David Zloty

CXCR3/Ligands Are Significantly Involved in the Tumorigenesis of Basal Cell Carcinomas

Basal cell carcinoma (BCC) is the most common skin malignancy encountered worldwide. We hypothesized that CXC chemokines, small cytokines involved in inducing directed leukocyte chemotaxis, could play a key role in the modulation of BCC growth. In this study, quantitative RT-PCR revealed that the chemokines CXCL9, 10, 11, and their receptor CXCR3 were significantly upregulated by an average 22.6-fold, 9.2-fold, 26.6-fold, and 4.9-fold, respectively in BCC tissue samples as compared with nonlesional skin epithelium. Immunohistochemistry analysis revealed that CXCR3, CXCL10, and CXCL11, but not CXCL9, colocalized with cytokeratin 17 (K17) in BCC keratinocytes. In addition, CXCR3 and its ligands were expressed in cells of the surrounding BCC stroma. The chemokines and K17 were also expressed in cultured human immortalized HaCaT keratinocytes. Exposure of HaCaT cells or primary BCC-derived cells to CXCL11 peptides in vitro significantly increased cell proliferation. In primary BCC-derived cell cultures, addition of CXCL11 progressively selected for K17+/CXCR3+ co-expressing cells over time. The expression of CXCR3 and its ligands in human BCC keratinocytes, the enhancement of keratinocyte cell proliferation by CXCL11, and the homogeneity of K17+ BCC cells in human BCC-isolated cell population supported by CXCR3/CXCL11 signaling all suggest that CXCR3 and its ligands may be important autocrine and/or paracrine signaling mediators in the tumorigenesis of BCC.

MICROCYSTIC ADNEXAL CARCINOMA INVOLVING A LARGE PORTION OF THE FACE: WHEN IS SURGERY NOT REASONABLE?

Background We report a case of microcystic adnexal carcinoma (MAC) involving a large portion of the face, one of the largest of any MAC reported thus far in this area, and review the literature regarding the nature of the tumor and available treatments. We also review all of the reported cases of metastases and the possible role of radiation in the etiopathogenesis of this tumor. Objective To review the literature about what is known about therapy for MAC and what options are available to patients who have this disease. Materials and Methods Case report and review of the literature. Results Of the 274 cases of MAC thus far reported, there are 6 cases of metastases, only 1 of which resulted in death. Conclusion Mohs surgery should be the treatment of choice for this tumor; however, when extirpation entails sufficiently large morbidity, given the low rate of metastases and mortality, observation is a reasonable alternative.

Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE): a randomised, regimen-controlled, double-blind, phase 2 trial

BACKGROUND Vismodegib, a first-in-class Hedgehog-pathway inhibitor, is approved for use in adults with advanced basal-cell carcinoma. Patients with multiple basal-cell carcinomas, including those with basal-cell nevus (Gorlin) syndrome, need extended treatment. We assessed the safety and activity of two long-term intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas. METHODS In this randomised, regimen-controlled, double-blind, phase 2 trial, we enrolled adult patients with multiple basal-cell carcinomas, including those with basal-cell nevus syndrome, who had one or more histopathologically confirmed and at least six clinically evident basal-cell carcinomas. From a centralised randomisation schedule accessed via an interactive voice or web-based response system, patients were randomly assigned (1:1) to treatment group A (150 mg oral vismodegib per day for 12 weeks, then three rounds of 8 weeks of placebo daily followed by 12 weeks of 150 mg vismodegib daily) or treatment group B (150 mg oral vismodegib per day for 24 weeks, then three rounds of 8 weeks of placebo daily followed by 8 weeks of 150 mg vismodegib daily). Treatment assignment was stratified by diagnosis of basal-cell nevus syndrome, geographical region, and immunosuppression status. The primary endpoint was percentage reduction from baseline in the number of clinically evident basal-cell carcinomas at week 73. The primary analysis was by intention to treat. The safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01815840, and the study is ongoing. FINDINGS Between April 30, 2013, and April 9, 2014, 229 patients were randomly assigned treatment, 116 in treatment group A and 113 in treatment group B. The mean number of basal-cell carcinoma lesions at week 73 was reduced from baseline by 62·7% (95% CI 53·0-72·3) in treatment group A and 54·0% (43·6-64·4) in treatment group B. 216 (95%) of 227 patients included in the safety analysis had at least one treatment-emergent adverse event deemed to be related to study treatment (107 [94%] of 114 in treatment group A and 109 [97%] of 113 in treatment group B). The most common grade 3 or worse treatment-related adverse events were muscle spasms (four [4%] patients in treatment group A vs 12 [11%] in treatment group B), increased blood creatine phosphokinase (one [1%] vs four [4%]), and hypophosphataemia (zero vs three [3%]). Serious treatment-emergent events were noted in 22 (19%) patients in treatment group A and 19 (17%) patients in treatment group B. Four (2%) patients died from adverse events; one (pulmonary embolism in treatment group A) was possibly related to treatment. INTERPRETATION Both intermittent dosing schedules of vismodegib seemed to show good activity in long-term regimens in patients with multiple basal-cell carcinomas. Further study is warranted. FUNDING F Hoffmann-La Roche.

Non-melanoma Skin Cancer in Canada Chapter 5 Management of Squamous Cell Carcinoma

Background Squamous cell carcinoma (SCC) is the second-most common form of non-melanoma skin cancer (NMSC). Objective To provide guidance to Canadian health care practitioners regarding management of SCCs. Methods Literature searches and development of graded recommendations were carried out as discussed in the accompanying introduction (chapter 1 of the NMSC guidelines). Results SCCs are sometimes confined to the epidermis, but they can also invade nearby tissues and, in some cases, metastasize to neighbouring lymph nodes or other organs. This chapter discusses the natural history, staging, prognosis, and management of SCC—a tumour type that is less common but typically more aggressive than BCC. For this reason, margin control is strongly preferred in treating SCCs. Conclusions Although approaches such as cryosurgery and radiation therapy may be considered for some patients, surgical excision—sometimes coupled with radiation—remains the cornerstone of SCC management. Patients with high-risk SCC may also be considered for referral to an appropriate multidisciplinary clinic.

Non-melanoma Skin Cancer in Canada Chapter 3: Management of Actinic Keratoses:

Background Actinic keratosis (AK) and cheilitis (AC) are lesions that develop on photodamaged skin and may progress to form invasive squamous cell carcinomas (SCCs). Objective To provide guidance to Canadian health care practitioners regarding management of AKs and ACs. Methods Literature searches and development of graded recommendations were carried out as discussed in the accompanying introduction (chapter 1 of the NMSC guidelines). Results Treatment of AKs allows for secondary prevention of skin cancer in sun-damaged skin. Because it is impossible to predict whether a given AK will regress, persist, or progress, AKs should ideally be treated. This chapter discusses options for the management of AKs and ACs. Conclusions Treatment options include surgical removal, topical treatment, and photodynamic therapy. Combined modalities may be used in case of inadequate response. AKs are particularly common following the longterm immunosuppression in organ transplant patients, who should be monitored frequently to identify emerging lesions that require surgery.

Bilateral Type 1 Complex Regional Pain Syndrome After Local Nerve Blocks for Palmar Hyperhidrosis

Botulinum toxin type A (BTX-A) is a recognized treatment for the temporary relief of refractory palmar hyperhidrosis. Unfortunately, intradermal injection of BTX-A can be painful. Several modalities to reduce the pain of injection have consequently been devised. Peripheral nerve blockade with lidocaine before BTX-A treatment of palmar hyperhidrosis is a safe and effective method of pain relief. Anesthesia of the palm can be achieved by injecting 4 to 6 mL of 2% lidocaine without epinephrine subcutaneously around the superficial branches of the radial, median, and ulnar nerves. Use of a short, bevelled needle is recommended to reduce the risk of iatrogenic nerve injury. The risk of nerve injury when using a 30-gauge needle in a conscious patient who can provide feedback concerning nerve puncture is remote.

Use of a Patient and Observer Scar Assessment Scale to Evaluate the V‐Y Advancement Flap for Reconstruction of Medial Cheek Defects

BACKGROUND The V‐Y advancement flap (VYF) is not commonly used to reconstruct defects located on the medial cheek. The quantitative assessment of VYF for this indication has not been reported. In evaluation of surgical scarring, the Patient and Observer Scar Assessment Scale (POSAS) has been validated for use in burn and breast surgery scars, but its usefulness in dermatologic surgery has not been determined. OBJECTIVE To present our experience with the use of the POSAS to assess the success of VYF reconstruction for surgical defects on the medial cheek. METHODS AND MATERIALS Fourteen patients with medium to large (>5 cm2) medial cheek Mohs defects reconstructed using VYF were assessed. Final cosmetic and functional results were analyzed after a follow‐up of 6 months to 2 years (mean follow‐up 21 months) using the POSAS. RESULTS Observers using the POSAS gave a mean score for VYF reconstructions of 9.1 ± 2.3 (5 represents normal skin, 50 represents worst imaginable scar). Patients using the POSAS gave a mean score for VYF reconstructions of 10 ± 4 (6 representing normal skin, 60 representing worst imaginable scar). CONCLUSION VYF reconstruction of medium to large defects of the medial cheek is a useful option. The POSAS may be a helpful tool for evaluating reconstructive results in dermatologic surgery.

Tumor Detection After Inflammation or Fibrosis on Mohs Levels

BACKGROUND In Mohs micrographic surgery (MMS), many surgeons will take an additional level based solely on the presence of inflammation or fibrosis. OBJECTIVE To determine the frequency with which this occurs and parameters predicting tumor discovery on successive levels. MATERIALS AND METHODS A retrospective study was performed on 22,419 cases treated with MMS between 1996 and May 2011. The surgeons reviewed their own slides in cases where tumor was detected after a level was taken for inflammation or fibrosis. RESULTS An additional level was taken for inflammation or fibrosis in 6,233 cases (27.8%), resulting in tumor detection in 121 cases (1.9%). Additional levels were taken for inflammation in 66.6% and fibrosis in 63.0%. Fourteen collision tumors were identified and were preceded by inflammation in 71% of cases. DISCUSSION Factors that may predict the presence of tumor at subsequent levels include eccentrically placed or shallow first levels failing to completely encompass a previous surgical scar. The presence of dense inflammation may signal an adjacent collision tumor. CONCLUSION Taking an additional Mohs level when dense inflammation or fibrosis is present may be warranted to ensure complete tumor removal.

Results of a survey regarding perioperative antiseptic practices.

Background: Currently, there are many options available for perioperative antiseptic techniques for cutaneous surgery. However, there is a paucity of scientific evidence available to suggest which techniques are worthwhile and which are not. Objectives: To determine if there is any consensus among dermatologic surgeons as to which perioperative techniques are being used and which are not. Methods: A questionnaire regarding perioperative techniques was mailed to the 641 members of the American College of Mohs Surgery (ACMS). Results: Forty-one percent of those queried returned the questionnaire within the allotted time. Surgical caps and booties were the least used antiseptic techniques. Respondents tended to use antiseptic techniques less often for less invasive procedures and more often for more invasive procedures. Few people used surgical caps, surgical gowns, or booties for any procedure. Conclusions: Many traditional perioperative antiseptic techniques are not being performed by respondents. Calculated infection rates are very low for all queried procedures.

Expression of Endothelins and Their Receptors in Nonmelanoma Skin Cancers

Background: Endothelins are paracrine peptides with growth-promoting and vasoactive functions for a variety of cell types. Elevated activation of the endothelin signaling pathway induces cell proliferation and/or survival and is implicated in a variety of malignancies. Increased endothelin 1 was described in solar lentigines in previous reports, raising the possibility that the endothelin pathway may be of significance in keratinocyte proliferation-related disorders. However, detailed investigation on endothelins in skin malignancies is lacking. Objectives: This study aims to survey the expression of endothelins and their receptors in keratinocyte-derived benign and malignant tumors of the skin and to test the effects of endothelin inhibitors on the growth and survival of cultured keratinocytes. Methods: Quantitative polymerase chain reaction was used to measure the level of gene transcription of three endothelins (ET-1, −2, and −3) and two endothelin receptors (ETRA and ETRB). The genes with significant messenger ribonucleic acid (mRNA) expression abnormalities were confirmed with immunohistochemical analysis to examine expression differences at the protein levels. To analyze the effect of endothelin inhibitors on the keratinocyte growth and survival, keratinocytes were cultured in the presence of various concentrations of endothelin inhibitors and subjected to tetrazolium bromide assay to quantify the cell numbers over time. Results: ET-1 mRNA was found to be significantly up-regulated in seborrheic keratosis and basal cell carcinoma. However, no significant expression increase was found in actinic keratosis, Bowens disease, or squamous cell carcinoma. Immunohistochemical analysis of ET-1 peptide confirmed increased expression. In cultured keratinocytes, peptide inhibitors of the endothelin pathway resulted in a marked reduction in cell survival. Conclusion: The endothelin signaling pathway, especially ET-1, is activated in basoloid keratinocyte neoplasms of the skin, such as basal cell carcinoma and seborrheic keratosis. Blockade of this pathway can reduce cell survival in vitro. Therefore, endothelin inhibitors potentially offer a novel method for the treatment of some keratinocyte-derived skin tumors.