Akshal S. Patel

Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects.

TIC10 is a small molecule that activates Foxo3a through dual inactivation of Akt and ERK, up-regulates the expression of the TRAIL gene, an endogenous tumor suppressor, and effectively improves the therapeutic properties and utility of TRAIL as an anticancer therapy. TIC’ing Up the TRAIL TRAIL is a naturally occurring tumor suppressor: It stimulates cell death pathways in a variety of human cancers and thus has been a popular target for the development of anticancer drugs. Previous TRAIL-targeting strategies include synthesis of the recombinant protein and stimulatory antibodies. All of these agents exhibit some of the typical drawbacks of protein-based therapeutics, such as short half-lives and a need to administer the drugs directly into the bloodstream or even into the tumor. Now, Allen and colleagues have discovered a drug, TIC10, which can stimulate production of TRAIL while avoiding the shortcomings of protein-based therapies. The authors demonstrated that TIC10 can increase TRAIL and stimulate the death of multiple types of human cancer cells both in culture and in mice. The drug was equally effective when given orally or intravenously and effectively penetrated the blood-brain barrier to target glioblastoma, a difficult-to-treat brain tumor. Whereas recombinant TRAIL displayed a short half-life of ~30 min, TIC10 activity persisted in the mice for days, allowing for once-a-week dosing. Toxicity analysis in mice showed no detectable adverse effects from treatment with TIC10. The authors also showed that TIC10 boosts TRAIL function through inactivation of the Akt and MEK signaling proteins, which results in translocation of the transcription factor Foxo3a into the cell nucleus, where it stimulates TRAIL gene expression. Before TIC10 can be used to treat patients, the drug will need to be tested in clinical trials to confirm safety and efficacy results from mouse studies. In addition, further work is needed to determine the mechanism by which TIC10 causes the dephosphorylation and resulting inactivation of Akt and MEK. However, the discovery of TIC10 clears a path to versatile TRAIL-based cancer therapies. Recombinant tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is an antitumor protein that is in clinical trials as a potential anticancer therapy but suffers from drug properties that may limit efficacy such as short serum half-life, stability, cost, and biodistribution, particularly with respect to the brain. To overcome such limitations, we identified TRAIL-inducing compound 10 (TIC10), a potent, orally active, and stable small molecule that transcriptionally induces TRAIL in a p53-independent manner and crosses the blood-brain barrier. TIC10 induces a sustained up-regulation of TRAIL in tumors and normal cells that may contribute to the demonstrable antitumor activity of TIC10. TIC10 inactivates kinases Akt and extracellular signal–regulated kinase (ERK), leading to the translocation of Foxo3a into the nucleus, where it binds to the TRAIL promoter to up-regulate gene transcription. TIC10 is an efficacious antitumor therapeutic agent that acts on tumor cells and their microenvironment to enhance the concentrations of the endogenous tumor suppressor TRAIL.

Association of the Extent of Resection With Survival in Glioblastoma: A Systematic Review and Meta-analysis

Importance Glioblastoma multiforme (GBM) remains almost invariably fatal despite optimal surgical and medical therapy. The association between the extent of tumor resection (EOR) and outcome remains undefined, notwithstanding many relevant studies. Objective To determine whether greater EOR is associated with improved 1- and 2-year overall survival and 6-month and 1-year progression-free survival in patients with GBM. Data Sources Pubmed, CINAHL, and Web of Science (January 1, 1966, to December 1, 2015) were systematically reviewed with librarian guidance. Additional articles were included after consultation with experts and evaluation of bibliographies. Articles were collected from January 15 to December 1, 2015. Study Selection Studies of adult patients with newly diagnosed supratentorial GBM comparing various EOR and presenting objective overall or progression-free survival data were included. Pediatric studies were excluded. Data Extraction and Synthesis Data were extracted from the text of articles or the Kaplan-Meier curves independently by investigators who were blinded to each others results. Data were analyzed to assess mortality after gross total resection (GTR), subtotal resection (STR), and biopsy. The body of evidence was evaluated according to Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria and PRISMA guidelines. Main Outcome and Measures Relative risk (RR) for mortality at 1 and 2 years and progression at 6 months and 1 year. Results The search produced 37 studies suitable for inclusion (41 117 unique patients). The meta-analysis revealed decreased mortality for GTR compared with STR at 1 year (RR, 0.62; 95% CI, 0.56-0.69; P < .001; number needed to treat [NNT], 9) and 2 years (RR, 0.84; 95% CI, 0.79-0.89; P < .001; NNT, 17). The 1-year risk for mortality for STR compared with biopsy was reduced significantly (RR, 0.85; 95% CI, 0.80-0.91; P < .001). The risk for mortality was similarly decreased for any resection compared with biopsy at 1 year (RR, 0.77; 95% CI, 0.71-0.84; P < .001; NNT, 21) and 2 years (RR, 0.94; 95% CI, 0.89-1.00; P = .04; NNT, 593). The likelihood of disease progression was decreased with GTR compared with STR at 6 months (RR, 0.72; 95% CI, 0.48-1.09; P = .12; NNT, 14) and 1 year (RR, 0.66; 95% CI, 0.43-0.99; P < .001; NNT, 26). The quality of the body of evidence by the GRADE criteria was moderate to low. Conclusion and Relevance This analysis represents the largest systematic review and only quantitative systematic review to date performed on this subject. Compared with STR, GTR substantially improves overall and progression-free survival, but the quality of the supporting evidence is moderate to low.

Pure neuritic leprosy presenting as ulnar nerve neuropathy: a case report of electrodiagnostic, radiographic, and histopathological findings

Hansens disease, or leprosy, is a chronic infectious disease with many manifestations. Though still a major health concern and leading cause of peripheral neuropathy in the developing world, it is rare in the United States, with only about 150 cases reported each year. Nevertheless, it is imperative that neurosurgeons consider it in the differential diagnosis of neuropathy. The causative organism is Mycobacterium leprae, which infects and damages Schwann cells in the peripheral nervous system, leading first to sensory and then to motor deficits. A rare presentation of Hansens disease is pure neuritic leprosy. It is characterized by nerve involvement without the characteristic cutaneous stigmata. The authors of this report describe a case of pure neuritic leprosy presenting as ulnar nerve neuropathy with corresponding radiographic, electrodiagnostic, and histopathological data. This 11-year-old, otherwise healthy male presented with progressive right-hand weakness and numbness with no cutaneous abnormalities. Physical examination and electrodiagnostic testing revealed findings consistent with a severe ulnar neuropathy at the elbow. Magnetic resonance imaging revealed diffuse thickening and enhancement of the ulnar nerve and narrowing at the cubital tunnel. The patient underwent ulnar nerve decompression with biopsy. Pathology revealed acid-fast organisms within the nerve, which was pathognomonic for Hansens disease. He was started on antibiotic therapy, and on follow-up he had improved strength and sensation in the ulnar nerve distribution. Pure neuritic leprosy, though rare in the United States, should be considered in the differential diagnosis of those presenting with peripheral neuropathy and a history of travel to leprosy-endemic areas. The long incubation period of M. leprae, the ability of leprosy to mimic other conditions, and the low sensitivity of serological tests make clinical, electrodiagnostic, and radiographic evaluation necessary for diagnosis. Prompt diagnosis and treatment is imperative to prevent permanent neurological injury.

Onyx-HD 500 Embolization of a Traumatic Internal Carotid Artery Pseudoaneurysm after Transsphenoidal Surgery.

Traumatic intracranial pseudoaneurysms present a challenge for treatment. Traditionally these lesions have required a deconstructive approach consisting of vessel sacrifice since their fragile nature often makes direct microsurgical repair or coil embolization hazardous. As a high‐viscosity liquid embolic agent that results in immediate, vessel sparing aneurysm occlusion, Onyx‐HD 500 represents a uniquely efficacious tool for this clinical situation.

Characterization of a Novel Anti-Cancer Compound for Astrocytomas

The standard chemotherapy for brain tumors is temozolomide (TMZ), however, as many as 50% of brain tumors are reportedly TMZ resistant leaving patients without a chemotherapeutic option. We performed serial screening of TMZ resistant astrocytoma cell lines, and identified compounds that are cytotoxic to these cells. The most cytotoxic compound was an analog of thiobarbituric acid that we refer to as CC-I. There is a dose-dependent cytotoxic effect of CC-I in TMZ resistant astrocytoma cells. Cell death appears to occur via apoptosis. Following CC-I exposure, there was an increase in astrocytoma cells in the S and G2/M phases. In in vivo athymic (nu/nu) nude mice subcutaneous and intracranial tumor models, CC-I completely inhibited tumor growth without liver or kidney toxicity. Molecular modeling and enzyme activity assays indicate that CC-I selectively inhibits topoisomerase IIα similar to other drugs in its class, but its cytotoxic effects on astrocytoma cells are stronger than these compounds. The cytotoxic effect of CC-I is stronger in cells expressing unmethylated O6-methylguanine methyltransferase (MGMT) but is still toxic to cells with methylated MGMT. CC-I can also enhance the toxic effect of TMZ on astrocytoma when the two compounds are combined. In conclusion, we have identified a compound that is effective against astrocytomas including TMZ resistant astrocytomas in both cell culture and in vivo brain tumor models. The enhanced cytotoxicity of CC-I and the safety profile of this family of drugs could provide an interesting tool for broader evaluation against brain tumors.

COX-2 Drives Metastatic Breast Cells from Brain Lesions into the Cerebrospinal Fluid and Systemic Circulation

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.

Detection of circulating tumor cells in the cerebrospinal fluid of a patient with a solitary metastasis from breast cancer: A case report

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.

Surgical advances for extracranial carotid stenosis.

Carotid endarterectomy is a commonly performed operation to prevent stroke in patients who have asymptomatic or symptomatic internal carotid artery atherosclerotic stenosis. Carotid angioplasty and stenting has also been advocated for treatment of these patients. In this article, we address a number of questions for which a review of available data will advance our understanding of the role of carotid endarterectomy in stroke prevention. These include the following: Are carotid endarterectomy and carotid angioplasty and stenting equivalent procedures for the treatment of carotid artery disease? Which patients should be deemed at high risk for carotid endarterectomy? Should carotid endarterectomy be an urgent procedure in symptomatic patients with severe internal carotid artery stenosis? Finally, what is the role of carotid endarterectomy in asymptomatic patients? We also review the senior authors personal experience with >2000 consecutive carotid endarterectomies, with special attention to his present approach to this operation. We believe that carotid endarterectomy, in experienced hands, is a minimally invasive operation that remains the procedure of choice for most patients with carotid artery disease who will benefit from invasive treatment.Carotid endarterectomy is a commonly performed operation to prevent stroke in patients who have asymptomatic or symptomatic internal carotid artery atherosclerotic stenosis. Carotid angioplasty and stenting has also been advocated for treatment of these patients. In this article, we address a number of questions for which a review of available data will advance our understanding of the role of carotid endarterectomy in stroke prevention. These include the following: Are carotid endarterectomy and carotid angioplasty and stenting equivalent procedures for the treatment of carotid artery disease? Which patients should be deemed at high risk for carotid endarterectomy? Should carotid endarterectomy be an urgent procedure in symptomatic patients with severe internal carotid artery stenosis? Finally, what is the role of carotid endarterectomy in asymptomatic patients? We also review the senior authors personal experience with >2000 consecutive carotid endarterectomies, with special attention to his present approach to this operation. We believe that carotid endarterectomy, in experienced hands, is a minimally invasive operation that remains the procedure of choice for most patients with carotid artery disease who will benefit from invasive treatment.

Endovascular embolization by parent artery reconstruction of a symptomatic fusiform posterior cerebral artery aneurysm using Onyx HD-500: a neurointerventional report.

Posterior cerebral artery aneurysms are treatment challenge for the neurosurgeon. Parent artery occlusion, trapping and bypass have been the classic treatment options for aneurysms in this location. With the introduction of newer embolic agents such as Onyx®, endovascular intervention is now a viable therapy for these aneurysms.

Abstract 3483: Modeling circulating tumor cells in the peripheral blood and CSF of breast cancer patients.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The enumeration of circulating tumor cells (CTCs) using the CellSearch system (Veridex LLC) is a valuable prognostic clinical tool in several epithelial malignancies. Surveillance methods for metastatic disease involving the central nervous system (CNS) lack adequate sensitivity, specificity, and reproducibility in the clinic. We previously reported a method to enumerate CTCs in the cerebrospinal fluid (CSF) of breast cancer patients with metastases involving the CNS. The enumeration of CTCs in CSF by this method is highly sensitive, accurate, reproducible, and correlates with disease burden by several measures. Here, we concomitantly monitor CTCs in the peripheral blood and CSF of five patients with neoplastic meningitis receiving intrathecal (IT) chemotherapy. In each patient, CTC counts have been more sensitive than conventional cytology, and have predicted the course of symptoms and overall survival more precisely than conventional cytology. We observed a striking inverse relationship between CTC counts in the peripheral blood and CSF. This observation generated the hypothesis that CTCs migrate from the blood to the CSF and the converse as sanctuary sites during compartmentalized therapy to result in systemic disease recurrence. To test this hypothesis we created mouse models of these clinical phenomena including injection of triple-negative breast cancer into the peripheral blood or intracranially. Injection of luciferase-infected MDA-MB-231 or MDA-MB-468 human triple-negative breast cancer cells into the brain of athymic nude mice resulted in primary tumors at the site of injection. The MDA-MB-231, unlike the MDA-MB-468, generated detectable tumor cell dissemination into the CSF of inoculated mice that correlated with a significantly declined survival. CSF collected from the cisterna magna of inoculated mice corroborated these observations. Current studies are examining the impact of compartmentalized therapy on the migration of these tumor cells as well as profiling unique genetic drivers of the subset of tumors cells that disseminate into the CSF. The intercompartmental cycling of tumor cells may represent an important mechanism for disease persistence and recurrence, and suggests that concurrent systemic and CNS-directed therapy may be warranted. Citation Format: Joshua E. Allen, Akshal S. Patel, David T. Dicker, Jonas M. Sheehan, Michael Glantz, Wafik S. El-Deiry. Modeling circulating tumor cells in the peripheral blood and CSF of breast cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3483. doi:10.1158/1538-7445.AM2013-3483