Beatrice Nardone

Mesotherapy for skin rejuvenation: assessment of the subepidermal low-echogenic band by ultrasound evaluation with cross-sectional B-mode scanning

ABSTRACT:  Skin‐targeted ultrasound is a noninvasive technique that has been extensively used to evaluate age‐related dermal changes, and the presence of a subepidermal low‐echogenic band (SLEB) has been related to chronic UVR exposure in several studies. Since SLEB echogenicity is photoage‐related, the aim of this study was to evaluate, through ultrasound imaging, the effects on skin photoaging of mesotherapy, a treatment approach currently used in cosmetic dermatology for skin rejuvenation. Twenty women (mean age: 46.7 range 40–60 years) with physical signs of moderate photoaging on the dorsum of the hands were enrolled and treated with multiple microinjections of hyaluronic acid (HA) salts of biotechnological origin (1.000 Kd) every week for 4 weeks. In all subjects, ultrasound evaluation was performed at each visit and 1 week after the last treatment to evaluate SLEB echogenicity changes during treatment. At the end of study, a statistically significant (p < 0.001) increase of SLEB echogenicity (with a mean increase of pixel numbers equal to 31.3%) was observed in 15 of 19 subjects who completed the study. Our preliminary study suggests that mesotherapy with HA may be an effective treatment for skin photoaging, as confirmed by ultrasound. Follow‐up investigations on larger series of patients are necessary to further evaluate the safety, effectiveness, and duration of effect of this possible therapeutic approach to skin photoaging.

The Tongue Enables Computer and Wheelchair Control for People with Spinal Cord Injury

Individuals with severe spinal cord injury control a computer and powered wheelchair by using a wireless tongue-operated assistive technology called the Tongue Drive System. Tying the Tongue to Motor Control Voluntary tongue motion may help people with limited upper limb mobility, such as those with high-level spinal cord injury, to access computers and to drive wheelchairs. The Tongue Drive System (TDS) is a wireless and wearable assistive technology that allows individuals with severe motor impairments to access their environments using voluntary tongue motion. Kim et al. report on a new study of TDS efficacy in patients with severe spinal cord injury. Two groups of able-bodied participants and a group of patients with spinal cord injury received a magnetic tongue barbell. Participants used the TDS during five to six testing sessions. Comparisons between the TDS and the keypad for the able-bodied groups and a sip-and-puff device (a traditional assistive technology) for those with tetraplegia were based on widely accepted measures of speed and accuracy. A combination of TDS flexibility and inherent human tongue abilities enabled individuals with severe motor impairments to access computers and drive wheelchairs more quickly but just as accurately as when using traditional assistive technologies. The Tongue Drive System (TDS) is a wireless and wearable assistive technology, designed to allow individuals with severe motor impairments such as tetraplegia to access their environment using voluntary tongue motion. Previous TDS trials used a magnetic tracer temporarily attached to the top surface of the tongue with tissue adhesive. We investigated TDS efficacy for controlling a computer and driving a powered wheelchair in two groups of able-bodied subjects and a group of volunteers with spinal cord injury (SCI) at C6 or above. All participants received a magnetic tongue barbell and used the TDS for five to six consecutive sessions. The performance of the group was compared for TDS versus keypad and TDS versus a sip-and-puff device (SnP) using accepted measures of speed and accuracy. All performance measures improved over the course of the trial. The gap between keypad and TDS performance narrowed for able-bodied subjects. Despite participants with SCI already having familiarity with the SnP, their performance measures were up to three times better with the TDS than with the SnP and continued to improve. TDS flexibility and the inherent characteristics of the human tongue enabled individuals with high-level motor impairments to access computers and drive wheelchairs at speeds that were faster than traditional assistive technologies but with comparable accuracy.

Histopathologic and Immunohistochemical Characterization of Rash to Human Epidermal Growth Factor Receptor 1 (HER1) and HER1/2 Inhibitors in Cancer Patients

Purpose: Human epidermal growth factor receptor (HER) 1 and HER 1/2 inhibitors have shown benefit against a wide range of solid tumors. However, their use is associated with rash in 40% to 90% of patients, which impacts quality of life and interrupts antineoplastic therapy. The pathologic characteristics of affected skin remain unclear, precluding development of rational therapies. The aim of this study was to evaluate differences in histologic and immunohistochemical alterations in rash caused by lapatinib, a dual HER1/2 inhibitor (HER1/2i), and the single HER1 inhibitors (HER1i) cetuximab, erlotinib, and panitumumab. Experimental Design: For each of the four drugs, skin biopsies were collected and analyzed from 8 patients with rash (n = 32). Blinded independent histologic analysis and automated measurement of 17 skin biomarkers involved in proliferation, differentiation, and inflammation were conducted. Results: Increased expression of pAKT and decreased dermal K16 and p27 for HER1/2i when compared with each of the HER1i were observed. In addition, decreased epidermal atrophy and follicular neutrophilic infiltrate were evidenced in the skin of patients on HER1/2i when compared with HER1i. Conclusions: We found a lower inhibition of epidermal kinetics and decreased inflammation in HER1/2i-induced rash. These findings underscore differences in skin toxicity as related to specificity of HER blockade, concordant with clinical tolerability and decreased severity of skin toxicity seen with the HER1/2i lapatinib compared with the HER1 inhibitors cetuximab, erlotinib, and panitumumab. Clin Cancer Res; 16(17); 4452–60. ©2010 AACR.

Adverse Event Reporting in Clinical Trials of Finasteride for Androgenic Alopecia A Meta-analysis

IMPORTANCE Two meta-analyses conclude that finasteride treatment of androgenic alopecia (AGA) is safe but do not assess quality of safety reporting. OBJECTIVE To assess safety reporting for clinical trial reports of finasteride for AGA. DATA SOURCES MEDLINE, ClinicalTrials.gov, and a clinical data repository for an academic medical center. STUDY SELECTION Published clinical trial reports for finasteride treatment of AGA. DATA EXTRACTION AND SYNTHESIS For each trial, we assessed quality of adverse event reporting, extracted the number and type of adverse events in treatment and placebo groups, and assessed duration of safety evaluation and adequacy of blinding. Two observers independently extracted the data; differences were resolved by consensus. We assessed generalizability in a large cohort of men prescribed finasteride, 1.25 mg/d or less, by assessing for eligibility in the finasteride-AGA pivotal trials. MAIN OUTCOMES AND MEASURES Quality was assessed as adequate, partially adequate, inadequate, or no events reported. We used funnel plots of the hazard ratio to assess bias. RESULTS Of 34 clinical trials, none had adequate safety reporting, 19 were partially adequate, 12 were inadequate, and 3 reported no adverse events. Funnel plots were asymmetric with a bias toward lower odds ratio for sexual adverse effects, suggesting systematic underdetection. No reports assessed adequacy of blinding, 18 (53%) disclosed conflicts of interest, and 19 (56%) received funding from the manufacturer. Duration of drug safety evaluation was 1 year or less for 26 of 34 trials (76%). Of 5704 men in the clinical data repository who were treated for AGA with finasteride, 1.25 mg/d or less, for AGA, only 31% met inclusion criteria for the pivotal trials referenced in the manufacturers full prescribing information and 33% took finasteride for more than 1 year. CONCLUSIONS AND RELEVANCE Available toxicity information from clinical trials of finasteride in men with AGA is very limited, is of poor quality, and seems to be systematically biased. In a cohort of men prescribed finasteride for routine treatment of AGA, most would have been excluded from the pivotal studies that supported US Food and Drug Administration approval for AGA. Published reports of clinical trials provide insufficient information to establish the safety profile for finasteride in the treatment of AGA.

Pediatric nephrogenic systemic fibrosis is rarely reported: a RADAR report

BackgroundNephrogenic systemic fibrosis is a fibrosing disorder associated with exposure to gadolinium-based contrast agents in people with severely compromised renal function.ObjectiveThe purpose of this study was to determine the reported number of cases of nephrogenic systemic fibrosis in children using three distinct publicly available data sources.Materials and methodsWe conducted systematic searches of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), the International Center for Nephrogenic Systemic Fibrosis Research (ICNSFR) registry and published literature from January 1997 through September 2012. We contacted authors of individual published cases to obtain follow-up data. Data sets were cross-referenced to eliminate duplicate reporting.ResultsWe identified 23 children with nephrogenic systemic fibrosis. Seventeen had documented exposure to gadolinium-based contrast agents. Six children had been reported in both the FAERS and the literature, four in the FAERS and the ICNSFR registry and five in all three data sources.ConclusionNephrogenic systemic fibrosis has been rarely reported in children. Although rules related to confidentiality limit the ability to reconcile reports, active pharmaco-vigilance using RADAR (Research on Adverse Drug events And Reports) methodology helped in establishing the number of individual pediatric cases within the three major data sources.

Pancreatitis in patients treated with brentuximab vedotin: a previously unrecognized serious adverse event

Background Brentuximab vedotin (BV) is a novel antibody drug conjugate consisting of an anti- CD30 IgG1 antibody, cAC10, linked to monomethylauristatin E, a potent inhibitor of microtubule polymerization. It is approved for treatment of relapsed classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) in the US (FDA; 8/2011) and Europe (EMA; 10/2012). Peripheral neuropathy was the most frequent treatment-related adverse event (AE) in phase II trials, and the most common Grade 3 or higher toxicity apart from cytopenias. Although abdominal pain has been observed in up to 25% of all patients, pancreatitis is a previously unrecognized AE. We now report 8 cases of BV-associated pancreatitis, 2 of them fatal. Methods Following a grade 5 AE from pancreatitis in a patient receiving single-agent BV on an ongoing clinical trial ([NCT01476410][1]), collaborating investigators examined their collective cases of pancreatitis associated with BV. Lymphoma specialists at other centers were solicited for additional events. IRB or Ethics Committee approval as required was obtained in all cases. AEs reported to the FDA Adverse Event Report Systems (FAERS) from 6/2011-7/2013 were also examined. Data was collected and analyzed through the Research on Adverse Drug Events and Reports Project. Immunohistochemical staining with the anti-CD30 antibody BER-H2 (DAKO) was performed on residual normal pancreas from one of the fatal cases and normal control pancreas. Results Eight cases of BV-associated pancreatitis were identified by collaborators, and one additional report with limited information was listed in FAERS. Demographic, treatment and AE information for the eight complete cases is detailed in [Table 1][2]. In all cases, BV was administered as a single agent. In seven cases, the dosing was 1.8 mg/kg every 21 days with a maximum of 180 mg; in one case, BV was administered weekly at 1.2 mg/kg (days 1,8,15, q 28). Two patients were retreated with BV after resolution of pancreatitis; one had no further evidence of pancreatitis and proceeded to a stem cell transplant, whereas the other patient, having recovered from Grade 4 pancreatitis, experienced a second episode (Grade 3). All patients demonstrated clinical evidence of pancreatitis as manifested by severe abdominal pain and nausea. In addition, all patients had biochemical and radiologic evidence of pancreatitis. Notably, no patient had an antecedent history of excess alcohol use or radiologic evidence of biliary pathology. Two patients developed progressive and fatal multiorgan dysfunction as a consequence of acute pancreatitis. An autopsy performed on one of the two fatalities showed evidence of acute necrotizing pancreatitis as the cause of death; diffuse pancreatic parenchymal necrosis and fat necrosis were seen but no cholelithiasis. Although the anti-CD30 antibody BER-H2 was previously reported to stain normal pancreas (BLOOD 1989 74:1678), routine immunohistochemical staining for CD30 on both the patient pancreas and normal pancreas controls were negative. View this table: Table 1 BV-associated pancreatitis (n = 8) Conclusion This is the first series describing pancreatitis as a rare, but serious and potentially fatal toxicity related to BV. Pancreatitis has been previously reported with other microtubule inhibitors such as taxanes and vinca alkaloids, but the mechanism, as with BV, remains unclear. Genetic factors that predispose to both acute and chronic pancreatitis have been reported and may underlie a susceptibility to this uncommon complication of treatment with BV. Clinicians prescribing BV should evaluate patients who present with abdominal pain for pancreatitis, and should consider pre-treatment biochemical assessments with serum lipase and/or amylase. Disclosures: Off Label Use: Brentuximab Vedotin is approved for relapsed, refractory Hodgkin Lymphoma in patients who have already had a transplant or are ineligible for one, or for patients with relapsed, refractory anaplastic large cell lymphoma. Patients treated on clinical trials or off label will be included in this presentation. Evens: Seattle Genetics : Consultancy, Honoraria. Fenske: Seattle Genetics: Consultancy. Hamlin: Seattle Genetics : Consultancy, Honoraria. Coiffier: Millennium Pharmaceuticals : Consultancy. Engert: Millennium Pharmaceuticals : Consultancy. Moskowitz: Seattle Genetics : Research Funding. Ghosh: Millennium Pharmaceuticals : Membership on an entity’s Board of Directors or advisory committees. Petrich: Seattle Genetics : Consultancy, Honoraria, Research Funding. Gordon: Seattle Genetics : Research Funding. Winter: Seattle Genetics : Research Funding. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01476410&atom=%2Fbloodjournal%2F122%2F21%2F4380.atom [2]: #T1

Anaphylaxis associated with gadolinium-based contrast agents: data from the Food and Drug Administration's Adverse Event Reporting System and review of case reports in the literature.

Objectives: To summarize reports of anaphylaxis associated with gadolinium-based contrast agents (GBCAs) reported to the Food and Drug Administrations Adverse Event Reporting System (FAERS), examine the safety signals of anaphylaxis from GBCAs, and perform a literature review of relevant case reports. Methods: FAERS (1/1988-8/2012) was searched using groups of preferred event terms for anaphylaxis combined with all drug names for GBCAs Signal detection involved determination of proportional reporting ratios (PRRs) and empirical Bayes geometric means (EBGM). Published case reports were identified through a Medline search (1/1988-7/2013). Results: There were 614 GBCA FAERS reports of anaphylaxis, resulting in a safety signal (PRR = 6.2, 95% confidence interval (CI) = 5.7 – 6.7; EBGM = 5.1 CI = 5.6 – 6.6). Among GBCAs, 43% were associated with gadopentetate dimeglumine (PRR = 4.9, CI = 4.3 – 5.5; EBGM = 4.8, CI = 4.3 – 5.4), 29% with gadobenate dimeglumine (PRR = 17.5, CI = 15.2 – 20.2; EBGM = 17.1, CI = 14.6 – 19.8) , and 17% with gadoteridol (PRR = 5.7, CI = 4.7 – 6.8; EBGM = 5.6, CI = 4.6 – 56.7). There were 14 anaphylaxis case reports in the literature. Conclusions: GBCAs used as medical imaging agents, can cause life-threatening or fatal anaphylaxis. There were differences in disproportionality of reporting between between agents. Although differences in numbers of reports of anaphylaxis reflect relative utilization rates of the various agents, disproportionality analyses (PRR, EBGM) disclose significant safety signals of anaphylaxis associated with most GBCAs.

Melanoma associated with tumour necrosis factor-α inhibitors: a Research on Adverse Drug events And Reports (RADAR) project

Tumour necrosis factor‐α inhibitors (TNFαIs) are used for treatment of inflammatory disorders. There is evidence linking these agents with occurrence of malignancies. For four out of five TNFαIs the Food and Drug Administration (FDA) label states, ‘melanoma has been reported in patients treated with these agents’.

Validation of International Classification of Disease Ninth Revision codes for atopic dermatitis

Evaluation of large‐scale data sets is needed to better understand the epidemiology, cost, and burden of atopic dermatitis (AD). We sought to validate the use of ICD‐9‐CM codes for identifying AD.

Life-threatening dermatologic adverse events in oncology.

The incidences of life-threatening toxicities such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are inconsistently reported. The potential association of anticancer agents with SJS or TEN has not been systematically investigated. We searched the literature (Ovid: 1950 to June 2013 and PubMed: 1948 to June 2013) using terms for SJS/TEN and anticancer therapies. Primary case reports, case series, and clinical trials were included. In addition, MedWatch, the Food and Drug Administration Adverse Event Reporting System (FAERS), was searched (1968 to August 2012) for SJS/TEN reports associated with anticancer therapies. Proportional reporting ratios (PRR>2, N>3), empirical Bayes geometric mean (EBGM>2, N>3), and lower 95% confidence interval (EBGM0.05>2) were used as thresholds to constitute a signal of association between SJS/TEN and anticancer drugs. There were 46 SJS and 37 TEN cases associated with 18 and 22 anticancer drugs in the literature, respectively. Among cases in the FAERS, significant signals were associated with SJS for bendamustine and with TEN for bendamustine, busulfan, chlorambucil, fludarabine, lomustine, and procarbazine. Several drugs reported in the published literature to be associated with SJS/TEN were not found to have significant signals in FAERS. Proactive pharmacovigilance to detect and define safety signals serves to aid oncology practitioners in the recognition of possible, yet uncommon, serious, and/or life-threatening skin reactions.