An Evaluation of High-Risk HPV in Squamous Cell Carcinomas of the Lip in a South African Cohort.

BACKGROUND: To determine the prevalence of HR-HPV in a series of lip SCC from South African patients, using currently accepted HPV-testing methodologies and to define the clinical and histomorphologic features of HPV-associated lip SCC. METHODS: Fifty SCC of lip and 50 control cases were tested for HR-HPV using p16 and HR-HPV DNA PCR. p16-equivocal/positive and HPV DNA PCR-positive SCC were further evaluated for the expression of HPV-16 and HPV-18 mRNA transcripts using reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) to confirm transcriptionally active HPV. RESULTS: p16 was positive in 22% (n = 11) and equivocal in 4% (n = 2) of the SCC. One p16-positive case showed positivity for both HPV-16 DNA and HPV-16 E6/E7 mRNA transcripts (HPV prevalence rate of 2%). The HPV-positive case was non-keratinizing and occurred in an 80-year-old female. The two p16-equivocal cases were HR-HPV DNA positive and mRNA PCR negative. p16 was found to have a positive predictive value of 9%. CONCLUSION: Findings from our cohort of lip SCC suggest that HR-HPV may have an insignificant role in the pathogenesis of SCC at this site. Due to its low ppv, p16 is insufficient to establish HR-HPV infection in SCC of the lip. The combination of p16 and DNA PCR appears to correlate with the presence of transcriptionally active virus. HPV E6/E7 mRNA detection is the gold standard for identifying HR-HPV. mRNA testing is not widely available in sub-Saharan Africa due to technical and financial constraints; however, the test appears to be of great value in p16-equivocal lip SCC.

Incorporating functional genomics into the pathology-supported genetic testing framework implemented in South Africa: A future view of precision medicine for breast carcinomas.

A pathology-supported genetic testing (PSGT) framework was established in South Africa to improve access to precision medicine for patients with breast carcinomas. Nevertheless, the frequent identification of variants of uncertain significance (VUSs) with the use of genome-scale next-generation sequencing has created a bottleneck in the return of results to patients. This review highlights the importance of incorporating functional genomics into the PSGT framework as a proposed initiative. Here, we explore various model systems and experimental methods available for conducting functional studies in South Africa to enhance both variant classification and clinical interpretation. We emphasize the distinct advantages of using in vitro, in vivo, and translational ex vivo models to improve the effectiveness of precision oncology. Moreover, we highlight the relevance of methodologies such as protein modelling and structural bioinformatics, multi-omics, metabolic activity assays, flow cytometry, cell migration and invasion assays, tube-formation assays, multiplex assays of variant effect, and database mining and machine learning models. The selection of the appropriate experimental approach largely depends on the molecular mechanism of the gene under investigation and the predicted functional effect of the VUS. However, before making final decisions regarding the pathogenicity of VUSs, it is essential to assess the functional evidence and clinical outcomes under current variant interpretation guidelines. The inclusion of a functional genomics infrastructure within the PSGT framework will significantly advance the reclassification of VUSs and enhance the precision medicine pipeline for patients with breast carcinomas in South Africa.

The complete Kaposi sarcoma-associated herpesvirus genome induces early-onset, metastatic angiosarcoma in transgenic mice.

Kaposi sarcoma (KS) is the most common cancer in persons living with HIV. It is caused by KS-associated herpesvirus (KSHV). There exists no animal model for KS. Pronuclear injection of the 170,000-bp viral genome induces early-onset, aggressive angiosarcoma in transgenic mice. The tumors are histopathologically indistinguishable from human KS. As in human KS, all tumor cells express the viral latency-associated nuclear antigen (LANA). The tumors transcribe most viral genes, whereas endothelial cells in other organs only transcribe the viral latent genes. The tumor cells are of endothelial lineage and exhibit the same molecular pattern of pathway activation as KS, namely phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR, interleukin-10 (IL-10), and vascular endothelial growth factor (VEGF). The KSHV-induced tumors are more aggressive than Ha-ras-induced angiosarcomas. Overall survival is increased by prophylactic ganciclovir. Thus, whole-virus KSHV-transgenic mice represent an accurate model for KS and open the door for the genetic dissection of KS pathogenesis and evaluation of therapies, including vaccines.

The clinicopathological spectrum of preclinical folliculitis keloidalis with correlation to its dermoscopic features: a cross-sectional analytical study.

BACKGROUND: Folliculitis keloidalis (FK) is a chronic hair disorder commonly affecting males with afro-textured hair. It typically affects the nuchal area, but disease may also occur at extra-nuchal sites. Few studies have investigated the histopathological aspects of preclinical FK. In addition to the histopathology of preclinical FK, this article is the first to describe the dermoscopic features of preclinical FK at extra-nuchal sites. MATERIALS AND METHODS: This study was conducted in a tertiary dermatological clinic. Twenty-eight patients with a clinical diagnosis of FK were prospectively enrolled from 2014 to 2016. Dermoscopy was used to identify features that were not evident with the naked eye (preclinical). These sites were subsequently biopsied. The clinical, dermoscopic, and histopathological features of these preclinical areas are described and correlated. RESULTS: Most patients suffered a chronic disease course (mean: 7.6 years) with 57.1% (n = 16) displaying extra-nuchal involvement. Dermoscopy-guided biopsy of preclinical lesions displayed perivascular dermatitis (82.1%), folliculocentric inflammation (46.3%), and fibrosis (64.3%). Novel dermoscopic findings were perifollicular scale, perifollicular erythema and pink-white areas. The perifollicular scale was associated with fibrosis on histopathology (P < 0.05). CONCLUSIONS: This article lends further evidence for the existence of preclinical FK and describes its histological features. For the first time, it describes the dermoscopic features of preclinical FK. Dermoscopy may therefore be a useful tool to assess disease progression and treatment response.

Staged Excision of Lentigo Maligna of the Head and Neck: Assessing Surgical Excision Margins With Melan A, SOX10, and PRAME Immunohistochemistry.

BACKGROUND: Staged excision has emerged as a superior treatment option for lentigo maligna (LM) of the head and neck when compared with conventional wide local excision. Assessing surgical excision margins for remaining LM poses a diagnostic challenge. OBJECTIVES: To determine whether immunohistochemical (IHC) staining with SOX10 and preferentially expressed antigen in melanoma (PRAME) aids in diagnosing LM on excision margins compared with conventional hematoxylin and eosin and Melan A IHC staining. METHODS: This study included cases of LM of the head and neck treated with staged excision. Histological findings were reviewed according to standard criteria for the diagnosis of LM and compared with the results after IHC staining for Melan A, SOX10, and PRAME. RESULTS: The cohort consisted of 35 sections. Based on hematoxylin and eosin and Melan A IHC staining, 23 sections were diagnosed as LM by the initial pathologist. Further staining with SOX10 IHC showed only 8 to be consistent with a diagnosis of LM and 9 revealing features of actinic melanocyte hyperplasia. PRAME was positive in 5 of the 8 cases of LM and negative in all 9 cases of actinic melanocyte hyperplasia (P = 0.009). The presence of melanocyte nests (P = 0.29) and pagetoid spread (P = 0.003) was the most reliable histological findings distinguishing LM from its mimics. CONCLUSION: SOX10 is a more specific and sensitive marker for melanocytes when assessing for LM on excision margins compared with Melan A. The addition of PRAME can be useful to confirm or exclude the diagnosis in challenging cases.

Superficial CD34 Positive Fibroblastic Tumour with Myxoid Stroma.

Superficial CD34 positive fibroblastic tumor is a rare low-grade neoplasm of the skin and subcutis with indolent behavior. This entity has been included in the current World Health Organisation (WHO) classification of soft tissue tumors. Pathological diagnosis can be challenging due to significant morphological overlap with other entities and the large spectrum of CD34 positive tumors. We report a case in a twenty-five male which showed characteristic diagnostic features, but in addition showed myxoid stroma. The presence of myxoid stroma has not been previously emphasized in this entity and broadens the histologic differential diagnosis significantly to include myxoid soft tissue tumors. A subset of these tumors harbor PRDM10-rearrangements, but a defining molecular feature has not yet been described, highlighting the need for further molecular characterization of this potentially genetically heterogenous tumor. Awareness of this entity among surgeons and pathologists is important to prevent misclassification as an aggressive sarcoma and avoid over-treatment.

The Prevalence of Epstein-Barr Virus in Plasma Cell Neoplasms is Higher in HIV-Positive Individuals.

AIMS: Epstein-Barr virus (EBV) is causally associated with many hematolymphoid malignancies. This laboratory-based study aimed to establish the prevalence of EBV in plasma cell neoplasms in a large South African cohort and to determine whether there is any correlation between EBV-positivity and human immunodeficiency virus (HIV) status in patients with plasma cell neoplasms, including plasma cell myeloma and plasmacytoma (solitary plasmacytoma of bone and extraosseous plasmacytoma). METHODS: This single-institution retrospective study included all patients with a histopathologic diagnosis of plasma cell neoplasm between 2003 and 2020. EBV-expression in the plasma cell neoplasms was assessed by EBV-encoded RNA (EBER) in situ hybridization (ISH) and correlated with HIV status. HIV status was determined by retrieving prior serologic results. Formalin-fixed paraffin-embedded tissue from HIV-unknown patients underwent HIV-1 p24 antibody testing. RESULTS: Sixteen of 89 plasma cell neoplasms (18%) were EBV-positive. There was a significant correlation between EBV and HIV infection in plasma cell neoplasms, with 6/10 tumors from HIV positive patients showing EBV-positivity in tumor cells. The EBV-positive cohort was significantly younger than the EBV-negative group. CONCLUSION: EBV-positivity in plasma cell neoplasms in this study is higher than previously reported. The significant occurrence of EBV in plasma cell neoplasms from HIV-positive patients suggests a co-carcinogenic relationship between the two viruses.

Solid-Phase Reference Baths for Fiber-Optic Distributed Sensing.

Observations from Raman backscatter-based Fiber-Optic Distributed Sensing (FODS) require reference sections of the fiber-optic cable sensor of known temperature to translate the primary measured intensities of Stokes and anti-Stokes photons to the secondary desired temperature signal, which also commonly forms the basis for other derived quantities. Here, we present the design and the results from laboratory and field evaluations of a novel Solid-Phase Bath (SoPhaB) using ultrafine copper instead of the traditional mechanically stirred liquid-phase water bath. This novel type is suitable for all FODS applications in geosciences and industry when high accuracy and precision are needed. The SoPhaB fully encloses the fiber-optic cable which is coiled around the inner core and surrounded by tightly interlocking parts with a total weight of 22 kg. The SoPhaB is thermoelectrically heated and/or cooled using Peltier elements to control the copper body temperature within ±0.04 K using commercially available electronic components. It features two built-in reference platinum wire thermometers which can be connected to the distributed temperature sensing instrument and/or external measurement and logging devices. The SoPhaB is enclosed in an insulated carrying case, which limits the heat loss to or gains from the outside environment and allows for mobile applications. For thermally stationary outside conditions the measured spatial temperature differences across SoPhaB parts touching the fiber-optic cable are <0.05 K even for stark contrasting temperatures of ΔT> 40 K between the SoPhaB's setpoint and outside conditions. The uniform, stationary known temperature of the SoPhaB allows for substantially shorter sections of the fiber-optic cable sensors of less than <5 bins at spatial measurement resolution to achieve an even much reduced calibration bias and spatiotemporal uncertainty compared to traditional water baths. Field evaluations include deployments in contrasting environments including the Arctic polar night as well as peak summertime conditions to showcase the wide range of the SoPhaB's applicability.

Lentigo Maligna of the head and neck: A retrospective study assessing surgical excision margins in a South African population.

Background: Lentigo maligna (LM) is a subtype of melanoma in situ that occurs on sun-damaged skin and is associated with significant subclinical extension beyond the clinical margins of the lesion. Objectives: This study aimed to determine if the standard recommended tumor excision margins for LM are adequate to achieve a 97% clearance rate and if any patient or tumor characteristics warranted wider margins. Methods: This study is a retrospective chart review of all patients who were diagnosed with LM of the head and neck and treated with staged excision. Results: The study included 64 patients. With a 6 mm surgical excision margin, only 60.9% of LM were completely excised. A 9 mm margin resulted in complete clearance of 71.9% of LM cases, and a 12 mm margin resulted in complete clearance in 90.6%. A surgical excision margin of 18 mm would have been required to excise 96.7% of tumors completely. Recurrent tumors (P = .01) and tumor size larger than 20 mm were associated with wider surgical excision margins (P = .154). Conclusion: This study of LM in a South African population corroborates that the standard surgical excision margins recommended by international melanoma guidelines for LM are inadequate to achieve a 97% clearance rate.

Workaholism across European and Asian cultures during the COVID-19 pandemic.

The current cross-cultural study examined the construct of workaholism across European and Asian cultures during the pandemic caused by coronavirus disease 2019 (COVID-19). A total of 2,617 recipients, aged 18-80 years from three Asian countries (China, India, and Indonesia) with higher levels of collectivistic values, and three European countries (Bulgaria, Germany, and Hungary) supposing to have higher individualistic values. The participants completed the online version of the two-dimensional measure, dubbed the Dutch Workaholism Scale (DUWAS). The goal of the study was to demonstrate that during the COVID-19 pandemic, it is the cultural context that mediates and influences the way of change in workaholics' attitudes. The results led to the conclusion that the way in which the COVID-19 crisis affects workaholism and workaholics' behavior depends on cultural and sex differences, and stages of the human life cycle. The data analysis revealed that cultural differences and sex affect the configuration of workaholism (excessive/compulsive): in the Asian sample, unlike the European, there was a significant increase in the level of workaholism compulsive; European female participants reported higher levels of workaholism compulsive and workaholism excessive, but the sex difference was not found in Asian sample. Along with cultural context, and sex differences, age also influences the configuration of workaholism. In this case, the separate stages of the human life cycle contribute in different ways to changes in levels of workaholism excessive and workaholism compulsive.

Health locus of control in a pandemic situation: cross-cultural differences between European and Asian respondents.

BACKGROUND: The present cross-cultural study examined the health locus of control construct during the COVID-19 pandemic. The scientific purpose of the study was to determine whether, during the pandemic situation, cultural and sex differences influence the health locus of control construct and change the internal health locus of control (IHLC), powerful others health locus of control (PHLC), and chance health locus of control (CHLC). PARTICIPANTS AND PROCEDURE: A total of 2617 recipients aged 18-70 years from Asia (China, India, and Indonesia), and Europe (Bulgaria, Germany, and Hungary) completed a questionnaire about their health. The participants completed an online version of the Multidimensional Health Locus of Control Scale - Form A. RESULTS: The survey shows that in a pandemic life-threatening situation, most individuals strive to rely on IHLC and/or PHLC, and fewer of them tend to rely on CHLC. However, there are differences (p < .001) between the two cultural samples: the representatives of Asian collectivistic culture are more dominated by PHLC, compared to the representatives of the European individualistic culture. When the comparison is between individuals from different cultures, sex differentiation affects the health locus of control, and as a result, significant differences in relation to IHLC, PHLC, and CHLC levels (p < .05) appear. CONCLUSIONS: In conclusion, the study indicates that cultural differences influence both the IHLC and PHLC levels, and that Asian participants are dominated by PHLC more than European respondents. Asian females are more likely to seek support from powerful others (PHLC) compared to European women, who perceive themselves as more independent. Asian male participants are prepared to rely on powerful others (doctors or medical institutions), while European male respondents are prone to rely on themselves mainly (IHLC). The results show that sex differences do not significantly affect the health locus of control within the same cultural group.

The Prevalence of Human Papillomavirus-Positive Oropharyngeal Squamous Cell Carcinoma at One of the Largest Tertiary Care Centers in Sub-Saharan Africa.

CONTEXT.­: Limited data exist on the prevalence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma in sub-Saharan Africa. OBJECTIVE.­: To determine the prevalence of HPV-positive oropharyngeal squamous cell carcinoma at a large tertiary care center in South Africa. DESIGN.­: A total of 266 oropharyngeal squamous cell carcinomas diagnosed during an 11-year period (2007-2017) were selected for evaluation. Cases staining positive for p16 immunohistochemistry were evaluated for high-risk HPV using the BD Onclarity assay (BD Diagnostics, Sparks, Maryland). RESULTS.­: Of 266 oropharyngeal squamous cell carcinomas, 14% (n = 36) were positive for p16. Polymerase chain reaction for high-risk HPV performed on the p16-positive cases was negative in 23 cases and positive in 13 cases (13 of 266; 5%). p16 showed a positive predictive value of 36.1%. The HPV subtypes were HPV-16 (n = 10), HPV-18 (n = 1), HPV-52 (n = 1), and HPV-31 (n = 1). Human papillomavirus-positive cases occurred in 10 men and 3 women (mean age, 51 years) and arose from the tonsil (n = 10) or base of the tongue (n = 3). The HPV-positive cases were non-keratinizing (n = 10) or partially keratinizing (n = 1). Partially/nonkeratinizing cases revealed a modest improvement in p16 positive predictive value (11 of 21; 52.4%). CONCLUSIONS.­: The presence of high-risk HPV in 5% of cases suggests that high-risk HPV is a minor etiologic agent in oropharyngeal squamous cell carcinoma in this region. Given its suboptimal positive predictive value, p16 is not a reliable marker for high-risk HPV infection in this region. When p16 is positive, HPV-specific testing is necessary. The identification of less common high-risk HPV types, HPV-52 and HPV-31, may influence current local vaccination strategies.

The development of active binocular vision under normal and alternate rearing conditions.

The development of binocular vision is an active learning process comprising the development of disparity tuned neurons in visual cortex and the establishment of precise vergence control of the eyes. We present a computational model for the learning and self-calibration of active binocular vision based on the Active Efficient Coding framework, an extension of classic efficient coding ideas to active perception. Under normal rearing conditions with naturalistic input, the model develops disparity tuned neurons and precise vergence control, allowing it to correctly interpret random dot stereograms. Under altered rearing conditions modeled after neurophysiological experiments, the model qualitatively reproduces key experimental findings on changes in binocularity and disparity tuning. Furthermore, the model makes testable predictions regarding how altered rearing conditions impede the learning of precise vergence control. Finally, the model predicts a surprising new effect that impaired vergence control affects the statistics of orientation tuning in visual cortical neurons.

Impact of Psychic Traumatization on the Development of Musicians' Dystonia: Six Exploratory Case Studies.

OBJECTIVE: Musician's dystonia represents a special case of focal dystonia. It is described as a task-specific movement disorder which presents itself as muscular incoordination or loss of voluntary fine-motor control of extensively trained movements while a musician is playing the instrument. Several triggering factors have been identified, such as overuse, chronic pain, perfectionism, and anxiety disorders. As a common feature, dysfunctional self-management and stress-coping mechanisms are at the root of the aforementioned behaviors. Based on long-term experience from our musicians' medicine outpatient clinic, we hypothesized that early psychic or somatic traumatization may be an underlying mechanism and therefore contribute essentially to focal dystonia. METHODS: In a qualitative study, we investigated the role of early traumatization as a potential cause of motor failures, such as musician's dystonia, employing an episodic interview on a sample of six professional musicians (age 30-57 yrs, 5:1 M:F) suffering from musician's dystonia. RESULTS: Using grounded theory methodology, we were able to derive one generalized etiological model describing contributing factors in the etiological understanding of focal dystonia from the six case studies. The qualitative interviews clearly revealed that all patients experienced early psychic traumatizations, including violence and parents' substance abuse. CONCLUSIONS: In this small sample, we theorize that in-depth, early traumatization most probably led to a dysfunctional stress-coping mechanism. We therefore propose in our model that there are two types of motor failures, one linked to stressful experiences, dysfunctional coping behaviors, and increased muscle tone, and one linked to genetic susceptibility of the motor-system without psychological triggering factors.

Clinicopathological Features of Seborrheic-Like Dermatitis in HIV-Infected Adults: A Single Institutional Descriptive Cross-Sectional Study.

BACKGROUND: Atypical and severe clinical presentations of seborrheic-like dermatitis (SLD) are associated with HIV infection, correlating with advanced disease or low CD4 counts. Previous studies documented histological findings characteristic of seborrheic dermatitis in HIV-positive patients. OBJECTIVE: To expand current knowledge of the clinicopathological characteristics of SLD in South African HIV-seropositive individuals. METHODS: This prospective study included HIV-seropositive adult patients presenting with SLD to a dermatology clinic from March 2017 to April 2018. A dermatologist established the diagnosis of SLD and the severity of the disease. Detail about antiretroviral therapy (ART), the latest CD4 count, and the viral load was retrieved from the patients' clinical records. Histopathological assessment of the patients' skin biopsies was recorded using standardized data sheets and semiquantifiable grades. RESULTS: This study included 13 women and 17 men. Fifty percent of patients showed severe or very severe SLD. Six (20.0%) patients presented with erythroderma. Statistical analysis did not show a significant correlation between severity of disease and CD4 count, viral load, or ART, respectively. This study confirmed that the presence of confluent parakeratosis, necrotic keratinocytes, plasma cells, neutrophils with leukocytoclasia, and leukoexocytosis are histopathological clues to SLD occurring in HIV-seropositive patients. CONCLUSION: SLD in HIV patients may present with varying clinical severity, including erythroderma. The association between the prevalence and severity of SLD with CD4 count, viral load, and ART requires further studies with larger patient populations. The presence of specific histopathological features in a skin biopsy of SLD is a clue to the diagnosis of HIV.