Pseudoxanthoma-elasticum-like changes on the soft palate.

Pseudoxanthoma elasticum (PXE) is an autosomal recessive genetic disorder characterized by aberrant fragmentation and calcification of elastic fibers, leading to characteristic cutaneous, ophthalmic, and cardiovascular manifestations. PXE demonstrates significant phenotypic variability; involvement of the oral mucosa may be the only clue to the diagnosis. Reports on mucous membrane involvement in PXE are scarce. Here, we present a case of PXE-like changes in the oral cavity. A 70-year-old male patient presented with a painless leukoplakic lesion on the soft palate. Biopsy revealed numerous degenerated fibers in the lamina propria. Verhoeff-van Gieson and von Kossa staining confirmed their identity as calcified elastic fibers. A histopathological diagnosis of PXE-like changes was made; the patient was referred to ophthalmology where angioid streaks were visualized fundoscopically. PXE-like changes in the absence of the characteristic genetic mutation have also been reported with or without systemic manifestations. Furthermore, PXE-like changes have been reported in up to 10% of oral biopsy specimens undertaken without clinical suspicion for PXE. Therefore, the significance of such changes in isolation is unclear. Clinicians and pathologists should be aware of the potential oral manifestations of PXE to facilitate prompt diagnosis and subspecialist referral.

Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study.

BACKGROUND: Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target identified in tumour-initiating cells and expressed in more than 80% of patients with small-cell lung cancer. We aimed to assess the safety and activity of rovalpituzumab tesirine in patients who progressed after one or more previous regimen. METHODS: We conducted a phase 1 open-label study at ten cancer centres in the USA. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed small-cell lung cancer or large-cell neuroendocrine tumours with progressive measurable disease (according to Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) previously treated with one or two chemotherapeutic regimens, including a platinum-based regimen. We assigned patients to dose-escalation or expansion cohorts, ranging from 0·05 mg/kg to 0·8 mg/kg rovalpituzumab tesirine intravenously every 3 weeks or every 6 weeks, followed by investigation of the dose schedules 0·3 mg/kg and 0·4 mg/kg every 6 weeks and 0·2 mg/kg every 3 weeks. Primary objectives were to assess the safety of rovalpituzumab tesirine, including the maximum tolerated dose and dose-limiting toxic effects. The primary activity endpoint was objective response by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT01901653. The study is closed to enrolment; this report focuses on the cohort with small-cell lung cancer. FINDINGS: Between July 22, 2013, and Aug 10, 2015, 82 patients were enrolled, including 74 patients with small-cell lung cancer and eight with large-cell neuroendocrine carcinoma, all of whom received at least one dose of rovalpituzumab tesirine. Dose-limiting toxic effects of rovalpituzumab tesirine occurred at a dose of 0·8 mg/kg every 3 weeks, including grade 4 thrombocytopenia (in two of two patients at that dose level) and grade 4 liver function test abnormalities (in one patient). The most frequent grade 3 or worse treatment-related adverse events in 74 patients with small-cell lung cancer were thrombocytopenia (eight [11%]), pleural effusion (six [8%]), and increased lipase (five [7%]). Drug-related serious adverse events occurred in 28 (38%) of 74 patients. The maximum tolerated dose of rovalpituzumab tesirine was 0·4 mg/kg every 3 weeks; the recommended phase 2 dose and schedule is 0·3 mg/kg every 6 weeks. At active doses of rovalpituzumab tesirine (0·2 mg/kg or 0·4 mg/kg every 3 weeks or 0·3 mg/kg or 0·4 mg/kg every 6 weeks), 11 (18%) of 60 assessable patients had a confirmed objective response. 11 (18%) of 60 assessable patients had a confirmed objective response, including ten (38%) of 26 patients confirmed to have high DLL3 expression (expression in 50% or more of tumour cells). INTERPRETATION: Rovalpituzumab tesirine shows encouraging single-agent antitumour activity with a manageable safety profile. Further development of rovalpituzumab tesirine in DLL3-expressing malignant diseases is warranted. FUNDING: Stemcentrx Inc.

Cocaine cardiovascular effects and pharmacokinetics after treatment with the acetylcholinesterase inhibitor donepezil.

BACKGROUND: In rodents, cholinesterase inhibitors can cause sustained decreases in the reinforcing effects of cocaine. Nonetheless, cocaine is metabolized by butyrylcholinesterase (BuChE), raising concerns that cholinesterase inhibition could increase its peripheral concentrations, perhaps augmenting toxicity. Although donepezil is approved for use in patients and selective for inhibiting acetylcholinesterase over BuChE, no studies have reported cocaine bioavailability in human subjects receiving donepezil. METHODS: Twelve cocaine-dependent veterans received three days of treatment with either oral placebo or 5 mg daily of donepezil, followed by cross-over to the opposite treatment. During both oral treatments, double-blind intravenous cocaine was administered at .0, .18, and .36 mg/kg in a laboratory setting, followed by determinations of heart rate, blood pressure, and plasma concentrations of cocaine and major metabolites. RESULTS: Intravenous cocaine produced dose-related increases in systolic blood pressure that were most pronounced over the initial 30 minutes after treatment. Oral donepezil attenuated drug-induced elevations of systolic blood pressure following low-dose cocaine (.18 mg/kg). No significant difference in blood pressure following treatment with placebo or donepezil after high-dose cocaine (.36 mg/kg). Peak values of blood pressure and heart rate were unaffected by donepezil. Plasma concentrations of cocaine and metabolites did not differ in donepezil- and placebo-treated participants. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: We conclude that donepezil can attenuate drug-induced increases in systolic blood pressure following low-dose cocaine, but does not otherwise modify the cardiovascular effects of intravenous cocaine. Clinically significant changes in cocaine bioavailability and cardiovascular effects do not occur following this dose of donepezil. (Am J Addict 2016;25:392-399).

Twin infant with lymphatic dysplasia diagnosed with Noonan syndrome by molecular genetic testing.

Noonan Syndrome is an autosomal dominant disorder characterized by short stature, congenital heart defects, developmental delay, dysmorphic facial features and occasional lymphatic dysplasias. The features of Noonan Syndrome change with age and have variable expression. The diagnosis has historically been based on clinical grounds. We describe a child that was born with congenital refractory chylothorax and subcutaneous edema suspected to be secondary to pulmonary lymphangiectasis. The infant died of respiratory failure and anasarca at 80 days. The autopsy confirmed lymphatic dysplasia in lungs and mesentery. The baby had no dysmorphic facial features and was diagnosed postmortem with Noonan syndrome by genomic DNA sequence analysis as he had a heterozygous mutation for G503R in the PTPN11 gene.

Individual predictors of the subjective effects of intravenous cocaine.

The subjective and reinforcing effects of addictive substances can vary greatly between individuals. This study compared the relative contributions of baseline drug use, craving, stressful life events, and social factors in determining the subjective effects of cocaine in individual participants. Twelve veterans meeting criteria for cocaine dependence were evaluated in a laboratory setting. Self-report of the subjective effects of intravenous cocaine was recorded following single- and double-blind, placebo-controlled injections. Increased positive subjective effects of cocaine, including drug-induced 'good' effects and the value of intravenous injections, were most strongly correlated with greater family and social dysfunction measured through the Addiction Severity Index (ASI). Social dysfunction was the strongest predictor of cocaine-induced euphoria, accounting for approximately one-half of its variability. Participants who were dissatisfied with their current marital status reported almost no 'bad' effects of cocaine but instead reported increased drug-induced 'high', euphoria, and injection value. Although further research is required to determine the generalizability of this association, our findings are parallel to recent preclinical results showing that social interaction can attenuate psychostimulant reward. Effects of substance abuse treatment that rely on improved social function may be mediated through changes in the brain's reinforcement system that modify the rewarding effects of cocaine.

Written emotional expression during recovery from cocaine dependence: group and individual differences in craving intensity.

We conducted a prospective, single-blind, parallel group, controlled trial to evaluate effects of written emotional expression in patients receiving intensive treatment for cocaine dependence in a residential-unit setting. Randomization to the emotional expression treatment produced changes in blood pressure and mood during writing sessions, possibly because of its ability to stimulate active coping behavior. At an initial follow-up visit, patients that had received written emotional expression reported lower values for craving intensity and were less likely to self-report use of cocaine. These results may indicate a therapeutic effect of written emotional expression during recovery from cocaine dependence.

Donepezil treatment and the subjective effects of intravenous cocaine in dependent individuals.

Acetylcholinesterase (AChE) inhibitors increase synaptic levels of acetylcholine (ACh) by inhibiting its breakdown. Donepezil is a reversible AChE inhibitor that is clinically available and relatively selective for inhibiting AChE but not other cholinesterases. Because AChE inhibitors have been shown to decrease the reinforcing effects of cocaine in animals, our hypothesis was that pretreatment with donepezil would attenuate the perceived value and other positive subjective effects of cocaine. We conducted a within-subject, double-blind, placebo-controlled, laboratory-based evaluation of the subjective effects produced by intravenous cocaine in human subjects receiving oral donepezil. Following three days of daily treatment with 5mg of donepezil or oral placebo, participants received intravenous placebo or cocaine (0.18 and 0.36 mg/kg). After a three-day washout period, participants were crossed over to the opposite oral treatment, which was followed by identical intravenous infusions. Donepezil was well-tolerated with only two drug-related adverse events reported that were mild and self-limiting. Treatment with donepezil increased ratings of 'any' and 'good' drug effect produced by low-dose cocaine, without modifying the response to high-dose cocaine. When collapsed across intravenous dose, treatment with donepezil decreased dysphoric effects and somatic symptoms, but did not modify the value of cocaine injections as determined by the Multiple Choice Questionnaire (MCQ). In summary, pretreatment with donepezil potentiated some measures for nonspecific and positive effects of low-dose cocaine. Across all intravenous treatments, participants receiving donepezil reported fewer somatic-dysphoric effects. Neither of these actions support the value of donepezil as a treatment for cocaine dependence.

Selective breeding for intravenous drug self-administration in rats: a pilot study.

Although the role of genetic factors in the response to drugs of abuse has been emphasized, no earlier studies have applied selective breeding to intravenous drug self-administration. Here we report the effects of six generations of selective breeding for rat lines with low or high levels of intravenous drug self-administration (LS and HS lines, respectively). Rats from the outbred founder population and the first selected generation were evaluated for intravenous self-administration of either morphine or cocaine. All subsequent generations were assessed for self-administration of cocaine, using a multifactorial score based on how rapidly self-administration behavior was acquired, levels of self-administration during acquisition, and the response to different doses of cocaine. All changes in cocaine self-administration that occurred in generations three through six were consistent with effects of selection, with most measures differing in sixth-generation LS and HS animals. Sixth-generation HS rats self-administered approximately five times more injections of low-dose cocaine than LS animals under fixed-ratio-5 (a schedule in which an injection is delivered after five lever presses). These findings support a role of genetic factors in influencing cocaine-reinforced behavior. Establishment of the LS and HS lines will allow future studies to evaluate the role of specific genetic factors that underlie these differences and may contribute to substance abuse disorders in humans.

Lidocaine patch 5 for carpal tunnel syndrome: how it compares with injections: a pilot study.

OBJECTIVES: A standard treatment option for mild-to-moderate carpal tunnel syndrome (CTS) is a local injection of anesthetic-corticosteroid, but this can be painful and may cause complications. This pilot clinical trial was designed to compare the safety and efficacy of daily applications of the lidocaine patch 5% to that of a single injection of 0.5 cc lidocaine 1% plus methylprednisolone acetate (Depo-Medrol) 40 mg. METHODS: In this randomized, parallel-group, open-label, single-center, active-controlled, prospective pilot study, participants aged 18-75 years with clinical/electrodiagnostic evidence of CTS were randomized to receive the lidocaine patch 5% or 1 injection of 0.5 cc lidocaine 1% plus Depo-Medrol 40 mg. Outcome assessments included the Brief Pain Inventory (measuring pain intensity, relief, and interference with quality of life, Patient and Global Clinical Impression of Improvement, Global Assessment of Treatment Satisfaction, and safety. RESULTS: Baseline characteristics of the 40 patients randomized to treatment with the lidocaine patch 5% (n=20) or injection (n=20) were similar between groups. After 4 weeks of treatment, patients in both groups reported significant changes (P<.05) in worst pain, average pain, and pain "right now." Composite interference scores, which are measures of how much patients' pain interfered with quality of life, also significantly improved in both treatment groups (patch, -13.9; injection, -16.7; P<.001 vs baseline for both groups). Eighty percent of patients in the lidocaine patch group and 59% of patients who received the injection reported being "satisfied" or "very satisfied," while investigators reported improvement in 88% of patients using the lidocaine patch and in 74% of those who received the injection. Both treatments were well tolerated, with treatment-related adverse events (AEs) reported in 3 patients in each group (15%). No systemic treatment-related AEs were observed with the lidocaine patch 5%. CONCLUSIONS: This pilot trial demonstrated that the lidocaine patch 5% was efficacious in reducing pain associated with CTS and was well tolerated. The lidocaine patch 5% may offer patients with CTS effective, noninvasive treatment for the management of their symptoms. Further controlled trials are warranted.