Cutaneous Squamous Cell Carcinoma Mimickers: Beware the Pruritic Papule on the Leg of an Older Female.

Background Correctly identifying cutaneous squamous cell carcinoma (cSCC) mimickers can be both clinically and histopathologically challenging. We present a series of patients with biopsy-proven cSCCs for whom multiple surgeries were avoided by assessing the clinical situation, recognizing an alternative diagnosis that pathologically mimics cSCC, and prescribing appropriate therapy for the underlying condition. Methodology Seven female patients presented for treatment of biopsy-proven cSCC affecting the lower leg. After further investigation, we observed that these women shared similar characteristics, including age ranging from the 5th to the 9th decade, often experiencing stress, exhibiting associated pruritus with diverse causes, having few or no previous skin cancers, and generally showing minimal photodamage. Results In all cases, surgery was deferred and patients demonstrated complete clinical response to therapies directed toward an alternative diagnosis. Repeat biopsies of treated lesions revealed no evidence of cSCC. Conclusions Not all histologically diagnosed cases of cSCC should be treated with surgery, and each patient should be worked up thoroughly to evaluate for an alternative diagnosis. Possible clinical and histologic cSCC mimickers include allergic contact dermatitis (ACD), stasis dermatitis, hypertrophic lichen planus (LP), and drug eruption, among others. In the described population, pruritic papules on the lower leg should prompt further investigation to prevent the morbidity associated with unnecessary surgery.

The Navicular Graft for Reconstructing Deep Alar Defects.

The reconstruction of deep nasal ala defects can be challenging. The often thick, sebaceous skin of the nose provides structural support helping maintain the ala shape and nasal patency; loss of this support may result in ala deformity and nasal vestibule collapse. Traditional full-thickness skin grafts of deep alar defects may result in depressed scars. We present a variation of the full-thickness skin graft to repair deeper alar defects, sculpting the graft into a boat-shaped or "navicular" form. This allows for sufficient volume restoration and good cosmesis while avoiding more extensive surgical repairs of the nasal ala. The navicular graft offers several advantages: the avoidance of more extensive procedures involving cartilage grafts and/or flaps, appropriate color/texture match, and volume restoration without pitting, notching, or retraction of nasal structures. In addition, no struts or bolsters are needed.

Excess active P13K rescues huntingtin-mediated neuronal cell death but has no effect on axonal transport defects.

High levels of oxidative stress is detected in neurons affected by many neurodegenerative diseases, including huntington's disease. Many of these diseases also show neuronal cell death and axonal transport defects. While nuclear inclusions/accumulations likely cause cell death, we previously showed that cytoplasmic axonal accumulations can also contribute to neuronal death. However, the cellular mechanisms responsible for activating cell death is unclear. One possibility is that perturbations in normal axonal transport alter the function of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-pathway, a signal transduction pathway that promotes survival/growth in response to extracellular signals. To test this proposal in vivo, we expressed active PI3K in the context of pathogenic huntingtin (HTT-138Q) in Drosophila larval nerves, which show axonal transport defects and neuronal cell death. We found that excess expression of active P13K significantly suppressed HTT-138Q-mediated neuronal cell death, but had no effect on HTT-138Q-mediated axonal transport defects. Expression of active PI3K also rescued Paraquat-mediated cell death. Further, increased levels of pSer9 (inactive) glycogen synthase kinase 3ß was seen in HTT-138Q-mediated larval brains, and in dynein loss of function mutants, indicating the modulation of the pro-survival pathway. Intriguingly, proteins in the PI3K/AKT-pathway showed functional interactions with motor proteins. Taken together our observations suggest that proper axonal transport is likely essential for the normal function of the pro-survival PI3K/AKT-signaling pathway and for neuronal survival in vivo. These results have important implications for targeting therapeutics to early insults during neurodegeneration and death.

Discovery of potent and selective inhibitors of calmodulin-dependent kinase II (CaMKII).

We hereby disclose the discovery of inhibitors of CaMKII (7h and 7i) that are highly potent in rat ventricular myocytes, selective against hERG and other off-target kinases, while possessing good CaMKII tissue isoform selectivity (cardiac γ/δ vs. neuronal α/ß). In vitro and in vivo ADME/PK studies demonstrated the suitability of these CaMKII inhibitors for PO (7h rat F = 73%) and IV pharmacological studies.

Standardized laboratory monitoring with use of isotretinoin in acne.

BACKGROUND: Laboratory monitoring for adverse effects to isotretinoin occurs with variability. Standardization of laboratory monitoring practices represents an opportunity to improve quality of care. OBJECTIVE: We sought to develop an evidence-based approach to laboratory monitoring of patients receiving isotretinoin therapy for acne. METHODS: We reviewed laboratory data from 515 patients with acne undergoing 574 courses of isotretinoin from March 2003 to July 2011. Frequency, timing, and severity of abnormalities were determined. RESULTS: Clinically insignificant leukopenia or thrombocytopenia occurred in 1.4% and 0.9% of patients, respectively. Elevated liver transaminases were detected infrequently and not significantly increased compared with baseline detection rates (1.9% vs 1.6% at baseline). Significant elevations occurred with triglyceride (19.3%) and cholesterol (22.8%) levels. The most severe abnormalities were grade 2 (moderate). Mean duration of treatment before abnormalities were detected was 56.3 days for hypertriglyceridemia, 61.9 days for alanine transaminitis, and 50.1 days for hypercholesterolemia. LIMITATIONS: This was a single-center experience examining variable isotretinoin laboratory monitoring practices. CONCLUSIONS: In healthy patients with normal baseline lipid panel and liver function test results, repeated studies should be performed after 2 months of isotretinoin therapy. If findings are normal, no further testing may be required. Routine complete blood cell count monitoring is not recommended.

Patient safety in dermatologic surgery: Part I. Safety related to surgical procedures.

Surgical procedures involve unique elements related to patient safety. One must be aware of potential complications and safety issues within the practice of dermatologic surgery. Developing a high level of competence in skin surgery will address some safety issues, while implementing protocols and redundancies provides systems-based correction for other safety issues. We provide an in-depth review of patient safety in dermatologic surgery. In particular, we highlight the most common safety issues and methods for reducing error.

Patient safety in procedural dermatology: Part II. Safety related to cosmetic procedures.

Cosmetic procedures are growing in popularity and are associated with unique risks. Considering potential complications and prioritizing patient safety will help practitioners improve outcomes of elective procedures. In part II of this continuing medical education article, we provide a comprehensive review of patient safety in cosmetic procedures, including medical and legal issues surrounding the supervision and training of physician extenders.

Disruption of axonal transport perturbs bone morphogenetic protein (BMP)--signaling and contributes to synaptic abnormalities in two neurodegenerative diseases.

Formation of new synapses or maintenance of existing synapses requires the delivery of synaptic components from the soma to the nerve termini via axonal transport. One pathway that is important in synapse formation, maintenance and function of the Drosophila neuromuscular junction (NMJ) is the bone morphogenetic protein (BMP)-signaling pathway. Here we show that perturbations in axonal transport directly disrupt BMP signaling, as measured by its downstream signal, phospho Mad (p-Mad). We found that components of the BMP pathway genetically interact with both kinesin-1 and dynein motor proteins. Thick vein (TKV) vesicle motility was also perturbed by reductions in kinesin-1 or dynein motors. Interestingly, dynein mutations severely disrupted p-Mad signaling while kinesin-1 mutants showed a mild reduction in p-Mad signal intensity. Similar to mutants in components of the BMP pathway, both kinesin-1 and dynein motor protein mutants also showed synaptic morphological defects. Strikingly TKV motility and p-Mad signaling were disrupted in larvae expressing two human disease proteins; expansions of glutamine repeats (polyQ77) and human amyloid precursor protein (APP) with a familial Alzheimer's disease (AD) mutation (APPswe). Consistent with axonal transport defects, larvae expressing these disease proteins showed accumulations of synaptic proteins along axons and synaptic abnormalities. Taken together our results suggest that similar to the NGF-TrkA signaling endosome, a BMP signaling endosome that directly interacts with molecular motors likely exist. Thus problems in axonal transport occurs early, perturbs BMP signaling, and likely contributes to the synaptic abnormalities observed in these two diseases.

Summertime scorcher: assessing and promoting sunscreen protection in an amusement park setting.

BACKGROUND/PURPOSE: Intense, intermittent exposure, the kind of exposure associated with attending an amusement park for example, is correlated with the development of basal cell carcinoma and melanoma. The goals of this study were to assess the use of the station by visitors and to identify opportunities to increase the utilization of the sunscreen station. METHODS: The study was a descriptive observational study of attendees at an amusement park in Pennsylvania. The study included a paper survey and observation of the station for frequency of use. RESULTS: The station was very infrequently used; observation showed that 0.9% (8/879) of attendees in proximity used the station. There were numerous suggestions from attendees about increased utilization by improved station signage and locations as well as station advertising. Surveys were collected from 283 attendees and 59% (n=165) had used sunscreen on the day of the study and 29% (n=81) reported typical sunscreen use as 'Never' or 'Rarely' used. Once visitors were made aware of the station, 76% (201/263) reported that they would utilize it. CONCLUSION: This study showed that sunscreen use at an amusement park can be improved, especially among men and young adults. Therefore, men and younger visitors need to be purposefully encouraged in advertising and marketing the sunscreen stations.

A case of inflammatory nonscarring alopecia associated with the tyrosine kinase inhibitor nilotinib.

IMPORTANCE: Nilotinib, a recently approved multitargeted tyrosine kinase inhibitor targeting the BCR-Abl translocation involved in chronic myelogenous leukemia, reportedly produces alopecia according to the package insert, but clinical and histologic descriptions of the alopecia are lacking. OBSERVATIONS: A 33-year-old woman with chronic myelogenous leukemia developed widespread alopecia involving scalp and body hair within weeks after starting nilotinib therapy. Biopsies revealed perifollicular lymphocytic inflammation and evidence of follicular injury but normal hair density, consistent with a nonscarring alopecia. CONCLUSIONS AND RELEVANCE: Nilotinib therapy may induce perifollicular inflammation and widespread persistent alopecia. We present the first clinical and histologic description of this potential adverse effect. Further investigation into the underlying mechanism of this adverse effect may produce insights into the hair growth cycle as well as potential therapeutic targets.

A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism.

PURPOSE: Given the complex tumor microenvironment, targeting multiple cellular components may be the most effective cancer treatment strategy. Therefore, we tested whether antiangiogenic and immune-based therapy might synergize by characterizing the activity of DC101, an antiangiogenic monoclonal antibody specific for vascular endothelial growth factor receptor-2 (VEGF-R2), alone and with HER-2/neu (neu)-targeted vaccination. EXPERIMENTAL DESIGN: Neu-expressing breast tumors were measured in treated nontolerant FVB mice and immune-tolerant neu transgenic (neu-N) mice. Neu-specific and tumor cell-specific immune responses were assessed by intracellular cytokine staining, ELISPOT, and CTL assays. RESULTS: DC101 decreased angiogenesis and increased tumor cell apoptosis. Although DC101 increased serum levels of the immunosuppressive cytokine VEGF, no evidence of systemic immune inhibition was detected. Moreover, DC101 did not impede the influx of tumor-infiltrating lymphocytes. In FVB mice, DC101 inhibited tumor growth in part through a T cell-dependent mechanism, resulting in both increased tumor-specific CD8(+) T cells and tumor regression. Combining DC101 with neu-specific vaccination accelerated tumor regression, augmenting the lytic activity of CD8(+) cytotoxic T cells. In tolerant neu-N mice, DC101 only delayed tumor growth without inducing frank tumor regression or antigen-specific T-cell activation. Notably, mitigating immune tolerance by inhibiting regulatory T cell activity with cyclophosphamide revealed DC101-mediated augmentation of antitumor responses in vaccinated neu-N mice. CONCLUSIONS: This is the first report of DC101-induced antitumor immune responses. It establishes the induction of tumor-specific T-cell responses as one consequence of VEGF-R2 targeting with DC101. These data support the development of multitargeted cancer therapy combining immune-based and antiangiogenic agents for clinical translation.