PPRX-1701, a nanoparticle formulation of 6'-bromoindirubin acetoxime, improves delivery and shows efficacy in preclinical GBM models.

Derivatives of the Chinese traditional medicine indirubin have shown potential for the treatment of cancer through a range of mechanisms. This study investigates the impact of 6'-bromoindirubin-3'-acetoxime (BiA) on immunosuppressive mechanisms in glioblastoma (GBM) and evaluates the efficacy of a BiA nanoparticle formulation, PPRX-1701, in immunocompetent mouse GBM models. Transcriptomic studies reveal that BiA downregulates immune-related genes, including indoleamine 2,3-dioxygenase 1 (IDO1), a critical enzyme in the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) immunosuppressive pathway in tumor cells. BiA blocks interferon-γ (IFNγ)-induced IDO1 protein expression in vitro and enhances T cell-mediated tumor cell killing in GBM stem-like cell co-culture models. PPRX-1701 reaches intracranial murine GBM and significantly improves survival in immunocompetent GBM models in vivo. Our results indicate that BiA improves survival in murine GBM models via effects on important immunotherapeutic targets in GBM and that it can be delivered efficiently via PPRX-1701, a nanoparticle injectable formulation of BiA.

Targeting glioma-initiating cells via the tyrosine metabolic pathway.

OBJECTIVE: Despite an aggressive multimodal therapeutic regimen, glioblastoma (GBM) continues to portend a grave prognosis, which is driven in part by tumor heterogeneity at both the molecular and cellular levels. Accordingly, herein the authors sought to identify metabolic differences between GBM tumor core cells and edge cells and, in so doing, elucidate novel actionable therapeutic targets centered on tumor metabolism. METHODS: Comprehensive metabolic analyses were performed on 20 high-grade glioma (HGG) tissues and 30 glioma-initiating cell (GIC) sphere culture models. The results of the metabolic analyses were combined with the Ivy GBM data set. Differences in tumor metabolism between GBM tumor tissue derived from within the contrast-enhancing region (i.e., tumor core) and that from the peritumoral brain lesions (i.e., tumor edge) were sought and explored. Such changes were ultimately confirmed at the protein level via immunohistochemistry. RESULTS: Metabolic heterogeneity in both HGG tumor tissues and GBM sphere culture models was identified, and analyses suggested that tyrosine metabolism may serve as a possible therapeutic target in GBM, particularly in the tumor core. Furthermore, activation of the enzyme tyrosine aminotransferase (TAT) within the tyrosine metabolic pathway influenced the noted therapeutic resistance of the GBM core. CONCLUSIONS: Selective inhibition of the tyrosine metabolism pathway may prove highly beneficial as an adjuvant to multimodal GBM therapies.

Oral tocotrienols are transported to human tissues and delay the progression of the model for end-stage liver disease score in patients.

The natural vitamin E family is composed of 8 members equally divided into 2 classes: tocopherols (TCP) and tocotrienols (TE). A growing body of evidence suggests TE possess potent biological activity not shared by TCP. The primary objective of this work was to determine the concentrations of TE (200 mg mixed TE, b.i.d.) and TCP [200 mg α-TCP, b.i.d.)] in vital tissues and organs of adults receiving oral supplementation. Eighty participants were studied. Skin and blood vitamin E concentrations were determined from healthy participants following 12 wk of oral supplementation of TE or TCP. Vital organ vitamin E levels were determined by HPLC in adipose, brain, cardiac muscle, and liver of surgical patients following oral TE or TCP supplementation (mean duration, 20 wk; range, 1-96 wk). Oral supplementation of TE significantly increased the TE tissue concentrations in blood, skin, adipose, brain, cardiac muscle, and liver over time. α-TE was delivered to human brain at a concentration reported to be neuroprotective in experimental models of stroke. In prospective liver transplantation patients, oral TE lowered the model for end-stage liver disease (MELD) score in 50% of patients supplemented, whereas only 20% of TCP-supplemented patients demonstrated a reduction in MELD score. This work provides, to our knowledge, the first evidence demonstrating that orally supplemented TE are transported to vital organs of adult humans. The findings of this study, in the context of the current literature, lay the foundation for Phase II clinical trials testing the efficacy of TE against stroke and end-stage liver disease in humans.

Oncolytic HSV-1 virotherapy: clinical experience and opportunities for progress.

Oncolytic virotherapy with mutants derived from Herpes simplex virus (HSV) type 1 exhibit significant antitumor effects in preclinical models. Several mutants have now been tested in clinical trials for a variety of cancer types, and all have been found to be safe. While there have been hints of antitumor efficacy with prolonged survival in some cases compared with historical controls, dramatic responses have been elusive. We review the clinical experience published to date and discuss some of the biologic factors that may be limiting for virus infection and spread, as well as new strategies currently under development to enhance antitumor efficacy.

Reversal of neurological deficit after chemotherapy in BCL-6-positive neurolymphomatosis. Case report.

Neurolymphomatosis, the infiltration of the peripheral nervous system (PNS) by malignant lymphatic cells, is a rare condition whose prognosis and treatment are not fully characterized. The authors report the case of a 69-year-old, previously healthy man who had a 1-month history of progressive pain in his right arm and associated weakness of several muscles of the right upper extremity when they first examined him. Initial MR imaging of the right brachial plexus showed no abnormalities, but over 3 months, symptoms gradually progressed to almost complete plegia of his right upper extremity. Subsequent MR imaging of his right brachial plexus showed an enhancing mass of the posterior cord of the plexus that encroached on the other cords. Positron emission tomography confirmed the presence of a hypermetabolic lesion in the right axillary region and also detected an asymptomatic hot spot in the gastric wall. Biopsy of the gastric lesion demonstrated a CD20+, diffuse large B-cell lymphoma that was immunohistochemically positive for BCL-6 and negative for p16. The patient underwent 6 cycles of dose-adjusted etoposide-vincristine-doxorubicin-cyclophosphamide-prednisone (EPOCH) and rituximab, intermixed with 3 cycles of high-dose intravenous and intrathecal methotrexate, and followed by 6 monthly doses of rituximab for consolidation. Follow-up MR imaging and PET of the plexus showed complete radiological response after 3 months of treatment, as demonstrated by normalization of brachial plexus caliber, contrast enhancement, and metabolic activity. Twenty-eight months after symptom onset and 20 months after beginning therapy, the patient was disease-free, had recovered most upper extremity neurological function, and had only minimal remaining weakness of the right wrist and finger extension.

A retrospective analysis of reasons for reoperation following initially successful peripheral nerve stimulation.

OBJECT: The authors investigated the causes for surgical reexploration in patients with complex regional pain syndrome Type II who received initial relief of pain from implantation of a peripheral nerve stimulator (PNS). METHODS: The authors reviewed the charts of 11 consecutive patients who underwent a total of 27 PNS-related operations at one institution. Duration of follow up ranged from 5 days to more than 24 months. Of 11 patients who received PNS implants, seven (64%) required one or more additional surgeries to relocate the PNS because initial pain relief following stimulation was lost and not restored by changing pulse generator settings. Loss of analgesia was attributed to migration of the sutured electrode strip paddle (nine [33%] of 27 surgeries), infection (four [15%] of 27), and the need for placement in an alternative location (three [11%] of 27). CONCLUSIONS: Although infection is attributable to surgical technique, most complications requiring repeated surgery (nine [33%] of 27) are caused by equipment design. Changes in PNS design or in implantation technique might substantially reduce the need for reoperation after PNS implantation.

In vivo 3-T MR spectroscopy in the distinction of recurrent glioma versus radiation effects: initial experience.

PURPOSE: To determine if 3-T magnetic resonance (MR) spectroscopy allows accurate distinction of recurrent tumor from radiation effects in patients with gliomas of grade II or higher. MATERIALS AND METHODS: This blinded prospective study included 14 patients who underwent in vivo 3-T MR spectroscopy prior to stereotactic biopsy. All patients received a previous diagnosis of glioma (grade II or higher) and high-dose radiation therapy (>54 Gy). Prior to MR spectroscopy, conventional MR imaging was performed at 1.5 T to identify a gadolinium-enhanced region within the irradiated volume. Diagnosis was assigned by means of histopathologic analysis of the biopsy samples. RESULTS: Sixteen of 17 biopsy locations could be classified as predominantly tumor or predominantly radiation effect on the basis of the ratio of choline at the biopsy site to normal creatine level by using a value greater than 1.3 as the criterion for tumor. The remaining case, classified as recurrent tumor on the basis of MR spectroscopy results, was diagnosed as predominantly radiation effect on the basis of histopathologic findings. Disease in this patient progressed to biopsy-proven recurrence within 3 months. Overall, the ratio of choline at the biopsy site to normal creatine level was significantly elevated (unpaired two-tailed Student t test, P <.002) in those biopsy samples composed predominantly of tumor (n = 9) compared with those containing predominantly radiation effects (n = 8). The ratio was not significantly different between the two histopathologic groups. CONCLUSION: In vivo 3-T MR spectroscopy has sufficient spatial resolution and chemical specificity to allow distinction of recurrent tumor from radiation effects in patients with treated gliomas.