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An 18-year-old woman with an established history of neurofibromatosis type 1 (NF-1) presented for her 1-year dermatologic follow-up. Physical examination revealed two subcutaneous nodules on her right arm, axillary freckling, scattered café-au-lait macules (CALMs) on the trunk, and a 12 cm × 17 cm hyperpigmented rectangular region on her right flank (Figure 1). The pigmented patch contained numerous new CALMs that were morphologically consistent with CALMs identified on prior examinations; neither the patch nor the CALMs within it were present at prior examinations. Interestingly, the appearance of the patch and associated CALMs was preceded by a rectangular-shaped, second-degree thermal burn. On further questioning, the patient revealed that she had burned herself with hot water 4 months prior to her presentation in clinic, and noted the development of multiple CALMs within the skin area of her prior burn approximately 4 weeks after the incident. Of note, her left flank had sparsely scattered CALMs, which was consistent with her prior skin examinations (Figure 2). A depigmenting cream was to be applied to the rectangular pigmented patch; unfortunately, post-inflammatory hyperpigmentation from the burn and the adjoining lesions resulting from the Koebner phenomenon continue to be refractory to treatment.

Apremilast (Otezla®) is an oral small molecule phosphodiesterase 4 (PDE4) inhibitor approved for the treatment of psoriasis, psoriatic arthritis, and oral ulcers associated with Behçet’s disease. While PDE4 inhibition overall is mechanistically understood, the effect of apremilast on the innate immune response, particularly inflammasome activation, remains unknown. Here, we assessed the effect of apremilast in a psoriasis mouse model and primary human cells. Psoriatic lesion development in vivo was studied in K5.Stat3C transgenic mice treated with apremilast for 2 weeks, resulting in a moderate (2 mg/kg/day) to significant (6 mg/kg/day) resolution of inflamed plaques after 2-week treatment. Concomitantly, epidermal thickness dramatically decreased, the cutaneous immune cell infiltrate was reduced, and proinflammatory cytokines were significantly downregulated. Additionally, apremilast significantly inhibited lipopolysaccharide- or anti-CD3-induced expression of proinflammatory cytokines in peripheral mononuclear cells (PBMCs). Notably, inflammasome activation and secretion of IL-1β were not inhibited by apremilast in PBMCs and in human primary keratinocytes. Collectively, apremilast effectively alleviated the psoriatic phenotype of K5.Stat3 transgenic mice, further substantiating PDE4 inhibitor-efficiency in targeting key clinical, histopathological and inflammatory features of psoriasis. Despite lacking direct effect on inflammasome activation, reduced priming of inflammasome components upon apremilast treatment reflected the indirect benefit of PDE4 inhibition in reducing inflammation.

Hair transplantation in areas of scalp scars is a clinical challenge. However, by creating the visual illusion of central bulking with the use of peripherally transplanted curled chest hairs, cicatricial alopecia can perhaps be cosmetically improved. In a case of a 34-year-old affected man, this strategic procedure was implemented with positive results, as the transplantation was successful, the scar was far less noticeable, and the patient was satisfied with the results. The “pseudo-dense hair transplantation” method can be applied to similar patients, noting that a more succinct procedure will need to be elucidated for the varying etiologies of cicatricial alopecia.

Backgrounds Folate Hydrolase‐1 (FOLH1; PSMA) is a type II transmembrane protein, luminally expressed by solid tumour neo‐vasculature. Monoclonal antibody (mAb), J591, is a vehicle for mAb‐based brachytherapy in FOLH1+ cancers. Brachytherapy is a form of radiotherapy that involves placing a radioactive material a short distance from the target tissue (e.g., on the skin or internally); brachytherapy is commonly accomplished with the use of catheters, needles, metal seeds and antibody or small peptide conjugates. Herein, FOLH1 expression in primary (p) and metastatic (m) Merkel cell carcinoma (MCC) is characterized to determine its targeting potential for J591‐brachytherapy. Materials & Methods Paraffin sections from pMCC and mMCC were evaluated by immunohistochemistry for FOLH1. Monte Carlo simulation was performed using the physical properties of conjugated radioisotope lutetium‐177. Kaplan–Meier survival curves were calculated based on patient outcome data and FOLH1 expression. Results Eighty‐one MCC tumours were evaluated. 67% (54/81) of all cases, 77% (24/31) pMCC and 60% (30/50) mMCC tumours were FOLH1+. Monte Carlo simulation showed highly localized ionizing tracks of electrons emitted from the targeted neo‐vessel. 42% (34/81) of patients with FOLH1+/− MCC had available survival data for analysis. No significant differences in our limited data set were detected based on FOLH1 status (p = 0.4718; p = 0.6470), staining intensity score (p = 0.6966; p = 0.9841) or by grouping staining intensity scores (− and + vs. ++, +++, +++) (p = 0.8022; p = 0.8496) for MCC‐specific survival or recurrence free survival, respectively. Conclusions We report the first evidence of prevalent FOLH1 expression within MCC‐associated neo‐vessels, in 60‐77% of patients in a large MCC cohort. Given this data, and the need for alternatives to immune therapies it is appropriate to explore the safety and efficacy of FOLH1‐targeted brachytherapy for MCC. What's already known about this topic? We report the first evidence of prevalent folate hydrolase‐1 (FOLH1; also known as prostate‐specific membrane antigen) expression within MCC‐associated neovessels. What does this study add? Herein, FOLH1 expression in Merkel cell carcinoma neovasculature is validated, and the therapeutic mechanism of specific, systemic targeting of disseminated disease with antibody‐based brachytherapy, is defined.

Dermatofibrosarcoma protuberans (DFSP) is a rare, infiltrative, soft tissue tumor. It has a propensity for deep invasion but a low risk for distant metastasis. The classic presentation is a slowly progressive, painless, and erythematous to purpuric patch on the trunk or arms. A deep, subcutaneous punch biopsy or incisional biopsy should be performed for diagnosis in all suspected cases; wide undermining of the skin is to be avoided for minimizing the risk of tumor seeding and for retaining the feasibility of histopathologic examination of re-excisions. Histopathologic distinction of DFSP from dermatofibroma requires immunohistochemical assessment for CD34, factor XIIIa, nestin, apolipoprotein D, and cathepsin K. Management of this cutaneous sarcoma involves a multidisciplinary oncologic approach. Surgical excision is usually the first step in management. DFSP has a high propensity for local recurrence, even when surgical margins are negative; therefore, radiation therapy or rarely systemic therapy is recommended, especially for locally advanced or metastatic cases. The indolent nature of DFSP requires lifelong surveillance for recurrence; however, most recurrences occur within 3 years of the primary excision. The median time for the development of a local recurrence is estimated to be 32 months. An emerging theragnostic transmembrane receptor target, folate hydrolase-1 (FOLH1; prostate-specific membrane antigen), has been expressed in benign dermatofibromas and in high-grade sarcomatous phenotypes. These findings suggest that DFSP may also express FOLH1, which could allow for surveillance with FOLH1 PET/CT and antibody-mediated brachytherapy.

Treatment of refractory palmar-plantar vitiligo is particularly challenging because the skin in these regions has a limited supply of follicle-derived melanocytic stem cells. Autologous hair transplantation monotherapy is effective in some forms of vitiligo through the provision of melanocytic stem cells. CO2 laser followed by exposure to light (i.e., sunlight or narrow-band ultraviolet-B [nbUVB]) has independently shown to be an effective treatment strategy. Recently, it was found that the combination of hair transplantation and CO2 laser followed by nbUVB exposure had superior efficacy to either modality as monotherapy. Similar to CO2 laser, microneedling produces skin cell proliferation and releases pro-pigmentary cytokines. Given the important role of the cytokines in vitiliginous skin, microneedling may also be an effective therapeutic modality for refractory vitiligo. Herein, we conducted a pilot study to evaluate the efficacy of hair transplantation and CO2 laser or microneedling followed by nbUVB. Microneedling and fractional CO2 laser in combination with hair transplantation and nbUVB both demonstrated utility in the induction of repigmentation in refractory palmar-plantar vitiligo; however, a larger trial would be needed to determine a difference in treatment efficacy. Nonetheless, microneedling is cost-effective and requires minimal training; therefore, microneedling can be easily incorporated into standard dermatological practice.

Cancer cells can be selectively targeted by identifying and developing antibodies to specific antigens present on the cancer cell surface. Cytotoxic agents can be conjugated to these antibodies that bind to these cell surface antigens in order to significantly increase the therapeutic index of whichever cytotoxic agent is utilized. This approach of conjugating the cytotoxic drugs to antibodies to target specific surface antigens enhances the anti-tumor activity of antibodies and improves the tumor-to-normal tissue selectivity of chemotherapy. Critical parameters in the development of these antibody-drug conjugates include: 1) selection of most appropriate antigen, 2) the ability of an antibody to be internalized after binding to the antigen, 3) cytotoxic drug potency and 4) stability of the antibody-drug conjugate. For prostate cancer, prostate-specific membrane antigen (PSMA, also known as folate hydrolase-1) is the most validated theragnostic target to date. PSMA is overexpressed on the prostate cancer cell surface, which makes it an even better target for selective drug delivery through conjugated antibodies. Here, we review the PSMA-based antibody-drug conjugates for metastatic castration-resistance prostate cancer (mCRPC).

Prostate cancer is the most common non-cutaneous cancer in men in the United States and is the second most common cause of cancer deaths after lung cancer in men. Despite all advances in the field of prostate cancer imaging and treatment, currently, it is sub-optimally responsive to all available treatment options. Radioimmunotherapy with a monoclonal antibody (mAb), J591, has shown promising results in the treatment of prostate cancer. J591 is a deimmunized mAb that targets the extracellular domain of prostate-specific membrane antigen (PSMA), a surface-bound and internalizing glycoprotein that is upregulated in prostate cancer. Phase I/II clinical trials have shown accurate tumor targeting, biochemical and radiographic responses, and increased overall survival in patients with mCRPC with tolerable, predictable, and reversible myelotoxicity. Ongoing studies focus on improving the therapeutic index of radiolabeled J591. Herein, the literature on published clinical trials involving therapeutic J591 conjugated to b-emitter, lutetium-177 for mCRPC, is sequentially reviewed.

Psychological morbidity, sexuality, and health/system information have been identified as the highest areas of support needs in patients undergoing management of their prostate cancer (PCa). Management of a patient's sexual function prior to, during and after PCa radiotherapy requires multidisciplinary coordination of care between radiation oncologists, urologists, dermatologists, pharmacists, and psychiatrists. The finale of this three-part review provides a framework for clinicians to better understand the role of mental healthcare providers in the management of sexual toxicities associated with prostatic radiotherapy. The authors recommend that patients be referred for psychological evaluation and possibly to individual, couples or group general or cognitive behavioral sex therapy at the time of their PCa diagnosis, for a more specialized focus on management of sexual toxicities and sexual recovery. The importance and implications of the masculine self-esteem, sexual orientation, gender identification, cultural expectations, relationship status and patient education are reviewed. Well-informed patients tend to have a better quality of life outcomes compared to patients that take on a passive role in their cancer management.

Prostate cancer is the most common malignancy and the second leading cause of cancer-related death in men. Radiotherapy is a curative option that is administered via external beam radiation, brachytherapy, or in combination. Erectile, ejaculatory and orgasm dysfunction(s) is/are known potential and common toxicities associated with prostate radiotherapy. Our multidisciplinary team of physicians and/or scientists have written a three (3) part comprehensive review of the pathogenesis and management radiation-induced sexual dysfunction. Part I reviews pertinent anatomy associated with normal sexual function and then considers the pathogenesis of prostate radiation-induced sexual toxicities. Next, our team considers the associated radiobiological (including the effects of time, dose and fractionation) and physical (treatment planning and defining a novel Organ at Risk (OAR)) components that should be minded in the context of safe radiation treatment planning. The authors identify an OAR (i.e., the prostatic plexus) and provide suggestions on how to minimize injury to said OAR during the radiation treatment planning process.

Prostate cancer is the most common malignancy in men and the second leading cause of cancer-related death in men. Radiotherapy is a curative option that is administered via external beam radiation, brachytherapy, or in combination. Sexual dysfunction is a common toxicity following radiotherapy, similar to men undergoing radical prostatectomy, but the etiology is different. The pathophysiology of radiation-induced sexual dysfunction is multi-factorial, and the toxicity is a major cause of impaired quality of life among long-term prostate cancer survivors. Management of a patient's sexual function during and after radiotherapy requires multidisciplinary coordination of care between radiation oncology, urology, psychiatry, pharmacy, and dermatology. This review provides a framework for clinicians to better understand prostatic radiotherapy-induced sexual dysfunction diagnosis, evaluation, and a patient-centered approach to toxicity preventive strategies and management.

LESSONS LEARNED: Hyperfractionation of lutetium‐177 ((177)Lu)‐J591 for patients with metastatic castration‐resistant prostate cancer did not appear to have any additional advantage over the single dose (177)Lu‐J591 or fractionated two‐dose (177)Lu‐J591 therapy. Definite conclusions were challenging because of the small sample size of this study, and so further studies are needed to evaluate the viability of the hypothesis. On the basis of available data, a registration study of (177)Lu‐J591 (also known as TLX591) is planned and will use the two‐dose fractionation schedule (Telix Pharma Q3 2019 update https://telixpharma.com/news-media/). BACKGROUND: Phase I and II single‐dose studies of lutetium‐177 ((177)Lu)‐J591, a radio‐labeled antibody binding prostate‐specific membrane antigen (PSMA), demonstrated safety and efficacy with dose response. Modest dose fractionation of (177)Lu‐J591 (2 doses) has less myelosuppression per similar cumulative dose, allowing higher doses to be administered safely. We hypothesized that additional dose fractionation would allow a higher cumulative dose, potentially with less toxicity and more efficacy. METHODS: Men with progressive metastatic castration‐resistant prostate cancer and adequate organ function were enrolled. (177)Lu‐J591 was administered at 25 mCi/m(2) every 2 weeks until the emergence of related grade 2 toxicity. (177)Lu‐J591 imaging was performed and circulating tumor cell (CTC) counts were measured before and after treatment along with standard monitoring. RESULTS: Six subjects in a single cohort, with a median age of 68.6 years, were enrolled. Patients received three to six doses (cumulative 75−150 mCi/m(2)). Two (33%) patients had >30% prostate‐specific antigen (PSA) decline and three (50%) had CTC count decline. Two (33%) experienced grade (Gr) 4 neutropenia (without fever), three (50%) had Gr 4 thrombocytopenia (without hemorrhage), and two (33%) required platelet transfusions. Following hematological improvement, two patients developed worsening cytopenia during prostate cancer progression; bone marrow biopsies revealed infiltrative tumor replacing normal marrow elements without myelodysplasia. Targeting of known disease sites was seen on planar imaging in all. CONCLUSION: Hyperfractionation of (177)Lu‐J591 is feasible but does not seem to have significant advantages over the two‐dose fractionation regimen.

Purpose Infection by Human Herpes Viruses (HHV) types 1–3, are prevalent throughout the world. It is known that radiotherapy can reactivate HHVs, but it is unclear how and to what extent reactivations can interact with or affect radiotherapeutic efficacy, patient outcomes and mortality risk. Herein, we aim to summarize what is known about Herpes Simplex Virus (HSV)-1,2 and Varicella Zoster Virus (VZV) pathophysiology as it relates to tumor biology, radiotherapy, chemo-radiotherapy, diagnosis and management so as to optimize cancer treatment in the setting of active HHV infection. Our secondary aim is to emphasize the need for further research to elucidate the potential adverse effects of active HHV infection in irradiated tumor tissue and to design optimal management strategies to incorporate into cancer management guidelines. Materials and methods The literature regarding herpetic infection, herpetic reactivation, and recurrence occurring during radiotherapy and that regarding treatment guidelines for herpetic infections are reviewed. We aim to provide the oncologist with a reference for the infectious dangers of herpetic reactivation in patients under their care and well established methods for prevention, diagnosis, and treatment of such infections. Pain management is also considered. Conclusions In the radiotherapeutic setting, serologic assays for HSV-1 and HSV-2 are feasible and can alert the clinician to patients at risk for viral reactivation. RT-PCR is specific in identifying the exact viral culprit and is the preferred diagnostic method to measure interventional efficacy. It can also differentiate between herpetic infection and radionecrosis. The MicroTrak® HSV1/HSV2/VZV staining kit has high sensitivity and specificity in acute lesions, is also the most rapid means to confirm diagnosis. Herpetic reactivation and recurrences during radiotherapy can cause interruptions, cessations, or prolongations of the radiotherapeutic course, thus decreasing the biologically effective dose, to sub-therapeutic levels. Active HHV infection within the treatment volume results in increased tumor radio-resistance and potentially sub-therapeutic care if left untreated. Visceral reactivations may result in fatality and therefore, a high index of suspicion is important to identify these active infections. The fact that such infections may be mistaken for acute and/or late radiation effects, leading to less than optimal treatment decisions, makes knowledge of this problem even more relevant. To minimize the risk of these sequelae, prompt anti-viral therapy is recommended, lasting the course of radiotherapy.

Angiogenesis is critical for tumor growth and survival and involves interactions between cancer and endothelial cells. Prostate-specific membrane antigen (PSMA/FOLH1) is expressed in the neovasculature of several types of cancer. However, the study of neovascular PSMA expression has been impeded as human umbilical vein endothelial cell (HUVEC) cultures are PSMA-negative and both tumor xenografts and patient-derived xenograft (PDX) models are not known to express PSMA in their vasculature. Therefore, PSMA expression was examined in HUVECs, in vitro and in vivo, and we tested the hypothesis that cancer cell–HUVEC crosstalk could induce the expression of PSMA in HUVECs. Interestingly, conditioned media from several cancer cell lines induced PSMA expression in HUVECs, in vitro, and these lines induced PSMA, in vivo, in a HUVEC coimplantation mouse model. Furthermore, HUVECs in which PSMA expression was induced were able to internalize J591, a mAb that recognizes an extracellular epitope of PSMA as well as nanoparticles bearing a PSMA-binding ligand/inhibitor. These findings offer new avenues to study the molecular mechanism responsible for tumor cell induction of PSMA in neovasculature as well as the biological role of PSMA in neovasculature. Finally, these data suggest that PSMA-targeted therapies could synergize with antiangiogenic and/or other antitumor agents and provide a promising model system to test therapeutic modalities that target PSMA in these settings. Implications: Cancer cells are able to induce PSMA expression in HUVECs, in vitro and in vivo, allowing internalization of PSMA-specific mAbs and nanoparticles bearing a PSMA-binding ligand/inhibitor. Mol Cancer Res; 14(11); 1045–53. ©2016 AACR.

Background Acne vulgaris is a common dermatologic disease that causes significant social and psychological morbidity. Isotretinoin, as a vitamin A derivative, is the most effective agent in the treatment of acne. Evidence suggests that isotretinoin’s therapeutic function is independent of hormonal mediation; however, the effect of isotretinoin on serum androgens and precursor androgen levels in humans remains unclear. Objective Herein, we aim to investigate the effect of low-dose isotretinoin on androgen levels in women and postulate the role of concomitant anti-androgen therapy (e.g., spironolactone). Methods A total of 36 women, age 18 to 30 years, with moderate-to-severe nodulocystic acne were treated with 20 mg isotretinoin (Roaccutane) daily for 3 months. A hormone panel was obtained at baseline and after completion of the treatment course. The panel included dehydroepiandrosterone (DHEA), 17-hydroxyprogestrone, testosterone, free testosterone, dihydrotestosterone (DHT), luteinizing hormone, follicle stimulating hormone, and prolactin. Results Serum levels of testosterone (p = .015), prolactin (p = .001), and DHT (p = .001) were significantly decreased, while serum levels of DHEA (p = .001) significantly increased after isotretinoin treatment. No significant change was found in the other hormones evaluated. Limitations The distribution of acne was not assessed in our patient population. We did not directly evaluate for associations between elevated DHEA levels and clinical response rates. Conclusion Isotretinoin alone can decrease androgen levels, but increase an important driver of acne pathogenesis (i.e., DHEA). The co-administration of an anti-androgenic agent (e.g., spironolactone) may optimize the therapeutic efficacy of isotretinoin by limiting iatrogenic increases in DHEA and perhaps allow for more widespread use of low-dose isotretinoin.

Background Fractional CO2 laser and autologous hair transplantation are independently effective in the treatment of refractory and stable vitiligo. Objective The authors' purpose was to evaluate the therapeutic efficacy of fractional CO2 laser pretreatment compared with autologous hair transplantation and phototherapy alone for refractory and stable vitiligo. Methods A total of 20 patients with refractory and stable vitiligo were enrolled from our clinic. Resistant lesions randomly divided into 2 regions as follows: (1) Part A: fractional CO2 laser pretreatment followed by autologous transplantation and phototherapy, and (2) Part B: autologous transplantation and phototherapy alone. Five days after fractional CO2 laser application to Part A, both treatment regions received a transplant of scalp grafts. On Day 11, the entire lesion was exposed to narrow-band UVB phototherapy, twice a week for 12 weeks. The diameter of perifollicular repigmentation was measured monthly with a caliper. Results Perifollicular repigmentation was detectable surrounding 74% of grafted hair follicles by Month 3. Furthermore, Part A demonstrated a significantly greater diameter of repigmentation with 6.6 ± 5.8 mm in Part A compared with 4.3 ± 1.8 mm in Part B (p = Conclusion In this study, our results demonstrate improved efficacy of autologous hair transplantation and narrow-band UVB with fractional CO2 laser pretreatment in refractory and stable vitiligo.

Lessons Learned Hyperfractionation of lutetium-177 (177Lu)-J591 for patients with metastatic castration-resistant prostate cancer did not appear to have any additional advantage over the single dose 177Lu-J591 or fractionated two-dose 177Lu-J591 therapy. Definite conclusions were challenging because of the small sample size of this study, and so further studies are needed to evaluate the viability of the hypothesis. On the basis of available data, a registration study of 177Lu-J591 (also known as TLX591) is planned and will use the two-dose fractionation schedule (Telix Pharma Q3 2019 update https://telixpharma.com/news-media/). Background Phase I and II single-dose studies of lutetium-177 (177Lu)-J591, a radio-labeled antibody binding prostate-specific membrane antigen (PSMA), demonstrated safety and efficacy with dose response. Modest dose fractionation of 177Lu-J591 (2 doses) has less myelosuppression per similar cumulative dose, allowing higher doses to be administered safely. We hypothesized that additional dose fractionation would allow a higher cumulative dose, potentially with less toxicity and more efficacy. Methods Men with progressive metastatic castration-resistant prostate cancer and adequate organ function were enrolled. 177Lu-J591 was administered at 25 mCi/m2 every 2 weeks until the emergence of related grade 2 toxicity. 177Lu-J591 imaging was performed and circulating tumor cell (CTC) counts were measured before and after treatment along with standard monitoring. Results Six subjects in a single cohort, with a median age of 68.6 years, were enrolled. Patients received three to six doses (cumulative 75−150 mCi/m2). Two (33%) patients had >30% prostate-specific antigen (PSA) decline and three (50%) had CTC count decline. Two (33%) experienced grade (Gr) 4 neutropenia (without fever), three (50%) had Gr 4 thrombocytopenia (without hemorrhage), and two (33%) required platelet transfusions. Following hematological improvement, two patients developed worsening cytopenia during prostate cancer progression; bone marrow biopsies revealed infiltrative tumor replacing normal marrow elements without myelodysplasia. Targeting of known disease sites was seen on planar imaging in all. Conclusion Hyperfractionation of 177Lu-J591 is feasible but does not seem to have significant advantages over the two-dose fractionation regimen.

Cutaneous injury can ignite excessive fibroproliferative growth that results in keloid formation. Keloids are associated with significant morbidity related to disfigurement and/or symptoms (e.g., pain and pruritus). First-line treatment of formed keloids involves topical or intralesional steroids. Recurrent or resistant keloids are managed by surgical excision or cryotherapy, followed by steroidal application or adjuvant irradiation. Although adjuvant irradiation appears to be most efficacious, alternative therapeutic options are needed for patients without access to radiation centers. Botulinum Toxin A (BTA) appears to have similar inhibitory effects to irradiation on the cell cycle via downregulation of pathogenic cytokines. Herein, we conducted a study to compare the efficacy of intralesional triamcinolone used alone, or in combination with BTA, in the treatment of formed keloid scars. Twenty patients with a cumulative of 40 keloids completed the study. There was no significant difference between treatment arms with respect to height vascularization, pliability, and pigmentation scores. The addition of BTA resulted in significant symptomatic improvement of pain and pruritus as compared to intralesional triamcinolone alone (p < 0.001). Irradiation is only effective when administered in the adjuvant setting where inhibitory effects on cell cycle and migration are optimized. Future studies with intralesional triamcinolone and BTA should be performed adjuvantly.

Human immunodeficiency virus (HIV) infection can present with a variety of cutaneous conditions. Inflammatory conditions associated with HIV infection range from the acute morbilliform eruption of seroconversion to an increase incidence of common conditions including seborrheic dermatitis, eczema, and psoriasis. Immunodeficiency-associated infections can be the presenting symptom of an underlying HIV infection, and these include an increase in common and opportunistic bacterial, fungal, and viral infections. Lastly, whereas great advancement in antiretroviral therapy has led to a significant reduction in morbidity and mortality associated with HIV infection, these agents have significant adverse cutaneous effects.

Background Hand, foot, and mouth disease (HFMD) is generally considered a rare illness in adults. Classically, HFMD has been strongly associated with coxsackievirus strain A16 and enterovirus 71. The coxsackievirus A6 (CVA6) strain has been linked to severe worldwide outbreaks since 2008. CVA6 is associated with a more severe and profound course of disease, affecting both children and adults. Objectives To present a series of five adult patients diagnosed with HFMD due to CVA6. We investigate method of diagnosis and compare clinical presentation of adult cases to those in children. Study design Each patient underwent a full-body skin exam as well as inspection of the oral cavity. Rapid plasma reagin (RPR) and serologic assays by complement fixation against coxsackievirus B (1–6) and A (2,4,7,9,10,16) were performed as indicated. As standard serological testing does not detect CVA6, real-time reverse transcription-polymerase chain reaction (qRT-PCR) of serum, buccal swabs, and skin scrapings were performed by the Centers for Disease Control and Prevention (CDC). Results Each patient had clinical findings consistent with various stages of HFMD. One patient presented with delayed onychomadesis and desquamation of the palms and soles. RPR and serologic assays by complement fixation against CVB (1–6) and CVA (2,4,7,9,10,16) were mostly negative, although elevated in two patients due to cross-reactivity. qRT-PCR identified CVA6 genetic material in samples from all patients. Conclusion This series demonstrates that there is a wide array of disease presentation of CVA6 associated HFMD in adults.

Objective Anti–tumor necrosis factor medications have demonstrated good efficacy in treating psoriatic arthritis (PsA). Clinical responses at the primary end point in recent clinical trials of golimumab in PsA subjects yielded lower American College of Rheumatology 20% criteria for improvement (ACR20) responses than those seen in the Infliximab Multinational Psoriatic Arthritis Controlled Trial 2 infliximab study. However, baseline C-reactive protein (CRP) levels of PsA subjects enrolled in these trials differed significantly. We hypothesized that baseline CRP levels predict the observed differing clinical response rates at the primary end point. Methods Combining the data from the infliximab and golimumab trials, we stratified the data by baseline CRP levels and then correlated these cohorts with response to treatment, specifically the Psoriasis Area and Severity Index and the ACR20, ACR50, and ACR70 responses. Results The mean baseline CRP level in the infliximab trial was 1.9 mg/dl versus 1.4 mg/dl in the golimumab trial. Only 23% of golimumab subjects had a CRP level ≥1.7 mg/dl versus 35% of infliximab subjects (P = 0.0023). All subjects with a CRP level ≥1.7 mg/dl at baseline achieved higher ACR20, ACR50, ACR70 response rates (56%, 36%, and 18%, respectively) at the primary end point of 14 weeks in the infliximab and golimumab clinical trials than any subjects with a CRP level

Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for treatment of renal cell carcinoma, subependymal giant cell astrocytoma, breast cancer, and progressive neuroendocrine tumors of pancreatic origin. Its use may be hindered because of adverse events, including rash. The reported incidence and risk of a rash to everolimus varies widely and has not been closely investigated. Therefore, we conducted a systematic review and meta-analysis of the literature to determine the incidence and risk of developing a rash.We searched PubMed and Web of Science databases and abstracts presented at the American Society of Clinical Oncology from 1998 to December 2011 using the keyword "everolimus" to identify relevant clinical trials. Eligible studies included prospective phase II and III clinical trials of cancer patients on 10 mg of everolimus daily with available data on incidence of rash. The summary incidence and relative risk (RR) of rash were calculated using either the random-effects or fixed-effects model, depending on the heterogeneity of the constituent studies.A total of 2242 patients with various malignancies from 13 clinical trials were included in the analysis. The summary incidences of all-grade and high-grade rash in patients on everolimus were 28.6% [95% confidence interval (CI), 20.8-38.0] and 1.0% (95% CI, 0.6-1.8), respectively. Everolimus was associated with a statistically significant increased risk of all-grade rash (RR=3.853, 95% CI, 2.470-6.013, P=0.000), but the RR for high-grade rash (RR=2.997, 95% CI, 0.633-14.185) was not statistically significant, with a P value of 0.166.Everolimus is associated with a significant risk of developing a rash. Management of rash to everolimus is critical to prevent dose modifications and decreased quality of life, both of which can negatively affect overall clinical outcomes.

Purpose/Objective(s): TTFields are FDA-approved for the treatment of recurrent and newly diagnosed Glioblastoma (GBM) in the supratentorial brain. The EF-14 trial showed that combining TTFields with adjuvant chemo-radiation leads to a significant increase in overall survival compared to adjuvant chemo-radiation alone. High-grade gliomas also occur in the infratentorium and brainstem of pediatric and adult patients. Brainstem gliomas have a median survival of 9 to 11 months, necessitating the exploration of novel treatment combinations, such as delivering TTFields to the infratentorial brain. We recently showed in a simulation-based study that TTFields can be successfully delivered to the infratentorium. Effective delivery was achieved by placement of the arrays on the vertex, bilateral posterolateral occiput, and superior-posterior neck; the array placement results in TTFields at therapeutic intensities throughout the brainstem and cerebellum of realistic computational head models. The previous simulation-based study was performed using realistic computational models of healthy individuals; it did not provide detailed insight into field distributions within tumor tissue located in the infratentorium. Here, we aim to expand the results of this previous study, by simulating the delivery of TTFields to the infratentorium of adult and pediatric patients with high-grade brainstem gliomas. Materials/Methods: A realistic computational model was created using MRI data of adult and pediatric patients with high-grade brainstem gliomas. Transducer arrays were placed on the model and the delivery of TTFields to the infratentorial brain was then simulated using a commercial numerical solver. The electric field distribution in the supratentorium, infratentorium, and within the tumor were derived from the simulations, and the dose in the tumor analyzed. Results: The distribution of calculated isofield lines demonstrates effective delivery of TTFields to infratentorial brain tumors. Conclusion: Our results provides rationale for clinically investigating the utility of TTFields in treating infratentorial high-grade gliomas. Citation Format: Marigdalia K. Ramirez-Fort, Brittany Cross, Ariel Naveh, Shearwood McClelland III, Melissa Mendez, Roberto Santiago, Sean S. Mahase, Jaime Matta, Ze'ev Bomzon, Christopher S. Lange. Simulating delivery of TTFields to the infratentorium in patients with brainstem gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4430.

After cutaneous injury, cytokine mediators recruit an inflammatory infiltrate that stimulates migration of keratinocytes and fibroblasts; subsequent proliferation of fibroblasts and keratinocytes begins 4 to 5 days later [1]. The formation of a keloid is dependent upon fibroblast migration, proliferation and type III collagen production [1]. First{\hyphen}line treatment of keloids involves topical or intralesional steroids. Recurrent or resistant keloids are managed by surgical excision or cryotherapy, followed by steroidal application, that presumably limits inflammation and cellular migration. Adjuvant irradiation to surgical excision is an alternative but underutilized modality that has demonstrated superior patient satisfaction and local control compared to post{\hyphen}cryotherapy or resection intralesional steroids, respectively [2, 3]. This article is protected by copyright. All rights reserved.

Herpes zoster (HZ) occurs as a reactivation of dormant varicella zoster virus (VZV), and occurs more frequently in the aging population or the immunocompromised due to waning cell-mediated immunity. Up to 1 million cases of HZ are reported annually in the USA with an estimated 10 - 30% of the population being affected by shingles in their lifetime. HZ is a debilitating illness, and while mortality is low, morbidity remains a significant cause for concern with prevention efforts aimed at reducing VZV reactivation and its complications. The HZ vaccine was approved by the US Food and Drug Administration for individuals aged 50-years or older. However, the Center for Disease Control and Prevention's Advisory Committee for Immunization Practices recommends the vaccine in individuals aged 60-years or older.Recent literature investigating the efficacy and indications of live attenuated zoster vaccine.Live attenuated zoster vaccine is safe and efficacious in preventing HZ and decreasing the morbidity associated with postherpetic neuralgia. The vaccine is FDA approved in individuals aged 50-years or older but further studies are warranted to investigate the vaccine's efficacy in immunosuppressed and immunocompromised patients.

Purpose of review Vector-borne diseases (VBDs) are difficult to prevent and control because it is hard to predict the complex habits of mosquitoes, ticks and fleas; most vector-borne viruses or bacteria infect animals as well as humans, which further adds to this difficulty. Thus, prevention is the best protection against VBD. Recent findings Vaccines are available for yellow fever, Japanese encephalitis and tick-borne encephalitis and several vaccines are in clinical trials for dengue fever. Antimalarial intermittent preventive therapy (sulfadoxine-pyrimethamine) and insecticide-treated mosquito nets are associated with a decreased risk of neonatal mortality and lower birth-weight. Permethrin-impregnated clothing for the prevention of tick bites has been shown effective in reducing tick bites. Summary Much progress has been made in terms of development of preventive vaccines and medicines, but there is more work that needs to be done. Efforts still need to continue on raising awareness for prevention of VBD.

The etiology of androgenic alopecia (AGA) involves several factors, including genetics, androgens, age and nutrition. Digit-length ratio of the index and ring finger (2D:4D) is an indicator of prenatal exposure to sex hormones. There is a paucity of studies that systemically review the possible positive predictive value of 2D:4D in the development of AGA. We performed a single-site, descriptive-analytical study among a racially homogeneous population. Our results revealed that no significant association was determined between right 2D:4D and AGA severity within our entire population (P=0.384, r=0.025), however a positive correlation coefficient was identified in subjects above the age of 40. Based on the receiver operating characteristic curve analysis, 2D:4D does not predict the development of AGA. AGA is truly a multifactorial disease. Further, our findings suggest that increased in utero exposure to androgens as a fetus does not predispose men to develop AGA.

Purpose/Objective(s) Prostate-specific membrane antigen (PSMA), also known as folate hydrolase 1 (FOLH1), is a highly specific biomarker and therapeutic target for prostate cancer (PC). J591, a monoclonal antibody specific to PSMA, is the primary method used to detect PSMA expression. It is currently under investigation as a vehicle to deliver targeted therapies to PC cells. Androgen deprivation therapy (ADT) upregulates PSMA. Preclinical models of androgen resistant (AR) xenografts demonstrate PSMA upregulation by ADT increases the therapeutic index of J591-drug conjugates, suggestive of enhanced drug uptake. We sought to evaluate the effect of external beam radiation (EBRT) on PSMA expression in PC cells ± ADT. Methods Androgen sensitive LNCaP and AR CWR22Rv1 PC cell lines were cultured in standard and charcoal-stripped media for two weeks. Both cell lines were grown in both media conditions, and received either no EBRT, EBRT in 2 Gray (Gy) daily fractions to a maximum of 10 Gy, or 7.5 Gy in 1 fraction. Cell surface PSMA expression was measured by flow cytometry as mean fluorescence intensity 24 hours after each 2 Gy fraction, or on days 1, 3, 5, 7, and 9 after 7.5 Gy. Results LNCaP in standard media upregulated PSMA by 2.97-fold (SEM ± 0.72) with fractionated EBRT to a cumulative dose of 4 Gy, peaking on days 2 and 3 after 4 Gy and 6 Gy cumulative doses, respectively. CWR22Rv1 in standard medium, upregulated PSMA expression by 3.21-fold (SEM ± 0.44) after a cumulative dose of 8 Gy, peaking on day 4. Under ADT (charcoal-stripped media), EBRT did not further increase LNCaP cell PSMA expression (maximal fold-change of 1.01 (SEM ± 0.02)) relative to ADT alone. Compared to CWR22Rv1 with ADT alone, ADT plus EBRT upregulated PSMA by 3.73-fold (SEM ± 0.44) after a cumulative fractionated dose of 8 Gy, and peaking on days 4 and 5. However, 7.5 Gy in one fraction did not significantly increase PSMA expression of LNCaP or CWR22Rv1 in standard media. LNCaP showed a maximal fold-change of 1.14 (SEM ± 0.29) on day 9. CWR22Rv1 showed a maximal fold-change of 1.27 (SEM ± 0.02) on day 1. Conclusions We show PSMA expression is independently enhanced by ADT and by low-dose fractionated EBRT, but not with single-fraction ablative EBRT. These observations warrant additional studies using in vitro and in vivo PC models to validate our findings. PSMA upregulation may aid in optimizing J591 targeting for treatment of local and disseminated or micrometastatic disease. Validation of PSMA upregulation by ADT and EBRT supports use of J591-drug conjugates as an adjunct treatment to these standard therapies for PC. Furthermore, if fractionated EBRT upregulates PSMA, then targeted brachytherapy using appropriately selected J591-radionucleotide conjugates may increase its own therapeutic index in a time-dependent manner as a result of regional low-dose rate beta or alpha emission. Citation Format: Marigdalia K. Ramirez-Fort, Sean S. Mahase, M. Junaid Niaz, He Liu, Vincent Navarro, Goran Rac, Harry S. Clarke, Scott T. Tagawa, Joseph M. Jenrette, Neil H. Bander, Christopher S. Lange. External beam radiation therapy and androgen deprivation therapy increase PSMA expression in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1774.

Folate hydrolase-1 (FOLH1) is a type II transmembrane protein. Oncologically, FOLH1 is upregulated throughout prostate cancer cells; it is also luminally expressed by the neovasculature of most solid tumors but not by normal vessels. J591, a monoclonal antibody (AB), is specific to, and is effectively endocytosed after extracellular binding to, FOLH1. J591 is presently being developed in clinical trials as a vehicle for AB-based brachytherapy in FOLH1+ cancers. Merkel cell carcinoma (MCC) is a rare, neuroendocrine tumor; metastatic (m) MCC is associated with poor survival. We characterized FOLH1 expression in MCC to determine its target potential for J591-brachytherapy. Paraffin sections from primary (p) and mMCC were deparaffinized and rehydrated. Samples were stained with 3E6 (DAKO), a mouse IgG1 monoclonal anti-human FOLH1. Mouse IgG1 (10 ug/mL in 1% bovine serum albumin) was used as an isotype-matched negative control. Anti-CD31 (IgG1) was used as a positive control. Kaplan-Meier survival curves were calculated based on patient outcome data and FOLH1 expression. 81 MCC tumors were evaluated. 67% (54/81) of all cases with 77% (24/31) of pMCC and 60% (30/50) of mMCC tumors demonstrated FOLH1+ neovessels. No cellular staining of tumor cells was identified. 34 patients with FOLH1 +/- MCC were demographically homogeneous in terms of sex, age, immunosuppression status, prior therapies, stage at diagnosis, and local or distant recurrences. No significant differences were detected based on FOLH1 status, in regards to MCC specific survival (P=0.905), or overall survival (P=0.687), as measured from time of diagnosis. FOLH1 is expressed in the majority of pMCC and mMCC cases and is nonprognostic. Our findings support further investigation of targeted therapy with J591-brachytherapy for the management of MCC. Citation Format: Barbara Meier, Marigdalia K. Ramirez-Fort, Kristina Lachance, Candice D. Church, Sean S. Mahase, Joseph M. Jenrette, Christopher S. Lange, Lars E. French, Paul Nghiem, Neil H. Bander. Folate hydrolase-1 is a novel target for J591-brachytherapy in Merkel cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2518.

Background: Acne vulgaris (AV) is a common inflammatory disease of the pilosebaceous unit. A variety of treatment modalities are available for the treatment of AV. Among the available options, oral azithromycin is popularly prescribed for its proven anti-inflammatory effects. Narrow band UVB (NBUVB) also has a potent anti-inflammatory action. Concomitant use of both modalities may result in a synergistic therapeutic response; however, the combined efficacy has not yet been evaluated for the treatment of inflammatory AV. Objective: The aim of this study was to compare the efficacy of oral azithromycin plus NBUVB (peak 311 nm) to oral azithromycin alone for the treatment of moderate to severe inflammatory AV. Materials and Methods: A randomized, open-label, clinical trial was conducted over 4 weeks. Subjects were randomized into two groups. Group 1 received 500 mg of oral azithromycin three times per week. Group 2 received 500 mg of oral azithromycin plus NBUVB three and two times per week, respectively. Concomitant topical or oral AV treatments were not permitted during the treatment period. Response to treatment was measured by photographic records at the primary endpoint (2 weeks) and at the end of treatment. Results: One hundred and four subjects were enrolled in the trial; 94 subjects completed the treatment period of the study. Group 2 demonstrated significant clinical improvement of the inflammatory papular lesions (88.55%) compared with group 1 (70.34%) at the end of treatment (P = 0.002). The clinical response of pustular (P = 0.562), nodular (P = 0.711) and cystic (P = 0.682) lesions did not significantly differ between the two treatment groups. Interestingly, response to treatment in group 2 had a significant anatomical predilection for the forehead (P = 0.023). There was no side-effect except erythema, which subsided within 1-2 days. Conclusion: NBUVB plus oral azithromycin is more effective than oral azithromycin alone for treating papular lesions of inflammatory AV. NBUVB is certainly a viable adjunct in acne therapy.

Background Benign chronic familial pemphigus (BFCP) is an autosomal dominant dermatosis characterized by flares of painful and often debilitating blistering lesions in high friction areas of the body such as the groin, axillae, lateral neck, and intergluteal cleft. Limited knowledge of its pathophysiology has made treatment of BFCP a considerable challenge and efficacy with current first line therapies, topical corticosteroids and antibiotics, is variable. Case Report We present a case of this disease in a 52 year old woman that has responded dramatically to the addition of oral cyclosporine to her existing regimen of oral acitretin, with significant improvement of skin lesions, mobility, and quality of life. Cyclosporine's mechanism of action in BFCP is poorly understood, although it possibly acts through inhibition of proinflammatory cytokines in keratinocytes or modulation of intracellular calcium. BFCP, the use of cyclosporine for its treatment, and possible mechanisms of action of cyclosporine are reviewed.

Background: Folate hydrolase-1 (FOLH1; NAALADase; PSMA) is a type II transmembrane protein that binds substrates with terminal glutamates. The MXXXL motif on the cytoplasmic N-terminal domain of FOLH1 interacts with clathrin and caveolin-1 to facilitate constitutive internalization upon substrate binding. J591, an established monoclonal antibody (AB) to FOLH1, is highly specific to and is effectively endocytosed after binding to the extracellular domain of FOLH1; J591 is presently being developed in the clinical trial setting, as a vehicle for AB-based brachytherapy in cancers that express FOLH1. Physiological FOLH1 is expressed in cellular regions that are protected by tight-junctions or the blood-brain-barrier, and are therefore not targeted by circulating J591. Functionally, FOLH1 is responsible for cerebral glutamate production. In the oncological setting, FOLH1 is upregulated throughout prostate cancer cellular membranes, and is luminally expressed by cancer neovessels. We have characterized neovascular FOLH1 expression in malignant melanoma (MM), a solid tumor of neural crest (NC) origin. Comparative RTqPCR analysis of normal skin, primary (p), and metastatic (m) MM revealed respective 10.64 and 18.21 -fold increases in FOLH1 gene-expression in pMM (p=0.0041) and mMM (p=0.042) samples as compared to normal skin. Immunohistochemistry of paraffin-embedded MM tumors revealed FOLH1 protein expression in the neovasculature of 4/11 (36%) of pMM and 9/14 (64%) of mMM cases; we noted a subset of keratinocytic and melanocytic FOLH1 positive cells. These results, and the known functional role of glutamate production in a subset of NC-derived tissue, suggest that MM cells may also express cellular FOLH1. Methods: Six (3 BRAF+; 3 BRAF-) MM cell lines were evaluated for cellular FOLH1 and Oct4 expression with J591-based and anti-Oct4 AB immunofluorescence (IF). Oct4 is a homeodomain binding protein encoded by POU5f1, widely accepted as a stem cell marker. FOLH1+ cell lines with permeablized and non-permeablized membranes were incubated with J591. The effect of γ-irradiation (0, 4.5, or 9 Gy) was also tested in FOLH1+ cell lines with harvesting 6 or 24 hours post-irradiation. Results: Ten to 40% of MM cells demonstrated intracellular FOLH1 expression in 2 BRAF-/6 MM cell lines, with a predominant perinuclear and terminal dendritic distribution (e.g., axonal morphology). IF co-labeling with J591 (cytoplasmic) and antibodies to Oct4 (nuclear) identified possible stemness of FOLH1+ / Oct4+ MM cells. RT-PCR analysis of the irradiated cell lines demonstrated ~2-fold increased FOLH1 mRNA levels in 1/2 MM cell lines. Conclusions: Herein is the first demonstration that MM cells express FOLH1. Given that FOLH1 glutamate production is closely linked to NC-originating glial cells, it can be reasonably postulated that this newly identified subset of FOLH1+/Oct4+ MM cells could be NC precursors, or cancer stem cells, for MM. Further, radiation-induced FOLH1 upregulation may increase the therapeutic ratio of AB-based brachytherapy. Citation Format: Marigdalia K. Ramirez-Fort, He Liu, Vicente Navarro, Barbara Meier, Mitch Levesque, Jonathan Moy, Jessica Vissicchio, Emmanuel Contassot, Sae Kim, Talal Syed, Michael Zhang, Vincent Tem, Paul J. Christos, Scott T. Tagawa, Neil H. Bander, Christopher S. Lange, Lars E. French. Possible cancer stem cells: Folate hydrolase-1 is expressed in a subset of Oct4-positive melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1905. doi:10.1158/1538-7445.AM2017-1905

Human papillomavirus (HPV) infection transcends multiple fields of science and medicine. The management of HPV-related disease is demanding and often requires a persistent multimodal approach involving various medical disciplines. In this volume, experts present a comprehensive view of HPV research with an emphasis on clinical presentations, diagnosis, management and vaccine development. The state of the art in molecular biology is provided in addition to discussions on clinical morphology and the utility of dermatoscopy in identifying HPV disease. In a multidisciplinary approach to dermatological, plastic and reconstructive, gynecological, otolaryngological and colorectal management, different treatment strategies are highlighted. Finally, Dr. Neil Christensen discusses viral immunology, and the difficulties and successes in the development of an HPV vaccine. Bringing together basic science and clinical information on HPV, this book is an excellent resource and reference for all researchers and clinicians who encounter human papillomavirus-related disease.

We present a case of a 60-year-old woman who, after using a blemish cream purchased at a health store, presented to our clinic with a large eschar on the right neck. The active ingredient in this cream was found to be Sanguinaria canadensis, a known escharotic. This substance is popularly marketed as a natural remedy for a host of skin diseases such as blemishes, moles, warts, skin tags, basal cell carcinomas, squamous cell carcinomas, actinic keratoses, and even melanoma. The patient was treated with topical corticosteroids but is still left with a scar from the healed eschar. Dermatologists must be aware of the increasing popularity of “natural” medicinal skin cancer therapies, such as bloodroot-containing “cancer salves” and “herbal cures,” and emphasize to their patients that conventional excision, micrographic surgery, electrodessication, and/or curettage are highly successful treatments for most skin cancers with little morbidity.

Human papillomaviruses (HPVs) are small, double-stranded DNA viruses that cause lesions in cutaneous and mucosal tissue and are responsible for carcinomas of the cervix, vagina, vulva and penis. HPVs sort into 5 genera with a total of approximately 150 species that have been sequenced. Its genome is comprised of an early (E) region encoding the viral regulatory proteins, a late (L) region encoding the viral structural proteins and a noncoding region that is essential to the viral life cycle. For infection to occur, the virus must access the basal epidermal layer where, following endocytosis and viral capsid disassembly, the L2 protein mediates viral genome transfer to the nuclei of mitotic keratinocytes. The viral genome is maintained in episomal form during the normal life cycle and replicates in synchrony with the host cell DNA under the mediation of E1, E2, E4 and E5 viral proteins. In most high-grade cervical neoplasms, however, the viral DNA is integrated into the host genome through the disruption of the E2 open reading frame. The oncoproteins E6 and E7, which were previously suppressed by E2, are then free to inhibit the Rb and p53 tumor suppressor pathways. The viral life cycle concludes with the packaging of the viral genome and virus release, which entails the E2-mediated recruitment of L2 to regions of replication, the expression of L1 and the assembly of the icosahedral capsid in the nucleus. Overall, the complex biology of HPV continues to be an important area of research with substantial implications for public health.