A phase 1, dose-escalation study of PF-06664178, an anti-Trop-2/Aur0101 antibody-drug conjugate in patients with advanced or metastatic solid tumors.

Purpose and Methods Trop-2 is a glycoprotein over-expressed in many solid tumors but at low levels in normal human tissue, providing a potential therapeutic target. We conducted a phase 1 dose-finding study of PF-06664178, an antibody-drug conjugate that targets Trop-2 for the selective delivery of the cytotoxic payload Aur0101. The primary objective was to determine the maximum tolerated dose and recommended phase 2 dose. Secondary objectives included further characterization of the safety profile, pharmacokinetics and antitumor activity. Eligible patients were enrolled and received multiple escalating doses of PF-06664178 in an open-label and unblinded manner based on a modified continual reassessment method. Results Thirty-one patients with advanced or metastatic solid tumors were treated with escalating doses of PF-06664178 given intravenously every 21 days. Doses explored ranged from 0.15 mg/kg to 4.8 mg/kg. Seven patients experienced at least one dose limiting toxicity (DLT), either neutropenia or rash. Doses of 3.60 mg/kg, 4.2 mg/kg and 4.8 mg/kg were considered intolerable due to DLTs in skin rash, mucosa and neutropenia. Best overall response was stable disease in 11 patients (37.9%). None of the patients had a partial or complete response. Systemic exposure of PF-06664178 increased in a dose-related manner. Serum concentrations of free Aur0101 were substantially lower than those of PF-06664178 and total antibody. No correlation of Trop-2 expression and objective response was observed, although Trop-2 overexpression was not required for study entry. The intermediate dose of 2.4 mg/kg appeared to be the highest tolerated dose, but this was not fully explored as the study was terminated early due to excess toxicity. Conclusion PF-06664178 showed toxicity at high dose levels with modest antitumor activity. Neutropenia, skin rash and mucosal inflammation were dose limiting toxicities. Findings from this study may potentially aid in future antibody drug conjugate design and trials.

A Phase 1 Dose-Escalation Study of PF-06671008, a Bispecific T-Cell-Engaging Therapy Targeting P-Cadherin in Patients With Advanced Solid Tumors.

P-cadherin is a cell-cell adhesion molecule that is overexpressed in several solid tumors. PF-06671008 is a T-cell-redirecting bispecific antibody that engages both P-cadherin on tumors and CD3ϵ on T cells and induces antitumor activity in preclinical models. We conducted a phase 1, open-label, first-in-human, dose-escalation study to characterize the safety and tolerability of PF-06671008, towards determining the recommended phase 2 dose. Adult patients with treatment-refractory solid tumors received PF-06671008 (1.5-400 ng/kg) as a weekly intravenous (IV) infusion on a 21-day/3-week cycle. Parallel cohorts evaluated dosing via subcutaneous injection (SC) or an IV-prime dose. Of the 27 patients enrolled in the study, 24 received PF-06671008 IV in escalating doses, two received SC, and one IV-prime. A dose-limiting toxicity of cytokine release syndrome (CRS) occurred in the 400-ng/kg IV group, prompting evaluation of SC and IV-prime schedules. In all, 25/27 patients who received PF-06671008 reported at least one treatment-related adverse event (TRAE); the most common were CRS (21/27), decreased lymphocyte count (9/27), and hypophosphatemia (8/27). Seven patients permanently discontinued treatment due to adverse events and no treatment-related deaths occurred. Cytokine peak concentrations and CRS grade appeared to positively correlate with Cmax. Although the study was terminated due to limited antitumor activity, it provides important insights into understanding and managing immune-related adverse events resulting from this class of molecules. Clinical Trial Registration: URL: https://clinicaltrials.gov/ct2/show/NCT02659631, ClinicalTrials.gov Identifier: NCT02659631.

The evolution of cyclin dependent kinase inhibitors in the treatment of cancer.

Introduction: The cell cycle cyclin-dependent kinases (CDKs) play a critical role in controlling the transition between cell cycle phases, as well as cellular transcription. Aberrant CDK activation is common in cancer, and deregulation of the cell cycle a key hallmark of cancer. Although CDK4/6 inhibitors are now a standard-of-care option for first- and second-line HR+/HER2- metastatic breast cancer, resistance inevitably limits their clinical benefit.Areas covered: Early pan-CDK inhibitors targeted the cell cycle and RNA polymerase II phosphorylation, but were complicated by toxicity, providing a rationale and need for the development of selective CDK inhibitors. In this review, we highlight selected recent literature to provide a narrative review summarizing the current CDK inhibitor therapeutic landscape. We detail the challenges associated with targeting CDKs for the treatment of breast and other cancers and review emerging biomarkers that may aid response prediction. We also discuss the risk-benefit ratio for CDK therapy and explore promising combination approaches.Expert opinion: Although CDK inhibitors may stem the proliferation of cancer cells, resistance remains an issue, and currently there are limited biomarkers to predict response to therapy. Ongoing research investigating CDK inhibitors in cancer is of paramount importance to define appropriate and effective treatment regimens.

Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks.

The vanilloid receptor TRPV1 is a homotetrameric, non-selective cation channel abundantly expressed in the nociceptors (c-fibers). TRPV1 is considered as a highly validated pain target because, i) its agonists such as capsaicin cause desensitization of TRPV1 channels that relieves pain behaviors in preclinical species, and ii) its antagonists relieve pain behaviors in rodent models of inflammation, osteoarthritis, and cancer. Hence, both agonists and antagonists of TRPV1 are being evaluated as potential analgesics in clinical trials. Clinical trial results of TRPV1 agonists such as resiniferatoxin in interstitial cystitis, NGX 4010 in post-herpetic neuralgia, and 4975 (Adlea) in osteoarthritis, bunionectomy, and Morton's neuroma have been reported. Similarly, clinical trial results of TRPV1 antagonists such as SB-705498 and AMG 517 have also been published recently. Overall, some molecules (e.g., capsaicin) demonstrated potential analgesia in certain conditions (postsurgical pain, postherpetic neuralgia, pain in diabetic neuropathy, osteoarthritis, bunionectomy, and Morton's neuroma), whereas others fell out of the clinic due to on-target liabilities or failed to demonstrate efficacy. This review summarizes recent advances and setbacks of TRPV1 agonists and antagonists in the clinic and predicts future directions.

Model-Based Characterization of the Pharmacokinetics, Target Engagement Biomarkers, and Immunomodulatory Activity of PF-06342674, a Humanized mAb Against IL-7 Receptor-α, in Adults with Type 1 Diabetes.

IL-7 receptor-α (IL-7Rα) blockade has been shown to reverse autoimmune diabetes in the non-obese diabetic mouse by promoting inhibition of effector T cells and consequently altering the balance of regulatory T (Treg) and effector memory (TEM) cells. PF-06342674 is a humanized monoclonal antibody that binds to and inhibits the function of IL-7Rα. In the current phase 1b study, subjects with type 1 diabetes (T1D) received subcutaneous doses of either placebo or PF-06342674 (1, 3, 8 mg/kg/q2w or 6 mg/kg/q1w) for 10 weeks and were followed up to 18 weeks. Nonlinear mixed effects models were developed to characterize the pharmacokinetics (PK), target engagement biomarkers, and immunomodulatory activity. PF-06342674 was estimated to have 20-fold more potent inhibitory effect on TEM cells relative to Treg cells resulting in a non-monotonic dose-response relationship for the Treg:TEM ratio, reaching maximum at ~ 3 mg/kg/q2w dose. Target-mediated elimination led to nonlinear PK with accelerated clearance at lower doses due to high affinity binding and rapid clearance of the drug-target complex. Doses ≥ 3 mg/kg q2w result in sustained PF-06342674 concentrations higher than the concentration of cellular IL-7 receptor and, in turn, maintain near maximal receptor occupancy over the dosing interval. The results provide important insight into the mechanism of IL-7Rα blockade and immunomodulatory activity of PF-06342674 and establish a rational framework for dose selection for subsequent clinical trials of PF-06342674. Furthermore, this analysis serves as an example of mechanistic modeling to support dose selection of a drug candidate in the early phases of development.

Analgesic efficacy of peripheral kappa-opioid receptor agonist CR665 compared to oxycodone in a multi-modal, multi-tissue experimental human pain model: selective effect on visceral pain.

BACKGROUND: Peripherally selective opioids may be beneficial in visceral pain management due to absence of centrally mediated side effects. The objectives of this study were: (1) to assess the effects of a peripherally selective tetrapeptide kappa-opioid receptor agonist, CR665, on experimental pain from multi-modal stimulation of skin, muscle, and viscera, and (2) contrast these effects with those of oxycodone (centrally acting opioid). METHODS: The study was designed as a single-center, single-dose, randomized, double-blind, placebo and active-controlled, double-dummy, three-way, crossover study in healthy males. Subjects received the following treatments in randomized order: (1) CR665 (0.36 mg/kg) administered intravenously over 1 h, (2) oxycodone (15 mg) administered orally, and (3) placebo administered intravenously and orally. The following pain tests were used: (1) cutaneous pinch pain tolerance threshold, (2) pressure pain detection and tolerance thresholds, (3) cuff pressure pain tolerance threshold, and (4) pain rating thresholds to distension and thermal stimulation of the esophagus. Measurements were performed before dosing and at 30, 60, and 90 min after dosing. RESULTS: Compared to placebo, oxycodone elevated cutaneous pinch pain tolerance (P < 0.001) and cuff pressure pain tolerance threshold (P < 0.001), as well as pain rating thresholds (visual analogue scale = 7) to esophageal distension (P < 0.001) and thermal stimulation (P < 0.002). Compared to placebo, CR665 significantly increased the pain rating threshold to esophageal distension (P < 0.005) but reduced the pain tolerance threshold to skin pinching (P = 0.007). CONCLUSION: CR665 had a selective effect on visceral pain. Oxycodone exhibited a generalized effect, elevating thresholds for cutaneous, deep somatic, and visceral pain stimulation.

Use of a lidocaine patch in the management of postsurgical neuropathic pain in patients with cancer: a phase III double-blind crossover study (N01CB).

OBJECTIVE: Current therapies often have limited efficacy and untenable side effects when used to treat persistent incisional pain following cancer-related surgery. Lidocaine patches reduce neuropathic pain from herpes zoster but their benefits for persistent cancer-related postsurgical incisional pain remain unclear. STUDY DESIGN: Multicenter, double-blind, randomized, two-period crossover trial. MATERIALS AND METHODS: Twenty-eight cancer patients with postsurgical incisional pain were randomly assigned to receive either lidocaine patches followed by placebo patches or the reverse. Each study period lasted 4 weeks. Patches were applied daily upon waking and left in place for a maximum of 18 h. The primary outcome measure, an 11-point pain intensity rating scale, was administered weekly. Secondary outcomes were administered weekly (Brief Pain Inventory-Short Form(BPI-SF), Subject Global Impression of Change) and at the end of each study period (Short Form-Magill Pain Questionnaire, Linear Analogue Self Assessment Scale, Neuropathy Pain Scale, Pain Catastrophizing Scale, Profile of Mood States Short Form). RESULTS: Twenty-one patients completed the first period and 18 completed their crossover second phase. No significant intergroup differences were detected in pain intensity ratings. Few secondary end points were significantly different when subjects used the lidocaine versus placebo patches. BPI-SF interference scores were lower in patients using the lidocaine patch during the first study period, including several scores that achieved statistical significance, general activity (p = 0.02), work (p = 0.04), and relations with others (p = 0.02). CONCLUSION: Lidocaine patch use did not significantly reduce pain intensity ratings or the majority of related secondary end points in cancer patients with persistent incisional pain.

Improving attribution of adverse events in oncology clinical trials.

Attribution of adverse events (AEs) is critical to oncology drug development and the regulatory process. However, processes for determining the causality of AEs are often sub-optimal, unreliable, and inefficient. Thus, we conducted a toxicity-attribution workshop in Silver Springs MD to develop guidance for improving attribution of AEs in oncology clinical trials. Attribution stakeholder experts from regulatory agencies, sponsors and contract research organizations, clinical trial principal investigators, pre-clinical translational scientists, and research staff involved in capturing attribution information participated. We also included patients treated in oncology clinical trials and academic researchers with expertise in attribution. We identified numerous challenges with AE attribution, including the non-informative nature of and burdens associated with the 5-tier system of attribution, increased complexity of trial logistics, costs and time associated with AE attribution data collection, lack of training in attribution for early-career investigators, insufficient baseline assessments, and lack of consistency in the reporting of treatment-related and treatment-emergent AEs in publications and clinical scientific reports. We developed recommendations to improve attribution: we propose transitioning from the present 5-tier system to a 2-3 tier system for attribution, more complete baseline information on patients' clinical status at trial entry, and mechanisms for more rapid sharing of AE information during trials. Oncology societies should develop recommendations and training in attribution of toxicities. We call for further harmonization and synchronization of recommendations regarding causality safety reporting between FDA, EMA and other regulatory agencies. Finally, we suggest that journals maintain or develop standardized requirements for reporting attribution in oncology clinical trials.

Hearing loss and cerebrospinal fluid pressure: case report and review of the literature.

A decrease in cerebrospinal fluid pressure may result in an endolymphatic hydrops through a patent cochlear aqueduct or through the fundus of the internal auditory canal. This hydrops typically leads to low-frequency sensorineural hearing loss. We describe the case of a man who presented with a subjective and objective hearing loss in addition to a headache 4 days after he had undergone a dural puncture. We treated him with a standard epidural blood patch. Immediately after treatment, his hearing improved and his headache resolved.

Precision of health-related quality-of-life data compared with other clinical measures.

To many clinicians, the assessment of health-related quality of life (HRQL) seems more art than science. This belief is due in part to the lack of formal training available to clinicians regarding HRQL measurement and interpretation. When HRQL is used systematically, it has been shown to improve patient-physician communication, clinical decision making, and satisfaction with care. Nevertheless, clinicians rarely use formal HRQL data in their practices. One major reason is unfamiliarity with the interpretation and potential utility of the data. This unfamiliarity causes a lack of appreciation for the reliability of data generated by formal HRQL assessment and a tendency to regard HRQL data as having insufficient precision for individual use. This article discusses HRQL in the larger context of health indicators and health outcome measurement and is targeted to the practicing clinician who has not had the opportunity to understand and use HRQL data. The concept and measurement of reliability are explained and applied to HRQL and common clinical measures simultaneously, and these results are compared with one another. By offering a juxtaposition of common medical measurements and their associated error with HRQL measurement error, we note that HRQL instruments are comparable with commonly used clinical data. We further discuss the necessary requirements for clinicians to adopt formal, routine HRQL assessment into their practices.

Percutaneous image-guided radiofrequency ablation of painful metastases involving bone: a multicenter study.

PURPOSE: Few options are available for pain relief in patients with bone metastases who fail standard treatments. We sought to determine the benefit of radiofrequency ablation (RFA) in providing pain relief for patients with refractory pain secondary to metastases involving bone. PATIENTS AND METHODS: Thirty-one US and 12 European patients with painful osteolytic metastases involving bone were treated with image-guided RFA using a multitip needle. Treated patients had > or = 4/10 pain and had either failed or were poor candidates for standard treatments such as radiation or opioid analgesics. Using the Brief Pain Inventory-Short Form, worst pain intensity was the primary end point, with a 2-unit drop considered clinically significant. RESULTS: Forty-three patients were treated (median follow-up, 16 weeks). Before RFA, the mean score for worst pain was 7.9 (range, 4/10 to 10/10). Four, 12, and 24 weeks following treatment, worst pain decreased to 4.5 (P <.0001), 3.0 (P <.0001), and 1.4 (P =.0005), respectively. Ninety-five percent (41 of 43 patients) experienced a decrease in pain that was considered clinically significant. Opioid usage significantly decreased at weeks 8 and 12. Adverse events were seen in 3 patients and included (1) a second-degree skin burn at the grounding pad site, (2) transient bowel and bladder incontinence following treatment of a metastasis involving the sacrum, and (3) a fracture of the acetabulum following RFA of an acetabular lesion. CONCLUSION: RFA of painful osteolytic metastases provides significant pain relief for cancer patients who have failed standard treatments.

Pancreatic cancer pain and its correlation with changes in tumor vasculature, macrophage infiltration, neuronal innervation, body weight and disease progression.

To begin to understand the relationship between disease progression and pain in pancreatic cancer, transgenic mice that develop pancreatic cancer due to the expression of the simian virus 40 large T antigen under control of the rat elastase-1 promoter were examined. In these mice precancerous cellular changes were evident at 6 weeks and these included an increase in: microvascular density, macrophages that express nerve growth factor and the density of sensory and sympathetic fibers that innervate the pancreas, with all of these changes increasing with tumor growth. In somatic tissue such as skin, the above changes would be accompanied by significant pain; however, in mice with pancreatic cancer, changes in pain-related behaviors, such as morphine-reversible severe hunching and vocalization only became evident at 16 weeks of age, by which time the pancreatic cancer was highly advanced. These data suggest that in mice as well as humans, there is a stereotypic set of pathological changes that occur as pancreatic cancer develops, and while weight loss generally tracks disease progression, there is a significant lag between disease progression and behaviors indicative of pancreatic cancer pain. Defining the mechanisms that mask this pain in early and mid-stage disease and drive the pain in late-stage disease may aid in earlier diagnosis, survival, and increased quality of life of patients with pancreatic cancer.

Patient, clinician, and population perspectives on determining the clinical significance of quality-of-life scores.

Despite the success of screening and treatment of major cancers in the United States, cancer remains a chronic condition dominated by symptoms and treatment-related adverse effects. Because of these often taxing symptoms and adverse effects, numerous studies have been conducted to document the effects of cancer diagnosis and treatment on the quality of life (QOL) of patients. But there has been limited investigation of the clinical significance of QOL scores. This article examines the clinical significance of QOL scores from 3 key perspectives: patients, clinicians, and the general population. The patient's perspective includes an evaluation of the size of difference in scores that individual patients can detect and regard as important. The clinician perspective relies on whether the clinician believes the patient's condition has stayed the same vs whether changes have occurred (decline or improvement). The population perspective represents a democratic process in which the input or votes of a community of people are used to determine if health state A is clinically significantly different from health state B. While many clinicians and researchers advocate for QOL to be defined from the patient's perspective, the reality is that QOL is often defined by clinicians in terms of observable events. Even when measures are used in which the patient identifies how his or her life has been affected, it is often the clinician who interprets the clinical importance of this information. The clinician's perspective has value in framing an experience within the context of what is usual for a group of individuals, and the population perspective provides inputs as to how society may use limited resources. However, we conclude that a more prominent role for the patient's QOL perspective is needed.

Effect of neurolytic celiac plexus block on pain relief, quality of life, and survival in patients with unresectable pancreatic cancer: a randomized controlled trial.

CONTEXT: Pancreatic cancer is an aggressive tumor associated with high mortality. Optimal pain control may improve quality of life (QOL) for these patients. OBJECTIVE: To test the hypothesis that neurolytic celiac plexus block (NCPB) vs opioids alone improves pain relief, QOL, and survival in patients with unresectable pancreatic cancer. DESIGN, SETTING, AND PATIENTS: Double-blind, randomized clinical trial conducted at Mayo Clinic, Rochester, Minn. Enrolled (October 1997 and January 2001) were 100 eligible patients with unresectable pancreatic cancer experiencing pain. Patients were followed up for at least 1 year or until death. INTERVENTION: Patients were randomly assigned to receive either NCPB or systemic analgesic therapy alone with a sham injection. All patients could receive additional opioids managed by a clinician blinded to the treatment assignment. MAIN OUTCOME MEASURES: Pain intensity (0-10 numerical rating scale), QOL, opioid consumption and related adverse effects, and survival time were assessed weekly by a blinded observer. RESULTS: Mean (SD) baseline pain was 4.4 (1.7) for NCPB vs 4.1 (1.8) for opioids alone. The first week after randomization, pain intensity and QOL scores were improved (pain intensity, P< or =.01 for both groups; QOL, P<.001 for both groups), with a larger decrease in pain for the NCPB group (P =.005). From repeated measures analysis, pain was also lower for NCPB over time (P =.01). However, opioid consumption (P =.93), frequency of opioid adverse effects (all P>.10), and QOL (P =.46) were not significantly different between groups. In the first 6 weeks, fewer NCPB patients reported moderate or severe pain (pain intensity rating of > or =5/10) vs opioid-only patients (14% vs 40%, P =.005). At 1 year, 16% of NCPB patients and 6% of opioid-only patients were alive. However, survival did not differ significantly between groups (P =.26, proportional hazards regression). CONCLUSION: Although NCPB improves pain relief in patients with pancreatic cancer vs optimized systemic analgesic therapy alone, it does not affect QOL or survival.

A population pharmacokinetic and pharmacodynamic study of a peripheral κ-opioid receptor agonist CR665 and oxycodone.

BACKGROUND: Peripherally acting opioids, particularly peripheral κ-opioid agonists, may be effective for treating visceral pain by activating receptors expressed on afferent nerves within the gut. OBJECTIVE: The objective of this study was to investigate the pharmacokinetic/pharmacodynamic profile of a novel peripherally selective κ-opioid agonist, CR665 (JNJ-38488502), and compare it to that of oxycodone, a non-selective brain-penetrant opioid. METHODS: In a randomized, placebo-controlled, double-blind, three-way crossover study, healthy male volunteers were administered CR665 (0.36 mg/kg, intravenous), oxycodone (15 mg, oral) or placebo (intravenous and oral), followed by assessment of visceral pain tolerance thresholds (VPTT) measured as volume of water (mL) in the bag placed on an oesophageal probe. Plasma drug concentration data were used to generate pharmacokinetic models, which were then used to fit the VPTT data using NONMEM(®) VI to generate population pharmacokinetic/pharmacodynamic models. RESULTS: CR665 kinetics were optimally fitted with a two-compartment model, while oxycodone kinetics were best described by a one-compartment model with transit compartment absorption feeding directly into the central compartment. For both drugs, the plasma concentration effects on VPTT were best fit by a direct linear model, i.e. without the concentration-analgesia delay characteristic of brain-penetrant opioids. The slope of oxycodone (0.089 mL per ng/mL) was steeper than that of CR665 (0.0035 mL per ng/mL) for the plasma drug concentration acting on the VPTT. CONCLUSION: The results are consistent with the peripheral selectivity of CR665, as well as the possibility that peripheral actions of oxycodone contribute to its visceral analgesic efficacy.

Efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled trial, N01C3.

BACKGROUND: Lamotrigine, an antiepileptic agent, has been reported as being effective in reducing symptoms of neuropathy associated with various etiologies. Based on such data, a multicenter double-blind, placebo-controlled, randomized trial was conducted to evaluate the effect of lamotrigine on pain and other neuropathic symptoms due to chemotherapy-induced peripheral neuropathy (CIPN). METHODS: Patients with symptomatic CIPN with symptom scores of either 1) >3 on a 0-10 Numerical Rating Scale (NRS) or 2) >1 on the 0-3 the Eastern Cooperative Oncology Group (ECOG) neuropathy scale (ENS) were eligible (higher numbers corresponding to greater severity of symptoms in both scales). Patients were randomly assigned to receive lamotrigine (target dose of 300 mg/day) or placebo for 10 weeks. Endpoints were measured biweekly. RESULTS: In all, 131 patients were enrolled. Both groups were well matched at baseline. Over the 10-week period of the trial, the average pain scores (NRS) for the lamotrigine and placebo arms declined in both arms, with no statistically significant difference noted between the changes in the 2 groups (0.3 and 0.5 unit reduction from baseline, respectively; P=.56). Similarly, decreases in the ENS with therapy were not statistically different (0.4 and 0.3, respectively; P=.3). Changes in other subjective symptom scales were also not found to be statistically different between the 2 groups. Toxicities were mild and similar in each group. CONCLUSIONS: The results suggest that lamotrigine is not effective for relieving neuropathic symptoms in patients because of CIPN.

Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy characterized by macrophage infiltration and injury to sensory neurons and their supporting cells.

Paclitaxel-induced peripheral neuropathy (PN) can be a significant problem for patients receiving chemotherapeutic regimens for the treatment of breast, ovarian, and lung cancer as PN can influence the quality of life and survivorship in these patients. To begin to understand the cellular changes that occur within the peripheral and central nervous system as PN develops, we intravenously infused rats with clinically relevant doses of paclitaxel. Ten days later, behavioral changes indicative of PN became evident that included mechanical allodynia, cold hyperalgesia, and deficits in ambulation/coordination. These behaviors were accompanied by increased expression of activating transcription factor 3 (ATF3; a marker of cellular injury) in a population of large>medium>small diameter sensory neurons, a population of satellite cells in the lumbar dorsal root ganglia (DRG) and in myelinating Schwann cells in the sciatic nerve. In addition, there was an increase in the expression of glial fibrillary acidic protein (GFAP) in DRG satellite cells and an increase in the number of CD68 positive activated macrophages within the DRG and peripheral nerve. Within lamina III-IV of the lumbar spinal cord, there was an increase in OX42 positive microglia. These data suggest that intravenous infusion of paclitaxel induces a peripheral neuropathy characterized by injury of neuronal and non-neuronal cells in the peripheral nervous system, macrophage activation in both the DRG and peripheral nerve, and microglial activation within the spinal cord. An understanding of the factors involved in the development and maintenance of PN may lead to mechanism based therapies that prevent/treat PN and thus improve the survival and quality of life of patients receiving chemotherapy.

Gabapentin for smoking cessation: a preliminary investigation of efficacy.

Gabapentin affects the glutamate and gamma amino butyric acid (GABA) neurotransmitters through which it may facilitate smoking abstinence. To obtain preliminary estimates of efficacy of gabapentin for smoking cessation, we conducted a single-arm, open-label study of gabapentin, 1,800-mg/day administered in three equal divided doses for 8 weeks. A total of 50 adult smokers were enrolled. All participants received a brief behavioral intervention at each medication visit. A total of 37 participants completed all follow-up assessments. At end-of-treatment the biochemically confirmed point-prevalence and prolonged smoking abstinence rates were 28% (95% CI=16%-42%) and 24% (95% CI=13%-38%), respectively. At 6 months, the biochemically confirmed point-prevalence and prolonged smoking abstinence rates were 20% (95% CI=10%-34%) and 16% (95% CI=7%-29%), respectively. Among subjects who continued to smoke and completed the follow-up assessments, the reported number of cigarettes smoked per day (mean+/-standard deviation) was significantly less than at baseline: -10.0+/-8.2 (p<.001). Adverse effects were minor and well tolerated. Our results suggest that gabapentin may increase smoking abstinence. An adequately powered randomized clinical trial assessing different doses of this drug against a placebo would be the reasonable next step.

Validation of the S-LANSS in the community setting.

The Self-Administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS), an assessment tool to determine if pain is predominantly neuropathic, has not been validated in a community setting. Previously identified residents of Olmsted County, Minnesota, with chronic pain were recruited using a stratified randomization process to increase the frequency of neuropathic pain in the study sample. Subjects completed the S-LANSS in mailed and telephone formats, and underwent clinical assessment to determine if a component of their pain was neuropathic. Sensitivity and specificity of the S-LANSS as compared to the clinical assessment were determined. Two hundred and five subjects participated in the study. Eighty-three subjects (40%) had a positive S-LANSS score in the mailed, as did 59 of 173 (34%) in the telephone format, with little inter-subject difference in scores (p=0.57). Clinical assessment identified a component of neuropathic pain in 37% of the sample (75/205). Compared to clinical assessment, sensitivity and specificity in the mailed S-LANSS were 57% (95% CI, 46-69%) and 69% (95% CI, 61-77%), respectively, and in the telephone S-LANSS were 52% (95% CI, 39-64%) and 78% (95% CI, 68-85%), respectively. The sensitivity and specificity of the S-LANSS in both formats were lower than the initial S-LANSS validation study. Differences in survey format and subject population could account for these differences, suggesting that the S-LANSS is best suited as a screening tool and its use to determine the prevalence of neuropathic pain in population studies should be viewed cautiously.

Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled, crossover trial (N00C3).

BACKGROUND: The antiepileptic agent, gabapentin, has been demonstrated to relieve symptoms of peripheral neuropathy due to various etiologies. On the basis of these data, a multicenter, double-blind, placebo-controlled, crossover, randomized trial was conducted to evaluate the effect of gabapentin on symptoms of chemotherapy-induced peripheral neuropathy (CIPN). METHODS: Patients with symptomatic CIPN who complained of 'average' daily pain scores of either 1) >/=4 on a 0-10 numerical rating scale (NRS); or 2) >/=1 on the 0-3 Eastern Cooperative Oncology Group neuropathy scale (ENS) were eligible (higher numbers indicate greater severity of symptoms in both scales). Patients were randomized to receive gabapentin (target dose, 2700 mg) or placebo for 6 weeks. Crossover occurred after a 2-week washout period. CIPN-related symptoms were evaluated weekly by questionnaires. Statistical methods followed established methods for crossover designs, including Student t tests to compare average intrapatient differences between treatments and linear models to adjust for potential concomitant covariates. RESULTS: There were 115 patients who were randomly assigned to the treatment or control arm. Both groups were well matched by symptoms at study entry. Changes in symptom severity were statistically similar between the 2 groups during the study. Adverse events were mild and similar in both groups. CONCLUSIONS: This trial failed to demonstrate any benefit to using gabapentin to treat symptoms caused by CIPN.