Phase 1 study of sorafenib and irinotecan in pediatric patients with relapsed or refractory solid tumors.

BACKGROUND: Sorafenib,an orally bioavailable, multitarget tyrosine kinase inhibitor, and irinotecan, a topoisomerase I inhibitor, have demonstrated activity in pediatric and adult malignancies. We evaluated the toxicity, pharmacokinetic (PK), and pharmacogenomic (PGX) profile of sorafenib with irinotecan in children with relapsed or refractory solid tumors and assessed the feasibility of incorporating patient-reported outcome (PRO) measures as an adjunct to traditional endpoints. METHODS: Sorafenib, continuous oral twice daily dosing, was administered with irinotecan, orally, once daily days 1-5, repeated every 21 days (NCT01518413). Based on tolerability, escalation of sorafenib followed by escalation of irinotecan was planned. Three patients were initially enrolled at each dose level. Sorafenib and irinotecan PK analyses were performed during cycle 1. PRO measurements were collected during cycles 1 and 2. RESULTS: Fifteen patients were evaluable. Two of three patients at dose level 2 experienced dose-limiting toxicity (DLT), grade 3 diarrhea, and grade 3 hyponatremia. Therefore, dose level 1 was expanded to 12 patients and two patients had DLT, grade 4 thrombocytopenia, grade 3 elevated lipase. Nine of 15 (60%) patients had a best response of stable disease with four patients receiving ≥6 cycles. CONCLUSIONS: The recommended dose for pediatric patients was sorafenib 150 mg/m2 /dose twice daily with irinotecan 70 mg/m2 /dose daily × 5 days every 21 days. This oral outpatient regimen was well tolerated and resulted in prolonged disease stabilization. There were no significant alterations in the PK profile of either agent when administered in combination. Patients were willing and able to report their subjective experiences with this regimen.

Novel Agents in Neuropathic Pain, the Role of Capsaicin: Pharmacology, Efficacy, Side Effects, Different Preparations.

PURPOSE OF REVIEW: Capsaicin is a natural substance used to treat neuropathic pain because of its ability to be used in a more direct form on patients and efficiently treat their pain without the amount of side effects seen in the use of oral medications. RECENT FINDINGS: Currently, the treatments for neuropathic pain are, control of the underlying disease process, then focused on symptomatic relief with pharmacotherapy, topical analgesics, or other interventions. When all pharmacological agents fail to relieve the pain, interventional strategies can be considered, such as neural blocks, spinal cord stimulation, and intrathecal administered medications. The response to current treatment of neuropathic pain is only modest relief of symptoms. Multiple treatment options may be attempted, while ultimately leaving patients with refractory neuropathic pain. For these reasons, a better treatment approach to neuropathic pain is greatly needed. Overall, capsaicin has great potential for becoming a first- or second-line treatment for neuropathic pain, and for becoming a therapeutic option for many other neuropathic pain-related disease states.

Conformational Fine-Tuning of Pore-Forming Peptide Potency and Selectivity.

To better understand the sequence-structure-function relationships that control the activity and selectivity of membrane-permeabilizing peptides, we screened a peptide library, based on the archetypal pore-former melittin, for loss-of-function variants. This was accomplished by assaying library members for failure to cause leakage of entrapped contents from synthetic lipid vesicles at a peptide-to-lipid ratio of 1:20, 10-fold higher than the concentration at which melittin efficiently permeabilizes the same vesicles. Surprisingly, about one-third of the library members are inactive under these conditions. In the negative peptides, two changes of hydrophobic residues to glycine were especially abundant. We show that loss-of-function activity can be completely recapitulated by a single-residue change of the leucine at position 16 to glycine. Unlike the potently cytolytic melittin, the loss-of-function peptides, including the single-site variant, are essentially inactive against phosphatidylcholine vesicles and multiple types of eukaryotic cells. Loss of function is shown to result from a shift in the binding-folding equilibrium away from the active, bound, α-helical state toward the inactive, unbound, random-coil state. Accordingly, the addition of anionic lipids to synthetic lipid vesicles restored binding, α-helical secondary structure, and potent activity of the "negative" peptides. While nontoxic to mammalian cells, the single-site variant has potent bactericidal activity, consistent with the anionic nature of bacterial membranes. The results show that conformational fine-tuning of helical pore-forming peptides is a powerful way to modulate their activity and selectivity.

Botryllamide G is an ABCG2 inhibitor that improves lapatinib delivery in mouse brain.

Introduction: Transporters comprising the blood-brain barrier complicate delivery of many therapeutics to the central nervous system. The present study ascertained whether the natural product botryllamide G is viable for in vivo inhibition of ABCG2 using lapatinib as a probe for ABCB1 and ABCG2-mediated efflux from the brain. Methods: Wild-type and Mdr1a/Mdr1b (-/-) mice were treated with botryllamide G and lapatinib ("doublet therapy"), and while a separate cohort of wild-type mice was treated with botryllamide, tariquidar and lapatinib ("triplet therapy"). Results: Botryllamide G demonstrates biphasic elimination with a rapid distribution, decreasing below the in vitro IC50 of 6.9 µM within minutes, yet with a relatively slower terminal half-life (4.6 h). In Mdr1a/Mdr1b (-/-) mice, doublet therapy resulted in a significant increase in brain lapatinib AUC at 8 h (2058 h*ng/mL vs 4007 h*ng/mL; P = .031), but not plasma exposure (P = .15). No significant differences were observed after 24 h. Lapatinib brain exposure was greater through 1 h when wild-type mice were administered triplet therapy (298 h*pg/mg vs 120 h*pg/mg; P < .001), but the triplet decreased brain AUC through 24 h vs. mice administered lapatinib alone (2878 h*pg/mg vs 4461hr*ng/mL; P < .001) and did not alter the brain:plasma ratio. Conclusions: In summary, the ABCG2 inhibitor, botryllamide G, increases brain exposure to lapatinib in mice lacking Abcb1, although the combination of botryllamide G and tariquidar increases brain exposure in wild-type mice only briefly (1 h). Additional research is needed to find analogs of this compound that have better pharmacokinetics and pharmacodynamic effects on ABCG2 inhibition.

Fascia iliaca block, history, technique, and efficacy in clinical practice.

The facsia iliaca block (FIB) is a relatively new regional technique where local anesthetic is delivered within the fascia iliaca region. Indications for a FIB include surgical anesthesia to the lower extremity after knee, femoral shaft, hip surgery, management of cancer pain or pain secondary to inflammatory conditions of the lumbar plexus, as well as treatment of acute pain in the setting of trauma, fracture, or burns. The FIB may be performed using either a loss of resistance technique or an ultrasound (US)-guided technique; however, the use of US has become commonplace and resulted in improved femoral nerve and obturator nerve motor blocks. The main targets of the FIB are the predominant nerves contained in the fascia iliaca compartment (FIC), namely the femoral nerve and the lateral femoral cutaneous nerve. The FIB US guided technique is beneficial to patients and the possibility to perform FIB should be discussed and coordinated with surgical staff appropriately, considering its superiority to general or epidural anesthesia.

Recent technological advancements in regional anesthesia.

Just two decades ago, regional anesthesia was performed blindly with dubious outcomes and little support from surgeons and patients. Technological advances in regional anesthesia have revolutionized techniques and largely improved outcomes. Ultrasound (US) technology continues to advance and has become more affordable. Improvements have come in the form of picture quality, resolution, portability, and smaller equipment. The US technology can identify otherwise unrecognized pathology and can help to optimize patient flow by allowing for more accurate triage and effective treatments and providing timelier interventions. In recent years, several different strategies to help improve and ease US-guided needle identification and placement have been developed, including magnetically guided needle US technology. Three-dimensional (3D) and four-dimensional (4D) US use is another potential way to help improve first-pass success and limit patient harm for regional anesthetics. The advent of echogenic needles and the resulting improvement in needle visualization under US has had a positive impact on physician comfort in performing regional anesthesia and on visualization time of the needle during US-guided procedures. To reduce variability and to reduce the anesthesiologist's workload, the use of robots in regional anesthesia has been assessed in recent years. Peripheral nerve stimulation (PNS) has also demonstrated efficacy in acute and chronic pain settings. Additional research and randomized controlled trials are necessary to evaluate novel technologies.

Update on the pharmacogenomics of pain management.

Pharmacogenomics is the study of genetic variants that impact drug effects through changes in a drug's pharmacokinetics and pharmacodynamics. Pharmacogenomics is being integrated into clinical pain management practice because variants in individual genes can be predictive of how a patient may respond to a drug treatment. Pain is subjective and is considered challenging to treat. Furthermore, pain patients do not respond to treatments in the same way, which makes it hard to issue a consistent treatment regimen for all pain conditions. Pharmacogenomics would bring consistency to the subjective nature of pain and could revolutionize the field of pain management by providing personalized medical care tailored to each patient based on their gene variants. Additionally, pharmacogenomics offers a solution to the opioid crisis by identifying potentially opioid-vulnerable patients who could be recommended a nonopioid treatment for their pain condition. The integration of pharmacogenomics into clinical practice creates better and safer healthcare practices for patients. In this article, we provide a comprehensive history of pharmacogenomics and pain management, and focus on up to date information on the pharmacogenomics of pain management, describing genes involved in pain, genes that may reduce or guard against pain and discuss specific pain management drugs and their genetic correlations.

Tissue preservation with mass spectroscopic analysis: Implications for cancer diagnostics.

Surgical intervention is a common treatment modality for localized cancer. Post-operative analysis involves evaluation of surgical margins to assess whether all malignant tissue has been resected because positive surgical margins lead to a greater likelihood of recurrence. Secondary treatments are utilized to minimize the negative effects of positive surgical margins. Recently, in Science Translational Medicine, Zhang et al describe a new mass spectroscopic technique that could potentially decrease the likelihood of positive surgical margins. Their nondestructive in vivo tissue sampling leads to a highly accurate and rapid cancer diagnosis with great precision between healthy and malignant tissue. This new tool has the potential to improve surgical margins and accelerate cancer diagnostics by analyzing biomolecular signatures of various tissues and diseases.

A sensitive and rapid ultra high-performance liquid chromatography with tandem mass spectrometric assay for the simultaneous quantitation of cyclophosphamide and the 4-hydroxycyclophosphamide metabolite in human plasma.

Analysis of cyclophosphamide (CP) and its metabolite, 4-hydroxycyclophosphamide (4OHCP), in a single assay has the ability to improve sampling techniques benefitting both the patients who are receiving the drug and the clinicians drawing samples. Due to instability in plasma (t1/2 = 4 min), immediate stabilization of 4OHCP with phenylhydrazine is necessary upon sample draw. After stabilization, 4OHCP and the stable CP prodrug concentrations can be analytically measured to elucidate the pharmacokinetics, including half-life and exposure parameters (Cmax and AUC). For this purpose, a sensitive analytical method was developed to measure both the prodrug and active metabolite. A liquid-liquid extraction recovered the analytes prior to analysis with an ultra HPLC-MS/MS. A Thermo Scientific™ Hypersil™ BDS C18, 2.1 × 100 mm, 3.0 µm column was used for compound separation. Mass transitions for CP (m/z 261.0 ➔ 140.0), the internal standard d4-CP (m/z 265.0 ➔ 140.0), 4OHCP (m/z 367.3 ➔ 147.1), and the internal standard AZD7451 (m/z 383.4 ➔ 341.1) were monitored over a calibration range of 34.24-34,240 ng/mL and 3.424-3424 ng/mL for CP and 4OHCP, respectively. Each calibration range proved accurate (<15% deviation) and precise (<15% RSD) for the desired compound. Using this method, CP and 4OHCP plasma levels can be measured in clinical samples from patients receiving this therapy.

Reactive astrocytic S1P3 signaling modulates the blood-tumor barrier in brain metastases.

Brain metastases are devastating complications of cancer. The blood-brain barrier (BBB), which protects the normal brain, morphs into an inadequately characterized blood-tumor barrier (BTB) when brain metastases form, and is surrounded by a neuroinflammatory response. These structures contribute to poor therapeutic efficacy by limiting drug uptake. Here, we report that experimental breast cancer brain metastases of low- and high permeability to a dextran dye exhibit distinct microenvironmental gene expression patterns. Astrocytic sphingosine-1 phosphate receptor 3 (S1P3) is upregulated in the neuroinflammatory response of the highly permeable lesions, and is expressed in patients' brain metastases. S1P3 inhibition functionally tightens the BTB in vitro and in vivo. S1P3 mediates its effects on BTB permeability through astrocytic secretion of IL-6 and CCL2, which relaxes endothelial cell adhesion. Tumor cell overexpression of S1P3 mimics this pathway, enhancing IL-6 and CCL-2 production and elevating BTB permeability. In conclusion, neuroinflammatory astrocytic S1P3 modulates BTB permeability.