of endovascular stroke treatment. We systematically reviewed this body of work, evaluated the strength of evidence, and performed a meta-analysis to define the clinical impact of these investigations. Terms were entered into search engines in a systematic fashion. Articles were reviewed independently by study authors, graded for level of evidence, and combined in a meta-analysis. The overall body of evidence was evaluated using GRADE criteria. Our search yielded 948 articles. Twenty-five met predefined inclusion criteria. We identified 12 grade I, 1 grade II, 5 grade III, and 7 grade IV studies (κ=0.86). Meta-analysis for independence at 90days showed a benefit of endovascular treatment (grade I studies OR 1.58 [1.20-2.07]). When limiting the analysis to studies using stent retriever, the OR increased to 2.44 (1.77-3.36). The number needed to treat (NNT) was 8. Endovascular treatment was not associated with increased symptomatic intracranial hemorrhage, and forgoing endovascular treatment was associated with death at 90 days. The quality of evidence according to GRADE criteria was "moderate." In summary, we found impressive evidence for a benefit of endovascular treatment of acute stroke, particularly when using stent retriever devices. Our meta-analysis is unique in that it includes all studies related to this topic and defines the clinical impact of the data, providing NNT. We show that thrombectomy is among the most effective stroke treatments currently available., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Familial atypical multiple mole melanoma syndrome (FAMMM) is characterised by dysplastic naevi, malignant melanoma and pancreatic cancer. Given that large deletions involving CDKN2A (cyclin-dependent kinase inhibitor 2A) account for only 2% of cases, we describe a family that highlights the co-occurrence of both melanoma and neural system tumours to aid clinical recognition and propose a management strategy. A patient with multiple neurofibromas was referred with a provisional diagnosis of neurofibromatosis type 1 (NF1). Prior molecular testing, though, had failed to identify an NF1 mutation by sequencing and multiplex ligation-dependent probe amplification. His family history was significant for multiple in situ/malignant melanomas at young ages and several different cancers reminiscent of an underlying syndrome. A search of the Familial Cancer Database, FaCD Online, highlighted several families with cutaneous melanoma and nervous system tumours who were subsequently identified to have large deletions spanning CDKN2A Although sequencing of CDKN2A and TP53 failed to identify a mutation, a heterozygous CDKN2A deletion was identified by targeted array comparative genomic hybridisation (CGH). Whole-genome oligonucleotide array CGH and SNP analysis identified an interstitial deletion of at least 1.5 Mb within 9p21.3 and spanning approximately 25 genes. Identification of the underlying molecular abnormality permits predictive testing for at-risk relatives. Given the young cancer diagnoses, a surveillance regimen was developed and a clinical team organised for ongoing management so that genetic testing could be offered to both adults and minor children. Surveillance recommendations addressed cancer risks associated with FAMMM, and other cancers exhibited by this family with a large contiguous gene deletion., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Many meningiomas are identified by imaging and followed, with an assumption that they are WHO Grade I tumors. The purpose of our investigation is to find clinical or imaging predictors of WHO Grade II/III tumors to distinguish them from Grade I meningiomas., Methods: Patients with a pathologic diagnosis of meningioma from 2002-2009 were included if they had pre-operative MRI studies and pathology for review. A Neuro-Pathologist reviewed and classified all tumors by WHO 2007. All Brain MRI imaging was reviewed by a Neuro-radiologist. Pathology and Radiology reviews were blinded from each other and clinical course. Recursive partitioning was used to create predictive models for identifying meningioma grades., Results: Factors significantly correlating with a diagnosis of WHO Grade II-III tumors in univariate analysis: prior CVA (p = 0.005), CABG (p = 0.010), paresis (p = 0.008), vascularity index = 4/4: (p = 0.009), convexity vs other (p = 0.014), metabolic syndrome (p = 0.025), non-skull base (p = 0.041) and non-postmenopausal female (p = 0.045). Recursive partitioning analysis identified four categories: 1. prior CVA, 2. vascular index (vi) = 4 (no CVA), 3. premenopausal or male, vi < 4, no CVA. 4. Postmenopausal, vi < 4, no CVA with corresponding rates of 73, 54, 35 and 10% of being Grade II-III meningiomas., Conclusions: Meningioma patients with prior CVA and those grade 4/4 vascularity are the most likely to have WHO Grade II-III tumors while post-menopausal women without these features are the most likely to have Grade I meningiomas. Further study of the associations of clinical and imaging factors with grade and clinical behavior are needed to better predict behavior of these tumors without biopsy.

Brain lesions identified following the diagnosis and eradication of primary cancers are often ambiguous in origin, existing as a solitary metastasis or an independent primary brain tumor. The brain is a relatively common site of metastasis with breast cancer, although determining whether metastases have originated from the breast or brain is often not possible without invasive biopsies. In the current case report, a patient presented with a brain lesion identified by radiography and was without systemic disease. The patient had previously exhibited a complete response to chemotherapy and surgery for a poorly differentiated invasive ductal carcinoma. The origin of the brain lesion could not be determined by magnetic resonance imaging, giving rise to a diagnostic dilemma with diverging treatment options. We previously reported a method to isolate and enumerate tumor cells of epithelial origin in the cerebrospinal fluid (CSF). CSF tumor cell analysis of the patient revealed massive CSF tumor cell burden of epithelial origin, indicating that the brain lesion was likely of breast origin. The current case report highlights the use of CSF tumor cell detection as a differential diagnostic tool, in addition to its previously demonstrated use as a marker of disease burden and therapeutic response.

Breast cancer is among the most common malignancies that metastasize to the brain, with 15% to 20% of patients with metastatic breast cancer eventually developing brain metastases. We previously reported a method to enumerate tumor cells in the cerebrospinal fluid (CSF) of patients with breast cancer with central nervous system (CNS) metastases, a setting that lacks sufficiently informative biomarkers. Here, we show that breast cancer cells can spontaneously disseminate into the CSF from brain lesions in mice in a COX-2-dependent manner and can escape from the CNS to systemic circulation. Enumeration of tumor cells in the peripheral blood (circulating tumor cells, CTC) and CSF (cerebrospinal fluid tumor cells, CSFTC) of nine breast cancer patients with brain metastases revealed dynamic changes in tumor cell burden in both the peripheral blood and CSF compartments that correlated with clinical disease progression. Interestingly, four of the enrolled patients exhibited rapid intercompartmental transitioning of the disease reflected in the CTC and CSFTC counts that preceded corresponding evidence by clinical imaging or neurologic symptoms. Two of these patients had systemic disease recurrence involving the primary malignant site. Intercompartmental cycling of tumor cells may represent an important mechanism for disease persistence and recurrence that may involve tumor self-seeding. Our findings demonstrate the involvement of COX-2 in the genesis of CSFTCs and suggest that COX-2 inhibitors should be investigated in patients with breast cancer with brain metastases for their ability to reduce CSFTC counts and prevent systemic recurrence., (©2014 AACR.)

The number of circulating tumor cells (CTCs) in the peripheral blood of metastatic breast cancer patients is now an established prognostic marker. While the central nervous system is a common site of metastasis in breast cancer, the standard marker for disease progression in this setting is cerebrospinal fluid (CSF) cytology. However, the significance of CSF cytology is unclear, requires large sample size, is insensitive and subjective, and sometimes yields equivocal results. Here, we report the detection of breast cancer cells in CSF using molecular markers by adapting the CellSearch system (Veridex). We used this platform to isolate and enumerate breast cancer cells in CSF of breast cancer patients with central nervous system (CNS) metastases. The number of CSF tumor cells correlated with tumor response to chemotherapy and were dynamically associated with disease burden. This CSF tumor cell detection method provides a semi-automated molecular analysis that vastly improves the sensitivity, reliability, objectivity, and accuracy of detecting CSF tumor cells compared to CSF cytology. CSF tumor cells may serve as a marker of disease progression and early-stage brain metastasis in breast cancer and potentiate further molecular analysis to elucidate the biology and significance of tumor cells in the CSF.

The spread of cancer into the central nervous system is a serious problem leading to neurological symptoms and rapid mortality. The current tools available for detecting the spread of cancer into the cerebrospinal fluid (CSF) are cytology, neurologic examination, and neuroimaging. All three of these methods can be applied in concert to reach a diagnosis, but they all suffer from a lack of sensitivity, leading to delays in treatment in many cases. An overview of research tools in the field of CSF cancer detection reveals a variety of promising technologies that can be used to answer questions about the biology of metastatic cancer and to develop more powerful clinical detection methods. Methods currently under investigation include new immunocytochemistry methods and flow cytometry for the in vitro detection of cells. Additionally, polymerase chain reaction, fluorescence in situ hybridization, capillary electrophoresis with laser-induced fluorescence, and mass spectrometry using matrix-assisted laser absorption-deionization time-of-flight and surface-enhanced laser desorption/ionization time-of-flight techniques are being tested for in vitro assessment of the non-cellular biomarkers in CSF. For in vivo detection of cancer in the CSF, research techniques include certain quantum dot platforms as well as magnetic iron oxide nanoparticles. As systemic therapies for cancer improve, the CNS is becoming a more common site of disease recurrence. This increases the importance of effective detection methods in the CSF, since early intervention can maximize therapeutic benefit. Furthermore, many cell-based detection methods can be combined with therapeutic agents to serve multiple medical functions through a common targeting system.

Central nervous system (CNS) involvement in non-Hodgkin lymphoma is a serious, potentially preventable complication that can occur in 5 to 10% of patients. Its occurrence is directly correlated with pathologic aggressiveness and ranges from less than 3% in the indolent, less-aggressive histologies to as high as 50% in the very aggressive ones such as Burkitt lymphoma. Aggressive treatment once detected can improve neurologic outcome, but because it is often associated with contemporaneous systemic relapse, is rarely associated with long-term survival. Preventing its occurrence, therefore, remains an important goal of initial treatment. Despite there being some suggestive evidence that the addition of systemic rituximab and several intracerebrospinal fluid chemotherapy regimens may have decreased the incidence of CNS involvement, both optimal selection of those patients who should receive prophylaxis as well as the best prophylactic regimen remain active areas of investigation., (Thieme Medical Publishers.)

Background: A study was undertaken to determine whether route (intraventricular vs intralumbar) of intracerebrospinal fluid (intra-CSF) drug administration influences progression-free survival in the treatment of patients with neoplastic meningitis, which occurs in 1% to 5% of patients with known cancer. Currently available treatment options result in modest responses, which is in part a reflection of obstacles to drug delivery into the leptomeningeal space., Methods: One hundred patients with clinically and cytologically or radiographically documented neoplastic meningitis because of solid cancers received intra-CSF liposomal cytarabine or methotrexate as specified in a randomized phase 4 trial. The 2 treatment arms were well balanced for demographic and tumor-related characteristics of known prognostic importance, including age, performance status, tumor type, extent of systemic and other central nervous system (CNS) disease, prior CNS therapy, and concurrent systemic chemotherapy., Results: One hundred patients were randomized and treated (52 with sustained-release cytarabine, and 48 with methotrexate). Progression-free survival (the primary study endpoint) was identical between the sustained-release cytarabine and methotrexate treatment arms for all 100 patients (35 vs 37.5 days, P = .79). When progression-free survival was examined as a function of route of chemotherapy administration (lumbar vs ventricular), there was no difference for patients treated with sustained-release cytarabine (29 vs 43 days, P = .35). For patients treated with methotrexate, however, there was a statistically significant difference favoring patients receiving intraventricular therapy (19 vs 43 days, P = .048)., Conclusions: Site of intra-CSF chemotherapy drug administration is clinically relevant with short half-life drugs such as methotrexate., ((c) 2010 American Cancer Society.)

Background: Life-threatening illness creates severe stress that may result in marital discord, separation, or divorce and may adversely impact treatment, quality of life, and survival. The few studies that are available to date have suggested that the risk of divorce is not higher in cancer patients, but to the authors' knowledge, no data exist to date that have examined the effect of gender on this rate., Methods: A total of 515 patients were prospectively identified as having either a malignant primary brain tumor (N = 214), a solid tumor with no nervous system involvement (N = 193), or multiple sclerosis (N = 108) who were married at the time of diagnosis. Basic demographic information and data regarding marital status were compiled. Patients were followed prospectively from enrollment until death or study termination., Results: Women composed 53% of the patient population. Divorce or separation occurred at a rate similar to that reported in the literature (11.6%). There was, however, a greater than 6-fold increase in risk after diagnosis when the affected spouse was the woman (20.8% vs 2.9%; P < .001). Female gender was found to be the strongest predictor of separation or divorce in each cohort. Marriage duration at the time of illness was also correlated with separation among brain tumor patients (P = .0001). Patients with brain tumors who were divorced or separated were more likely to be hospitalized, and less likely to participate in a clinical trial, receive multiple treatment regimens, complete cranial irradiation, or die at home (P < .0001)., Conclusions: Female gender was found to be a strong predictor of partner abandonment in patients with serious medical illness. When divorce or separation occurred, quality of care and quality of life were adversely affected.

Background: The most frequent central nervous system complication of systemic non-Hodgkin's lymphoma (NHL) is lymphomatous meningitis (LM)., Objective: A clinical series to test the feasibility of combining intra-CSF liposomal ara-C and rituximab for the treatment of recurrent LM., Design: Clinical series of 14 patients with CSF positive lymphomatous meningitis., Setting: Tertiary-care university medical center., Results: Fourteen patients with recurrent, cytologically positive lymphomatous meningitis were treated. All 14 received liposomal ara-C and rituximab utilizing an Ommaya reservoir. Six patients also received involved-field radiotherapy (brain only two patients; brain and spine two patients; spine only two patients). Best response to treatment included 10 partial responses and four with progressive disease. Estimated median duration of response was 4.0 months (range 1-6 months). Survival ranged from 1.5 to 7 months with an estimated median of 5 months, four patients remain alive and continue to be followed. Cause of death was progressive neurological disease in 7, systemic disease in 1, and combined systemic and neurological disease in 2 patients., Conclusions: The combination of intra-CSF liposomal ara-C and rituximab administered in this schedule appears to have no additive toxicity and has modest palliative activity in patients with recurrent LM.

Background: The prognostic significance of Karnofsky performance status in neoplastic meningitis (NM) has not been demonstrated in patient groups similarly matched for known prognostic variables., Objective: To determine the effect of performance status on survival in NM., Design: Retrospective comparison., Setting: A university tertiary medical center., Patients: Two well-matched cohorts with cytologically positive NM with (n = 30; group A) and without (n = 30; group B) independence in activities of daily living as defined by a Karnofsky performance status score of 70 or greater or less than 70, respectively., Main Outcome Measures: Groups were matched on age, primary tumor, site of NM disease (cranial nerves or spinal cord), treatment (radiotherapy and chemotherapy; systemic and intraventricular), and absence of cerebrospinal fluid compartmentalization, NM-related encephalopathy, and neuroradiographic bulky central nervous system disease. Primary tumor histologic diagnoses included breast cancer (20 patients), non-Hodgkin lymphoma (10 patients), lung cancer (10 patients), melanoma (8 patients), and others (12 patients). At presentation, NM revealed cranial neuropathy (30 patients) or spinal cord dysfunction (39 patients). Radiotherapy was administered to 49 patients (whole brain only in 12 patients; restricted spine only in 35; whole brain and restricted spine in 2). All the patients received intraventricular chemotherapy, and 49 received concurrent tumor-specific systemic chemotherapy., Results: Median survival was 6 weeks (range, 3-10 weeks) in group B compared with 15.5 weeks (range, 8-58 weeks) in group A (P < .001). No treatment-related deaths were observed. All the patients demonstrated progressive disease and died of either NM or systemic cancer., Conclusions: A low Karnofsky performance status score predicts poor survival in patients with NM. Patients with a low Karnofsky performance status score may be best served by offering supportive care.

Background: Intracranial meningiomas are common, they frequently recur after surgery or radiotherapy, and there are limited data regarding the treatment of intracranial meningiomas with chemotherapy. A phase 2 study was designed to estimate the 6-month progression-free survival of patients with recurrent, treatment-refractory, World Health Organization grade 1 meningiomas who were treated with interferon-alpha., Methods: Thirty-five patients with recurrent meningiomas ranging in age from 36 years to 88 years (median age, 61 years) were treated according to a prospective phase 2 study. All patients had received prior surgery, radiotherapy, (involved-field radiotherapy in 35 patients andstereotactic radiotherapy in 22 patients), and chemotherapy (hydroxyurea in 19 patients and other in 17 patients). On radiographic documentation of progressive disease, interferon-alpha (at a dose of 10 million U/m(2) administered subcutaneously every other day) was initiated. A complete blood count and chemistry panel was obtained before every cycle, and cranial magnetic resonance images were obtained every 3 months., Results: The most common grade 3 and 4 toxicities were fatigue (6 patients; 17%), anemia (3 patients; 8.6%), and leukopenia (3 patients; 8.6%) (toxicities were graded according to the National Cancer Institute's Common Toxicity Criteria [version 3.0]). Three patients went off study because of toxicity, and 7 patients required a dose reduction. There were no treatment-related deaths or delays in therapy reported. All patients were assessable for response. No patient demonstrated a neuroradiographic complete or partial response. Twenty-six patients demonstrated stable disease after the first 3 cycles of interferon-alpha, and 9 patients had progressive disease. The progression-free survival rate was 54% at 6 months and 31% at 12 months. The median time to tumor progression was 7 months (range, 2-24 months). The median survival was 8 months (range, 3-28 months)., Conclusions: Treatment with interferon-alpha for recurrent meningiomas was found to be tolerated moderately well and was modestly effective., ((c) 2008 American Cancer Society.)

Objective: Hemangiopericytoma (HPC) is an uncommon primary brain tumor with an almost invariable tendency to recur and metastasize. We undertook a retrospectively collected case series of recurrent intracranial HPCs treated with salvage chemotherapy with the primary objective of evaluating progression-free survival., Methods: Fifteen patients, ages 26 to 62 years, with recurrent HPC and who were previously treated with surgery and involved-field radiotherapy were studied. Eight (53%) of these patients had undergone re-resection before study entry. Ten patients (67%) were treated with stereotactic radiotherapy. Chemotherapy was administered to 5 patients at first relapse, 8 at second relapse, and 2 at third relapse (none of these patients were candidates for reoperation or stereotactic radiotherapy). Eight patients developed disseminated disease, all with multifocal intracranial disease (5 with cerebrospinal fluid dissemination, 4 with extraneural metastases). All patients were initially treated with cyclophosphamide, doxorubicin, and vincristine (CAV). After disease progression despite the administration of CAV in clinically appropriate patients, alpha-interferon (alpha-IFN) (9 patients) was administered. Five patients were treated with ifosfamide, cisplatin, and etoposide after they failed to respond to alpha-IFN. Neurological and neuroradiographic evaluations were performed every 8 weeks., Results: All patients were evaluable. A median of 4 cycles of CAV; 8 cycles of alpha-IFN; and 2 cycles of ifosfamide, cisplatin, and etoposide were administered. Chemotherapy-related toxicity included alopecia (100%), anemia (40%), thrombocytopenia (27%), and neutropenia (40%). Best response included 6 patients (40%) with a neuroradiographic partial response (2 with CAV, 4 with alpha-IFN), 14 (93%) had stable disease (9 with CAV, 5 with alpha-IFN), and 9 (60%) had progressive disease (4 with CAV, 5 with ifosfamide, cisplatin, and etoposide). The median overall survival was 14 months (range, 2-24 mo)., Conclusion: Salvage chemotherapy demonstrated modest efficacy with acceptable toxicity in this cohort of adult patients with recurrent surgery- and radiotherapy-refractory intracranial HPC.

Objective: A Phase II study of CPT-11 in adults with recurrent, temozolomide (TMZ)-refractory, 1p19q co-deleted, anaplastic oligodendroglioma (AO) with a primary objective of determining 6-month progression free survival (PFS)., Background: There is no standard therapy for alkylator-resistant AO., Methods: Twenty-two patients (11 men; 11 women) ages 26-65 (median 40), with radiographically recurrent AO were enrolled. All patients had previously been treated with surgery, involved-field radiotherapy, and adjuvant chemotherapy (TMZ in 15; BCNU in 6). Fifteen patients were treated at first recurrence with an alternative chemotherapy. 13 patients underwent repeat surgery. All patients were treated at either first or second recurrence with CPT-11 administered intravenously once every 3 weeks. Neurological and neuroradiographic evaluations were performed every 8-9 weeks., Results: All patients were evaluable for toxicity and response. A total of 141 cycles of CPT-11 (median 3 cycles; range 3-18) were administered. CPT-11 related toxicity included diarrhea (14 patients; 4 grade 3), neutropenia (8; 4 grade 3), fatigue (12; 3 grade 3), and delayed nausea/vomiting (12; 3 grade 3). 5 patients (23%) demonstrated a partial radiographic response, 8 (36%) demonstrated stable disease and 9 (41%) had progressive disease following three cycles of CPT-11. Time to tumor progression ranged from 2 to 13.5 months (median: 4.5 months). Survival ranged from 3 to 21 months (median: 5.5 months). Six-month and 12-month PFS were 33% and 4.5% respectively., Conclusions: CPT-11 demonstrated modest efficacy (similar to other salvage glioma regimens) with acceptable toxicity in this cohort of adults with recurrent, 1p19q co-deleted AO all of whom had failed prior TMZ chemotherapy.

Background: The primary objective of this prospective phase 2 study of CPT-11 in adult patients with recurrent temozolomide-refractory anaplastic astrocytoma (AA) was to evaluate 6-month progression-free survival (PFS)., Methods: Forty patients (27 men and 13 women) ages 17 to 58 years (median age, 38 years) with radiographically recurrent AA were treated. All patients had been treated previously with surgery, involved-field radiotherapy, and adjuvant chemotherapy. Fifteen patients were treated at first recurrence with an alternative chemotherapy. All patients were treated at either first or second recurrence with CPT-11 administered intravenously once every 3 weeks, which was defined operationally as a single cycle. Neurologic and neuroradiographic evaluations were performed every 9 weeks., Results: All patients were evaluable for toxicity, and 39 patients were evaluable for response. In total, 302 cycles of CPT-11 (median, 6 cycles; range, 1-22 cycles) were administered. CPT-11-related toxicity included diarrhea (19 cycles), leukopenia (16 cycles), fatigue (11 cycles), anemia (6 cycles), delayed nausea/vomiting (5 cycles), neutropenia (5 cycles), and renal failure (1 patient, 1 toxic death). Two patients (5%) patients required erythrocyte transfusions. Nine patients (23%) demonstrated a radiographic complete response (1 patient) or partial response (8 patients), 16 patients (41%) demonstrated stable disease, and 14 patients (36%) had progressive disease after 3 cycles of CPT-11. The median time to tumor progression was 4.1 month. The median survival was 6.9 months, and the 6-month and 12-month PFS rates were 40% and 5%, respectively., Conclusions: CPT-11 demonstrated modest efficacy with acceptable toxicity in this cohort of adult patients with recurrent AA, all of whom had failed on prior temozolomide chemotherapy.

To determine the therapeutic efficacy (13-week and 26-week CNS progression-free survival [PFS], response rate, and overall survival) and safety of intraventricular (IVent) topotecan in patients with neoplastic meningitis (NM), we conducted a phase II, open-label, nonrandomized, single-arm trial of IVent topotecan in patients with NM using 400 mug of topotecan IVent twice weekly for 6 weeks, followed by evaluation with imaging, cerebrospinal fluid (CSF), and physical examinations. In the absence of disease progression, patients were then treated with IVent topotecan weekly for 6 weeks, twice monthly for 4 months, and monthly thereafter. Sixty-two patients (23 males and 39 females) were enrolled from April 2001 through March 2006. Median age and KPS at enrollment were 56 (range 5-83) and 80 (range 60-100), respectively. Primary cancers included breast (19), lung (13), CNS (14), and others (16). Forty patients (65%) completed the 6-week induction period, among whom 13 (21%) had CSF clearance of malignant cells. Kaplan-Meier estimates of PFS at 13 and 26 weeks were 30% (95% confidence interval [CI], 20%-45%) and 19% (95% CI, 11%-34%). Overall median survival (50 deaths) was 15 weeks (95% CI, 13-24 weeks). The most common side effect was chemical meningitis in 32% of patients (5% grade 3); 32% experienced no drug side effects. IVent topotecan is well tolerated, but provides no added benefit over other IVent therapies. Because of its modest side effect profile, combining IVent topotecan with other IVent or systemic interventions should be considered.

Anaplastic astrocytomas (AA), WHO grade III gliomas, comprise 10-15% of all glial neoplasms. Currently, the only factors that have been shown to influence prognosis in patients with AA are age and Karnofsky performance status. Attempts have been made to identify biological prognostic factors for response to therapy and clinical outcome, as well as potential targets for new therapies. The most important predictor of response to therapy and survival in AA tumors is the presence or absence of the 1p19q co-deletion, a translocation that defines a subset of oligodendroglial tumors, and anaplastic oligodendrogliomas in particular. A further likely prognostic biomarker is the methylation status of O(6)-methylguanine-DNA-methyltranferase gene (the predominant DNA repair enzyme following alkylator-based chemotherapy-induced injury). Owing to a paucity of clinical trials specifically in patients with AA, most patients receive temozolomide-containing regimens, based on data acquired from patients with glioblastoma multiforme. At present, there are no cooperative group trials being conducted for the adjuvant treatment of AA, although several randomized trials have been proposed. Evidence-based management of patients with AA supports maximum safe resection followed by involved-field radiotherapy for newly diagnosed patients, and temozolomide for recurrent disease. This treatment paradigm varies considerably from actual practice.

Concurrent temozolomide (TMZ) and radiotherapy is the new standard of care for patients with newly diagnosed glioblastoma. In 51 consecutive patients treated according to this regimen, 7 patients (14%) manifested surgically confirmed early necrosis without evidence of recurrent tumor. This observation suggests that daily TMZ may represent a potent radiosensitizing regimen.

Purpose: The efficacy and safety of intrathecal topotecan were assessed in patients with neoplastic meningitis (NM) by retrospective chart review., Summary: Fourteen patients (median age, 57 years) with NM were treated with the standard of care (i.e., regional or systemic chemotherapy or irradiation or both) plus intrathecal topotecan between January 2004 and September 2005. Three patients developed NM in the setting of systemic cancer; 11 patients had primary central nervous system (CNS) malignancies. All patients received 0.4 mg of topotecan intrathecally two times per week. The efficacy of intrathecal topotecan was assessed on the basis of the number of doses to cerebrospinal fluid (CSF) cytologic clearing--defined as the disappearance of malignant cells from a previously positive CSF cytology. Safety was evaluated by chart documentation of adverse events that might have been associated with topotecan given intrathecally. Of the 11 patients with primary CNS tumors, 6 patients achieved CSF clearing after the first dose of intrathecal topotecan, 2 patients after the second dose, and 1 patient after the fifth dose. For the 3 patients with secondary CSF tumors, 1 patient achieved CSF clearing after the third dose and 2 patients did not reach the primary endpoint. Overall, 6 of the 14 patients achieved CSF clearing after the first dose of intrathecal topotecan; in 10 of the 14 patients, CSF clearing of malignant cells was observed at some point during treatment. Toxicity was modest. The most common adverse effect reported was fatigue., Conclusion: Intrathecal topotecan appeared to be effective and safe in adult patients with NM.

Background: Intracranial meningiomas are common and comprise 20% of all primary brain tumors. Meningiomas infrequently metastasize; however, to the authors' knowledge there are limited data regarding the spread of disease through cerebrospinal fluid (CSF)., Methods: Eight of 200 consecutive patients (4%) with meningiomas manifested CSF dissemination. CSF cytology was positive in all patients, and neuroradiographic studies were consistent with CSF dissemination in eight patients. The patients (6 women and 2 men) ranged in age from 24-87 years (mean age, 52 years). All patients had undergone prior surgery (range, one to five surgeries; median, two surgeries), radiotherapy (involved-field radiotherapy in seven patients and stereotactic radiotherapy in six patients), and chemotherapy (hydroxyurea in eight patients). Multiple sites of metastases were seen in all patients and were both within the nervous system (subarachnoid or ventricular tumor: intracranial in eight patients, spinal cord in four patients) and extraneural (subcutaneous, cervical lymph nodes, orbit, or pulmonary in five patients). Treatment utilized both systemic chemotherapy (temozolomide in four patients, irinotecan in three patients, hydroxyurea in three patients, interferon-alpha in two patients, and doxorubicin plus ifosfamide in one patient) and intraventricular chemotherapy (liposomal cytosine arabinoside in seven patients, thiotepa in one patient, and busulfan in one patient)., Results: Treatment-related toxicity was seen in eight patients, including chemical meningitis in eight patients (Grade 2), neutropenia in five patients (Grade 2 in four patients and Grade 3 in one patient), fatigue in one patient (Grade 2), and gastrointestinal toxicity in one patient (Grade 2). The best response was stable disease in seven patients and progressive disease in one patient. The response duration ranged from 2-31 months (median, 3.5 months). The median survival was 5.5 months, and 3 patients were alive with disease at the time of last follow-up., Conclusions: The treatment of CSF-disseminated meningioma, although feasible and comparatively nontoxic, was associated with modest outcomes despite combined systemic and intraventricular chemotherapy., (Copyright 2005 American Cancer Society.)

Background: The authors compared the quality of life of patients with solid tumor neoplastic meningitis treated in a controlled trial that compared conventional intrathecal methotrexate with a depot cytosine arabinoside liposomal injection (DepoCyt). The authors evaluated the trade-off between toxicity and improved clinical outcome., Methods: Quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis was used to evaluate data collected prospectively from a randomized clinical trial that compared DepoCyt with methotrexate. Sixty-one patients with confirmed solid tumor neoplastic meningitis were randomized to receive either methotrexate or DepoCyt., Results: Within the 12-month follow-up, the average patient in the DepoCyt arm (compared with the methotrexate arm) achieved 71 more days of neurologic progression-free survival and 52 more days of overall survival, but experienced slightly more days with toxicity. The DepoCyt regimen provided greater quality-adjusted survival regardless of the quality-of-life valuations placed on time with toxicity and time following disease progression (range, 44-79 days). This gain was significant (P < 0.05) for all patients except for those who placed a high relative value on time following disease progression., Conclusions: The clinical benefits of DepoCyt offset a trend toward additional toxicity among patients with sold tumor neoplastic meningitis. The magnitude of the benefit depends on how the patient values time spent in toxicity and disease progression. The results of this analysis can be used at the bedside to make evidence-based individual treatment decisions., (Copyright 2003 American Cancer Society.)

Injury to the central and peripheral nervous systems is an increasingly frequent consequence of standard radiation treatment protocols for tumors involving or adjacent to nervous system structures. Characteristic temporal, clinical, radiographic, and laboratory features distinguish a number of specific radiation injury syndromes, but meticulous and repeated evaluations over time are often required to establish a diagnosis. These syndromes vary with regard to prognosis and therapeutic options, and competing diagnoses with very different natural histories and therapies often mask or mimic the signs and symptoms of radiation-related nervous system injury. The ability to efficiently negotiate this complicated differential diagnostic landscape allows for early diagnosis of tumor recurrence or an alternative etiology, prompt institution of appropriate therapy, avoidance of unnecessary diagnostic studies, and confident prognostication for patients and families. Even after the diagnosis of a radiation-related complication is made, continued vigilance for additional sites or manifestations of radiation injury is mandatory. Meanwhile, further research into treatment, prevention, and the causes of individual susceptibility to radiation injury are essential.

Purpose: Motexafin gadolinium is a redox mediator that selectively targets tumor cells, is detectable by magnetic resonance imaging (MRI), and enhances the effect of radiation therapy. This lead-in phase to a randomized trial served to evaluate radiologic, neurocognitive, and neurologic progression end points and to evaluate the safety and radiologic response of motexafin gadolinium administered concurrently with 30 Gy in 10-fraction whole-brain radiation therapy for the treatment of brain metastases., Patients and Methods: Motexafin gadolinium (5.0 mg/kg/d for 10 days) was administered before each radiation treatment in this prospective international trial. Patients were evaluated by MRI, neurologic examinations, and neurocognitive tests. Prospective criteria and centralized review procedures were established for radiologic, neurocognitive, and neurologic progression end points., Results: Twenty-five patients with brain metastases from lung (52%) and breast (24%) cancer, recursive partitioning analysis class 2 (96%), and an average of 11 brain metastases were enrolled. Neurocognitive function was highly impaired at presentation. Motexafin gadolinium was well tolerated. Freedom from neurologic progression was 77% at 1 year. Median survival was 5.0 months. In 29% of patients, the cause of death was brain metastasis progression. The radiologic response rate was 68%. Motexafin gadolinium's tumor selectivity was established with MRI., Conclusion: (1) Centralized neurologic progression scoring that incorporated neurocognitive tests was implemented successfully. (2) Motexafin gadolinium was well tolerated. (3) Local control, measured by radiologic response rate, neurologic progression, and death caused by progression of brain metastasis, seemed to be improved compared with historical results. A randomized phase III trial using these methods for evaluation of efficacy has just been completed.

Neoplastic meningitis is recognized clinically in 4% to 7% of patients with extraneural cancer, but it remains dramatically under-diagnosed. The frequency of neoplastic meningitis is increasing because of heightened clinical suspicion, improved neuroimaging techniques, and longer survival in patients with extraneural cancer Longer survival allows residual tumor cells within central nervous system sanctuary sites time to become symptomatic. Affected patients may present with cerebral, cranial nerve, or spinal signs and symptoms, depending on the specific sites of central nervous system (CNS) involvement. Magnetic Resonance Imaging (MRI) seems to be sensitive for detecting metastatic deposits along the neuraxis. However, metastases at a microscopic level are below the resolution of MRI scanning. As a result, the standard diagnostic test for neoplastic meningitis remains the cytologic identification of malignant cells in cerebrospinal fluid (CSF). Although CSF cytology is useful, malignant cells are not detected in as many as one third of patients who have compelling clinical or radiographic evidence of neoplastic meningitis. Novel assays are being tested that may enhance the early identification of malignant cells in CSF. Currently, the diagnosis occurs generally after the onset of neurologic manifestations and heralds a rapidly fatal course for most patients. By the time symptoms appear, most tumors have disseminated widely within the CNS, due to cortical irritation, compression of nervous system structures, or obstruction of CSF flow. At this stage surgery, cranial irradiation, and chemotherapy are rarely, if ever, curative. The goals of treatment are to improve or to stabilize the neurologic status of patients and to prolong survival. A major problem in treating neoplastic meningitis is that the entire neuraxis must be treated. If only symptomatic areas are treated, reseeding of the neuraxis with tumor cells will occur. Therefore, intrathecal chemotherapy remains a mainstay of therapy. Currently, four therapeutic agents are available for intrathecal treatment: methotrexate, ara-C, sustained-release ara-C (DepoCyt; Chiron Therapeutics, San Francisco, CA), and thiotepa. Unfortunately, intrathecal chemotherapy does not treat bulky disease in the subarachnoid space, and often is slow to stabilize progressive neurologic deficits. For these reasons, radiation therapy to sites of symptomatic disease and sites of bulky disease on imaging studies is recommended. High dose intravenous methotrexate may be as effective as intrathecal methotrexate. Alternative approaches (which offer less toxicity, enhanced therapeutic effect, and prolonged survival) are being investigated.

Background: Changes in the glycosylation process by tumor cells result in larger amounts of sialoproteins on their surface compared with normal cells. Sialoproteins then are released into the surrounding environment primarily by shedding or cell lysis. In the current study, the authors attempted to evaluate whether lipid-associated sialoprotein (LSP) in the cerebrospinal fluid (CSF) can distinguish patients with primary and metastatic brain tumors from those without brain tumors as well as determine response to treatment., Methods: CSF samples were obtained from a tissue bank. The concentration of LSP was determined after chloroform:methanol extraction followed by protein precipitation. One-way analysis of variance and Scheffe pairwise comparisons were used for statistical analysis., Results: The CSF of neurologically normal controls, patients with a normal leukocyte count (< or = 5/microl), and patients with various neurologic disorders or systemic tumors without central nervous system (CNS) malignancies contained similar levels of LSP. The CSF from patients with a normal leukocyte count and newly diagnosed primary or metastatic brain tumors contained on average 3.7-fold higher levels of LSP compared with CSF from patients without CNS tumors (P = 0.0001). The CSF from patients with brain tumors with progressive disease not responding to treatment contained high levels of LSP comparable to the levels found in newly diagnosed patients. The CSF from treatment-responsive patients contained decreased levels of LSP similar to that found in control patients., Conclusions: The LSP in CSF may be a useful marker with which to determine the presence of intracranial malignancies and assess response to treatment., (Copyright 2001 American Cancer Society.)

DepoCyte is a slow-release formulation of cytarabine designed for intrathecal administration. The goal of this multi-centre cohort study was to determine the safety and efficacy of DepoCyte for the intrathecal treatment of neoplastic meningitis due to breast cancer. DepoCyte 50 mg was injected once every 2 weeks for one month of induction therapy; responding patients were treated with an additional 3 months of consolidation therapy. All patients had metastatic breast cancer and a positive CSF cytology or neurologic findings characteristic of neoplastic meningitis. The median number of DepoCyte doses was 3, and 85% of patients completed the planned 1 month induction. Median follow up is currently 19 months. The primary endpoint was response, defined as conversion of the CSF cytology from positive to negative at all sites known to be positive, and the absence of neurologic progression at the time the cytologic conversion was documented. The response rate among the 43 evaluable patients was 28% (CI 95%: 14-41%); the intent-to-treat response rate was 21% (CI 95%: 12-34%). Median time to neurologic progression was 49 days (range 1-515(+)); median survival was 88 days (range 1-515(+)), and 1 year survival is projected to be 19%. The major adverse events were headache and arachnoiditis. When drug-related, these were largely of low grade, transient and reversible. Headache occurred on 11% of cycles; 90% were grade 1 or 2. Arachnoiditis occurred on 19% of cycles; 88% were grade 1 or 2. DepoCyte demonstrated activity in neoplastic meningitis due to breast cancer that is comparable to results reported with conventional intrathecal agents. However, this activity was achieved with one fourth as many intrathecal injections as typically required in conventional therapy. The every 2 week dose schedule is a major advantage for both patients and physicians., (Copyright 2001 Cancer Research Campaign.)

In this study, the records of 17 adult patients with medulloblastoma treated with craniospinal radiation and 1 of 2 multiagent chemotherapy protocols were reviewed for progression-free survival, overall survival, and toxicity, and the patients were compared with each other and with similarly treated children and adults. Records of patients treated at 3 institutions were reviewed. Seventeen medulloblastoma patients (11 female, 6 male) with a median age of 23 years (range, 18-47 years) were treated with surgery, craniospinal radiation (CSRT) plus local boost, and 1 of 2 adjuvant chemotherapy regimens. All tumors were infratentorial (10 in 4th ventricle and 7 in left or right hemisphere). Ten patients presented with hydrocephalus, and 7 of them were shunted. Eight patients had gross total resection, 7 had subtotal resection (>50% removed), and 2 had partial resection (<50% removed). Postoperatively, 3 patients had positive cytology and 3 had positive spinal MRI. Five patients were classified as good risk and 12 were classified as poor risk (Chang staging system). Ten patients were treated with the "Packer protocol," consisting of CSRT plus weekly vincristine followed by 8 cycles of cisplatin, lomustine, and vincristine. Seven patients were treated with the Pediatric Oncology Group (POG) protocol, consisting of alternating courses of cisplatin/etoposide and cyclophosphamide/vincristine, followed by CSRT. Eight of 17 patients relapsed, with all 8 relapsing at the primary site. Other relapse sites included the leptomeninges (5), bone (1), and brain (1). The estimated median relapse-free survival (Kaplan-Meier) for all patients was 48 months (95% confidence interval, >26 months to infinity). Median relapse-free survival for patients on the Packer protocol was 26 months, and for those on the POG regimen was 48 months (P = 0.410). Five of 10 on the Packer protocol were relapse-free, while 4 of 7 were relapse-free on the POG regimen. Two patients relapsed during chemotherapy and 6 relapsed after completing all therapy at 18, 18, 26, 30, 40, and 48 months. The estimated median survival of all patients was 56 months (95% confidence interval, 27 to infinity) with 11 patients alive; for the Packer protocol, median survival was 36 months, and for the POG protocol, it was 57 months (P = 0.058). The hazard ratio was 0 (95% confidence interval, 0 to infinity). Toxicity during the Packer protocol was moderately severe, with only 1 of 10 patients able to complete all therapy. Two patients had severe abdominal pain during CSRT + vincristine, and 5 had peripheral neuropathy during vincristine therapy. Hearing loss (>20 dB) occurred in 7, neutropenia (<500 microl) in 6, thrombocytopenia (<50,000 microl) in 6, nephrotoxicity (>25% decrease by creatinine clearance) in 2, and decreased pulmonary function (diffusing capacity for carbon monoxide decrease >40%) in 1. On the POG protocol, only 1 patient had persistent nausea and vomiting, 2 had peripheral neuropathy, and 3 had hearing deficit (>20 dB) or tinnitus. The POG and Packer protocols did not have a statistically significant difference in relapse-free or overall survival because of the small sample size. The POG protocol seemed to have less nonhematologic toxicity. Adults on the Packer protocol appeared to have shorter median survival and greater toxicity than did children. To know whether adding adjuvant chemotherapy to craniospinal radiation in adult therapy increases relapse-free and overall survival, we must await the results of a larger randomized controlled clinical trial.

Leptomeningeal metastases (LMs) are common metastatic complications, occurring in at least 5% of patients with disseminated cancer. Cerebrospinal fluid (CSF) cytology remains the standard for diagnosis and assessment of treatment response, but may be inadequate. Our objective was to compare ventricular and lumbar CSF cytology in patients who had cytologically proven LM and were receiving intra-CSF chemotherapy. Sixty patients with LM, positive lumbar CSF cytology documented at diagnosis, limited extent of CNS disease, and no evidence of CSF flow obstruction were treated with a variety of intra-CSF chemotherapies. All patients underwent a single simultaneous ventricular and lumbar CSF sampling (mean volume of CSF per site examined, 10 ml) to assess response to therapy at either 1 or 2 months after treatment initiation. Ventricular CSF cytology was positive in 44 patients (73%), 35 of whom were also positive by lumbar CSF cytology. Lumbar CSF cytology was positive in 45 patients (75%), of which 35 were also positive by ventricular CSF cytology. Samples were negative at both ventricular and lumbar sites in 6 patients (10%). Paired CSF cytologies were discordant in 19 (32%) patients. The lumbar cytology was negative in 9, whereas the ventricular cytology was positive (lumbar false-negative rate of 17%); the ventricular cytology was negative in 10, whereas the lumbar cytology was positive (ventricular false-negative rate of 20%). In the presence of spinal signs or symptoms of LM, the lumbar CSF cytology was more likely to be positive than was the ventricular (odds ratio = 2.86; 95% confidence interval, 0.86-9.56). Conversely, in the presence of cranial signs or symptoms, the ventricular CSF cytology was more likely to be positive than was the lumbar (odds ratio = 2.71; 95% confidence interval, 0.76-9.71). In this cohort of patients, whose LM was documented initially by positive lumbar CSF cytology, ventricular and lumbar CSF samples obtained during treatment had similar false-negative rates, depending on the site of clinical or radiologic disease. This suggests that both lumbar and ventricular sites must be sampled when assessing treatment response. If clinical or radiographic disease is present only at 1 site, then CSF from that site is more likely to be positive than is CSF obtained from the more distant site.

Purpose: Delirium is a common and distressing syndrome seen in patients with advanced cancer. Behavioral manifestations of delirium, such as agitation, may result in medical intervention, stress to family caregivers, and inpatient hospice admission. The purpose of this study was to examine the frequency, characteristics, and presumed causes of delirium in patients with advanced cancer., Description of Study: Records of all patients with cancer who were admitted to an inpatient hospice facility in 1995 were reviewed retrospectively (N = 210). Patients were classified as delirious based on the clinical judgment of the admitting physician., Results: Delirium was the third most common reason for admission (20%). Male gender (P = .04) and the presence of a primary or metastatic brain tumor (P = .03) were significant risk factors for delirium, while advanced age and primary or metastatic liver, lung, or bone cancer were not. Resolution of the agitation, the most disruptive symptom of delirium, occurred in 69% of patients before death or discharge., Clinical Implications: Delirium is common in hospice patients with cancer and is an important cause of family distress and increased cost of care. The recognition of early clinical signs and predisposing factors should facilitate prompt diagnosis. Appropriate intervention is usually successful in alleviating the most distressing symptoms of delirium.