Drivers underpinning the malignant transformation of giant cell tumour of bone.

The rare benign giant cell tumour of bone (GCTB) is defined by an almost unique mutation in the H3.3 family of histone genes H3-3A or H3-3B; however, the same mutation is occasionally found in primary malignant bone tumours which share many features with the benign variant. Moreover, lung metastases can occur despite the absence of malignant histological features in either the primary or metastatic lesions. Herein we investigated the genetic events of 17 GCTBs including benign and malignant variants and the methylation profiles of 122 bone tumour samples including GCTBs. Benign GCTBs possessed few somatic alterations and no other known drivers besides the H3.3 mutation, whereas all malignant tumours harboured at least one additional driver mutation and exhibited genomic features resembling osteosarcomas, including high mutational burden, additional driver event(s), and a high degree of aneuploidy. The H3.3 mutation was found to predate the development of aneuploidy. In contrast to osteosarcomas, malignant H3.3-mutated tumours were enriched for a variety of alterations involving TERT, other than amplification, suggesting telomere dysfunction in the transformation of benign to malignant GCTB. DNA sequencing of the benign metastasising GCTB revealed no additional driver alterations; polyclonal seeding in the lung was identified, implying that the metastatic lesions represent an embolic event. Unsupervised clustering of DNA methylation profiles revealed that malignant H3.3-mutated tumours are distinct from their benign counterpart, and other bone tumours. Differential methylation analysis identified CCND1, encoding cyclin D1, as a plausible cancer driver gene in these tumours because hypermethylation of the CCND1 promoter was specific for GCTBs. We report here the genomic and methylation patterns underlying the rare clinical phenomena of benign metastasising and malignant transformation of GCTB and show how the combination of genomic and epigenomic findings could potentially distinguish benign from malignant GCTBs, thereby predicting aggressive behaviour in challenging diagnostic cases. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Female Genital Tract Melanoma: 10 Years of Experience at a Single Tertiary Center.

OBJECTIVE: Malignant melanoma of the female genital tract is a rare disease with poor prognosis, with controversies remaining in its staging and management. In this study, we investigate clinical, pathological, and outcome data for patients referred to a tertiary cancer center with female genital tract melanoma over a decade. METHODS: Patients were retrospectively identified using a search of pathology reports to identify all cases of female genital tract melanoma from 2007 to 2019. Electronic patient records were used to record clinical information. Histopathology specimens were reviewed by a gynecological and dermatological pathology specialist. RESULTS: We identified 30 cases of genital tract melanoma, of which 19 were vulvar, 10 were vaginal, and 1 cervical. Overall survival at 1, 3, and 5 years was found to be 80%, 60%, and 57%. Patients who died were not significantly older at presentation than patients who survived (62 y vs 69 y, p = .215). No association was found between mortality and microscopic ulceration, lymphovascular invasion, pigmentation, resection margins, or radical versus local surgery.Nonvulvar lesions were significantly associated with mortality compared with vulvar lesions (p = .0018), despite similar age and Breslow thickness. Five patients were diagnosed at in situ stage, all of these were vulvar. Even after excluding these melanomas in situ, nonvulvar melanomas still had a significantly worse mortality rate (p = .048). A higher proportion of nonvulvar lesions than vulvar lesions displayed loss of pigmentation (p = .026). CONCLUSIONS: Nonvulvar genital tract melanomas carry a significantly worse prognosis. Survival was not related to resection margins, supporting the use of more conservative surgical margins.

The Chemotherapy Response Score (CRS): Interobserver Reproducibility in a Simple and Prognostically Relevant System for Reporting the Histologic Response to Neoadjuvant Chemotherapy in Tuboovarian High-grade Serous Carcinoma.

A 3-tier histopathologic scoring system, the chemotherapy response score (CRS), was previously devised for reporting the histologic response to neoadjuvant chemotherapy in interval debulking surgery specimens of stage IIIc/IV tuboovarian high-grade serous carcinoma. This has been shown to predict the outcome and offer additional information to other methods of assessing the treatment response. In the present study, the reproducibility of this scoring system was assessed by determining the interobserver agreement among reporting pathologists. A total of 5 groups each comprising 3 pathologists with different levels of expertise were selected. The participants underwent an online tutorial on how to apply the CRS system. 40 cases (38 cases in 2 appraiser groups) were scored individually by each of the 15 pathologists. The interobserver reproducibility was calculated using Fleiss' κ, Kendall's coefficient of concordance, and the absolute agreement between (a) individual pathologists within 1 group, (b) with the majority score agreement between all groups, and (c) with all individual scores. The CRS system was found to be highly reproducible among all the pathologists' groups (κ=0.761). The agreement in identifying the group of patients with the best response to chemotherapy was exceptionally high (κ=0.926). We conclude that CRS has a high interobserver reproducibility, especially in identifying the subgroup of patients with the best chemotherapy response, justifying its inclusion in clinical trials and reporting practice.

Nailbed HPV-related Bowen's disease in a man living with HIV.

Human papillomavirus (HPV) is a common sexually transmitted infection with wide-ranging clinical manifestations. High-risk anogenital HPV genotypes have also been reported to cause extragenital disease. We describe the case of a 69-year-old male patient living with HIV who was diagnosed with HPV-16 associated Bowen's Disease (BD) of the right middle finger nailbed, despite good virologic control and immune reconstitution. The lesion was managed surgically with adjunctive post-exposure HPV vaccination. This case adds to the growing body of evidence of extra-genital HPV disease attributable to anogenital genotypes in people living with HIV.

Primary vulval melanoma and genital lichen sclerosus.

Background: Lichen sclerosus (LS) is a chronic, inflammatory skin disease with a predilection for the genitalia. Although, the association between squamous cell cancer and genital LS is well established, a link with genital melanoma has not been thoroughly explored. However, we have recently published a case series of penile melanoma where 9/11 (82%) of patients seen over a 10 year period with penile melanoma were retrospectively found to have histological and/or clinical evidence of genital LS on review. Objectives: The aim of this study was to illuminate further the relationship between vulval melanoma and genital LS by reviewing all the cases managed by our hospital and undertaking a literature review. Methods: We identified all the cases with a diagnosis of vulval melanoma over a 16-year period (2006-2022) where histology was available. The clinical notes were retrospectively reviewed, and the histological features of all cases were reassessed by two independent mutually 'blinded' histopathologists. We also performed a literature review of genital LS in patients with vulval melanoma. Results: A total of 11 patients with vulval melanoma were identified for the review. Histopathological review found evidence of genital LS in seven of them (64%). Genital LS was not documented in any of the original histology reports. Clinical notes and letters were available in nine cases. The literature review identified 12 relevant studies with a total of 18 patients. Twelve cases concerned adult women, and six concerned female children. Conclusion: The presence of genital LS in as high as 64% of our vulval melanoma cases might indicate a causative relationship between genital LS and vulval melanoma. The pathogenesis of vulval melanoma remains largely unknown. Although ultraviolet radiation is an important pathogenic factor for cutaneous melanoma, it cannot be a factor in vulval melanoma. While possible mechanisms behind this association remain unclear, it is possible that chronic inflammation from genital LS leads to melanocytic distress and increased mutagenesis.

Genital lichen sclerosus and melanoma; a systematic review.

Background: Lichen sclerosus (LSc) is a chronic, inflammatory, destructive skin disease with a predilection for the genitalia (GLSc). An association with vulval (Vu) and penile (Pe) squamous carcinoma (SCC) is now well established but melanoma (MM) has only rarely been reported complicating GLSc. Methods: We have performed a systematic literature review of GLSc in patients with genital melanoma (GMM). Only articles that mentioned both GMM and LSc affecting either the penis or vulva were included. Results: Twelve studies with a total of 20 patients were included. Our review shows that an association of GLSc with GMM has been more frequently reported in women and female children than men viz, 17 cases compared with three. It is notable that five of the cases (27.8%) concerned female children aged under twelve. Discussion: These data suggest a rare association between GLSc and GMM. If proven, there arise intriguing questions about pathogenesis and consequences for counselling of patients and follow-up.

Primary penile melanoma and genital lichen sclerosus.

Background: There is a well-established association between squamous cell cancer and genital lichen sclerosus (GLSc). Although there have been several reported cases of vulval melanoma (MM) associated with LSc, particularly in the paediatric population, fewer cases of male genital (M) GLSc and penile (Pe)MM have been published. Objectives: The aim of this study was to explore further the relationship between PeMM and MGLSc by reviewing all the cases managed by our multidisciplinary service over a finite period. Methods: All patients known to our tertiary urology and male genital dermatology service with a diagnosis of PeMM and where histology was available for review were identified over an 11-year period (2011-2022). The histology was reviewed by two independent, mutually 'blinded' histopathologists. Photographs and clinical notes, where available, were retrospectively reviewed by two independent dermatologists for signs or symptoms of LSc. Results: Eleven patients with PeMM were identified for review. Histopathological examination found evidence of LSc in nine patients, and review of clinical photos corroborated the presence of LSc in three. Overall, features of LSc were present in nine out of eleven cases (82%). Conclusion: The presence of LSc in 9 out of 11 cases of PeMM is suggestive of a causative relationship between LSc and PeMM. This may be due to chronic melanocytic distress created by chronic inflammation secondary to LSc.

Beyond Services and Prescriptions: Reimagining Healthy Lifestyle Centers as Cooperative Enterprises.

While the health-enhancing benefits of exercise and good nutrition have been well documented, the ability of health professionals to encourage healthier lifestyle behaviors among those they serve continues to prove challenging. Creating the conditions where healthier living can both occur and be sustained requires thinking beyond the traditional provision of services and prescriptions that occur in healthcare settings. Healthy Lifestyle Centers are emerging as a way of deploying lifestyle medicine practices. Turning these centers into cooperative businesses has the potential to make them more effective. Cooperative business principles are well established, and they enable individuals to become makers and producers of their own healthy lifestyles, providing a greater opportunity for sustained lifestyles changes. The purpose of this article is to further examine the role of engagement practices and coproduction as they relate to cooperative business models and to propose a framework for a Cooperative Healthy Lifestyle Center.

Fibroadenoma in vulval ectopic breast tissue in a patient with PTEN Hamartoma Tumour Syndrome.

PTEN is a tumour suppressor gene involved in regulating cell division. Pathogenic germline variants in PTEN predispose to benign and malignant growths of numerous organs, including of the breast. In the following report, we describe the first documented case of a fibroadenoma developing in ectopic breast tissue of the vulva in a patient with a germline pathogenic variant in PTEN. This highlights the risk of hyperplasia developing in any breast tissue, including rare ectopic sites, particularly in patients with underlying germline variants in cancer susceptibility genes.

Erythema multiforme major with ocular involvement following COVID-19 infection.

We report a case of membranous conjunctivitis and erythema multiforme major (EMM) after a coronavirus disease 2019 (COVID-19) diagnosis. A previously well 18-year-old man presented with increasingly erythematous eyes and oral and genital ulceration 2 weeks after confirmation of COVID-19 infection. Clinical examination showed sloughy membranous conjunctivitis with normal visual acuity. He was reviewed by dermatology and diagnosed with EMM secondary to severe acute respiratory syndrome coronavirus 2 infection. The symptoms resolved with oral and topical steroids, lubricants and chloramphenicol eye drops. Erythema multiforme has been reported in association with COVID-19, although the major form is rare. Ophthalmologists should consider current or previous COVID-19 infection in patients presenting with conjunctivitis or pseudomembrane formation. Prompt initiation of steroids aids resolution.

Computers as a formal continuing education tool: moving beyond intention.

OBJECTIVE: To identify factors related to health promotion professionals' decisions to use computer-mediated instruction for continuing education (CMI-CE). METHODS: Employing a cross-sectional survey design, data were collected from 500 respondents using an online survey. RESULTS: Among respondents having positive intentions toward CMI-CE, characteristics distinguishing between individuals with positive and negative CMI-CE behavior included perceived behavioral control, license/ certification, lack of programs and relevant program topics, and availability of technical support. CONCLUSIONS: Health promotion professionals have positive intentions toward CMI-CE, and introducing relevant programs accompanied by strong technical support teams will help move them beyond intention and into action.

Next-Generation Sequencing-Assisted DNA-Based Digital PCR for a Personalized Approach to the Detection and Quantification of Residual Disease in Chronic Myeloid Leukemia Patients.

Recent studies indicate that 40% of chronic myeloid leukemia patients who achieve sustained undetectable BCR-ABL1 transcripts on tyrosine kinase inhibitor therapy remain disease-free after drug discontinuation. In contrast, 60% experience return of detectable disease and have to restart treatment, thus highlighting the need for an improved method of identifying patients with the lowest likelihood of relapse. Here we describe the validation of a personalized DNA-based digital PCR (dPCR) approach for quantifying very low levels of residual disease, which involves the rapid identification of t(9;22) fusion junctions using targeted next-generation sequencing coupled with the use of a dPCR platform. t(9;22) genomic breakpoints were successfully mapped in samples from 32 of 32 patients with early stage disease. Disease quantification by DNA-based dPCR was performed using the Fluidigm BioMark platform on 46 follow-up samples from 6 of the 32 patients, including 36 samples that were in deep molecular remission. dPCR detected persistent disease in 81% of molecular-remission samples, outperforming both RT-dPCR (25%) and DNA-based quantitative PCR (19%). We conclude that dPCR for BCR-ABL1 DNA is the most sensitive available method of residual-disease detection in chronic myeloid leukemia and may prove useful in the management of tyrosine kinase inhibitor withdrawal.

Perceived psychological stress among high school basketball officials.

The purpose of this study was to survey certified high school basketball officials during midseason to assess whether the sources and magnitude of perceived psychological stress would be consistent with previous studies of officials in other sports. The sources and magnitude of perceived psychological stress were measured among 324 high school basketball officials (N=324; 312 men, 12 women) using a revised version of the Ontario Soccer Officials Survey. The mean age was 37.6 yr. (SD= 9.4), and the mean years of basketball refereeing experience was 11.7 yr. (SD=8.3). A random sample (N=498) of all basketball officials in a midwestern state (N=1,011) was used, and 324 of the surveys were returned (65%). The overall variance accounted for with the four factors was 84.7%. The magnitude of stress for these factors ranged from below mild to moderate.