The pathogenesis of cutaneous squamous cell carcinoma in organ transplant recipients

Dermatology-oncolog

Extramammary Paget disease of the perianal region:the potential role of imiquimod in achieving disease control

Extramammary Paget disease (EMPD) is a rare perineal neoplasia associated with a high rate of local recurrence. Surgical excision is the standard treatment; however, this has high rates of post-operative morbidity in combination with potentially mutilating results. Previous literature has demonstrated good response with imiquimod 5% cream in patients with vulval EMPD, yet its effectiveness in primary perianal disease is unknown. We describe the case of a 40-year-old woman presenting with EMPD of the perianal region, providing detailed histological and pictoral evidence of its response to topical imiquimod 5% cream over a 16-week period, which initially resulted in remission prior to metastatic lymph node recurrence. This case demonstrates the potential for topical imiquimod cream to avoid major surgery and its associated complications in patients presenting with EMPD of the perianal region. We discuss the current evidence for treating this rare condition with medical therapy, how this case adds to current literature and possible future directions

The new 8th edition of TNM staging and its implications for skin cancer:a review by the British Association of Dermatologists and the Royal College of Pathologists, U.K.

The 8th edition of TNM (tumour, node and metastasis) has numerous and important changes compared with the 7th edition. Public Health England and the Royal College of Pathologists, U.K., have adopted the 8th edition of TNM (TNM8) published by the Union for International Cancer Control for skin cancer staging. These changes will have an impact on the management and commissioning of melanoma and nonmelanoma skin cancer (NMSC). The T1–T3 categories for NMSC staging require the clinician to measure the maximum dimension (usually diameter) of every potential invasive cancer. For squamous, basal and adnexal carcinomas, but not Merkel cell carcinoma (MCC), the T1–T3 categories are defined by new 20-mm and 40-mm divisions based on the maximum dimension of the lesion. In addition, new risk factors upstage T1 or T2 to T3. For melanoma, mitotic index no longer influences separation of pathological stage (pT1). There is a new, additional stratification level at 0·8-mm Breslow thickness. Subdivision pT1b, with a negative sentinel lymph node biopsy (SLNB) of pN0, is now stage IA compared with the previous IB. For MCC, SLNB is now included specifically in the pN staging system. The pT1 subdivision requires clinical information as to whether histologically involved nodes were clinically occult or detectable. For both melanoma and MCC the clinician must state whether the lymph nodes are occult or clinically detectable. Eyelid carcinoma continues to have a staging system different from that in general skin and the system is substantially revised in TNM8.</p

Targeting the spliceosome for cutaneous squamous cell carcinoma therapy:a role for c-MYC and wild-type p53 in determining the degree of tumour selectivity

This study was supported by DEBRA International and funded by DEBRA Austria (Saville-Proby 1). I.M.L and M.K.S were supported by an ERC Advanced Investigator Award (250170, Principal Investigator I.M.L.). C.M.P. and I.M.L. were supported by a Cancer Research UK Programme Grant (A13044)

Keratinocyte Carcinomas:Current concepts and future research priorities

Cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) are keratinocyte carcinomas (KC), the most frequently diagnosed cancers in fair-skinned populations. Ultraviolet radiation (UVR) is the main driving carcinogen for these tumors but immunosuppression, pigmentary factors, and aging are also risk factors. Scientific discoveries have improved the understanding of the role of human papillomaviruses (HPV) in cSCC as well as the skin microbiome and a compromised immune system in the development of both cSCC and BCC. Genomic analyses have uncovered genetic risk variants, high-risk susceptibility genes, and somatic events that underlie common pathways important in KC tumorigenesis and tumor characteristics which have enabled development of prediction models for early identification of high-risk individuals. Advances in chemoprevention in high-risk individuals and progress in targeted and immune-based treatment approaches have the potential to decrease the morbidity and mortality associated with these tumors. As the incidence and prevalence of KC continue to increase, strategies for prevention, including effective sun protective behavior, educational interventions and reduction of tanning bed access and usage are essential. Gaps in our knowledge requiring additional research in order to reduce the high morbidity and costs associated with KC include better understanding of factors leading to more aggressive tumors, the roles of microbiome and HPV infection, prediction of response to therapies including immune checkpoint blockade, and how to tailor both prevention and treatment to individual risk factors and needs.</p

The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma

We performed a small interfering RNA screen to identify targets for cutaneous squamous cell carcinoma (cSCC) therapy in the ubiquitin/ubiquitin-like system. We provide evidence for selective anti-cSCC activity of knockdown of the E3 ubiquitin ligase MARCH4, the ATPase p97/VCP, the deubiquitinating enzyme USP8, the cullin-RING ligase (CRL) 4 substrate receptor CDT2/DTL, and components of the anaphase-promoting complex/cyclosome (APC/C). Specifically attenuating CRL4CDT2 by CDT2 knockdown can be more potent in killing cSCC cells than targeting CRLs or CRL4s in general by RBX1 or DDB1 depletion. Suppression of the APC/C or forced APC/C activation by targeting its repressor EMI1 are both potential therapeutic approaches. We observed that cSCC cells can be selectively killed by small-molecule inhibitors of USP8 (DUBs-IN-3/compound 22c) and the NEDD8 E1 activating enzyme/CRLs (MLN4924/pevonedistat). A substantial proportion of cSCC cell lines are very highly MLN4924-sensitive. Pathways that respond to defects in proteostasis are involved in the anti-cSCC activity of p97 suppression. Targeting USP8 can reduce the expression of growth factor receptors that participate in cSCC development. EMI1 and CDT2 depletion can selectively cause DNA re-replication and DNA damage in cSCC cells

Basal cell carcinomas without histological confirmation and their treatment : an audit in four European regions

Summary- Background: Limited data are available on how often basal cell carcinomas (BCCs) are clinically diagnosed without histological confirmation and how they are treated. Objectives Within the framework of the EPIDERM project, an audit was conducted in four European countries to study the occurrence of clinically diagnosed BCCs without histological confirmation and to investigate how these are treated. Methods: In the Netherlands, Scotland, Finland and Malta studies were performed within different timeframes. Patients with one or more BCC(s) were selected and the number of clinically diagnosed BCCs without histological confirmation and their treatment was investigated by (manually) reviewing the (electronic) patient records and checking the (hospital) pathology databases to find evidence of histological confirmation. Results: In the Netherlands, 1089 patients with a first histologically confirmed BCC developed 1974 BCCs of which 1833 (92.9%) were histologically confirmed and 141 (7.1%) were not. A 4-month retrospective study conducted in Scotland selected 294 patients with 344 BCCs; 306 (89.0%) were histologically confirmed and 38 (11.0%) were not. A 3-month prospective study performed at the same centre in Scotland identified 44 patients who developed 58 BCCs; 44 (75.9%) of these were histologically confirmed and 14 (24.1%) were not. In Finland, there were 701 patients who developed 977 BCCs, of which 807 (82.6%) were histologically and 170 (17.4%) nonhistologically confirmed. In Malta, there were 420 patients with 477 BCCs. Only three (0.7%) of them were clinically diagnosed without histological confirmation. In the Netherlands and Finland, clinically diagnosed BCCs without histological confirmation were most often treated with cryotherapy, whereas in Scotland 5% imiquimod cream was the preferred treatment modality. Conclusions: Although the frequency of clinically diagnosed BCCs without histological confirmation differed between the four European regions (range 0.7-24.1%), this confirms that the burden of BCC in Europe is underestimated when based on data from pathology and/or cancer registries.peer-reviewe

Perceptions of Women Receiving Services from Domestic Violence Advocacy and Counseling Programs

Abstract The purpose of this qualitative study was to examine domestic violence victims’ perceptions of advocacy and counseling programs that provide women with safe refuge, prevention education, mental health treatment, and other services. Many women in the United States are victims of intimate partner violence. Review of existing literature found that little is known about the extent to which the needs of these victims are met from available advocacy and counseling services. The health belief model was used to theorize victims’ perceptions of services and risk factors for re-abuse. A phenomenological design was used to answer research questions, and in-depth interviews were conducted with 8 women who stayed at a domestic violence shelter and used shelter services, such as advocacy, emergency shelter, and individual and family counseling. Data from the transcripts were inductively analyzed using NVivo 10.0 and hand coding techniques for emergent themes. The findings revealed that women were pleased with the services received, and most had no awareness of advocacy or counseling services until they sought shelter. Also, most agreed that counseling and advocacy services could help prevent re-abuse. Recommendations include establishing a google page for domestic violence shelters, which can provide information on available advocacy and counseling services and how they can assist victims of domestic violence. Study findings can promote positive social change by increasing awareness of advocacy and counseling programs and their importance to prevent re-abuse. This may also provide useful information for implementing new programs to help victims of domestic violence

Perceptions of Women Receiving Services from Domestic Violence Advocacy and Counseling Programs

Abstract The purpose of this qualitative study was to examine domestic violence victims’ perceptions of advocacy and counseling programs that provide women with safe refuge, prevention education, mental health treatment, and other services. Many women in the United States are victims of intimate partner violence. Review of existing literature found that little is known about the extent to which the needs of these victims are met from available advocacy and counseling services. The health belief model was used to theorize victims’ perceptions of services and risk factors for re-abuse. A phenomenological design was used to answer research questions, and in-depth interviews were conducted with 8 women who stayed at a domestic violence shelter and used shelter services, such as advocacy, emergency shelter, and individual and family counseling. Data from the transcripts were inductively analyzed using NVivo 10.0 and hand coding techniques for emergent themes. The findings revealed that women were pleased with the services received, and most had no awareness of advocacy or counseling services until they sought shelter. Also, most agreed that counseling and advocacy services could help prevent re-abuse. Recommendations include establishing a google page for domestic violence shelters, which can provide information on available advocacy and counseling services and how they can assist victims of domestic violence. Study findings can promote positive social change by increasing awareness of advocacy and counseling programs and their importance to prevent re-abuse. This may also provide useful information for implementing new programs to help victims of domestic violence