Characterization of ALTO-encoding circular RNAs expressed by Merkel cell polyomavirus and trichodysplasia spinulosa polyomavirus.

Circular RNAs (circRNAs) are a conserved class of RNAs with diverse functions, including serving as messenger RNAs that are translated into peptides. Here we describe circular RNAs generated by human polyomaviruses (HPyVs), some of which encode variants of the previously described alternative large T antigen open reading frame (ALTO) protein. Circular ALTO RNAs (circALTOs) can be detected in virus positive Merkel cell carcinoma (VP-MCC) cell lines and tumor samples. CircALTOs are stable, predominantly located in the cytoplasm, and N6-methyladenosine (m6A) modified. The translation of MCPyV circALTOs into ALTO protein is negatively regulated by MCPyV-generated miRNAs in cultured cells. MCPyV ALTO expression increases transcription from some recombinant promoters in vitro and upregulates the expression of multiple genes previously implicated in MCPyV pathogenesis. MCPyV circALTOs are enriched in exosomes derived from VP-MCC lines and circALTO-transfected 293T cells, and purified exosomes can mediate ALTO expression and transcriptional activation in MCPyV-negative cells. The related trichodysplasia spinulosa polyomavirus (TSPyV) also expresses a circALTO that can be detected in infected tissues and produces ALTO protein in cultured cells. Thus, human polyomavirus circRNAs are expressed in human tumors and infected tissues and express proteins that have the potential to modulate the infectious and tumorigenic properties of these viruses.

Response to Alpelisib in Clinically Distinct Pediatric Patients With PIK3CA -related Disorders.

PIK3CA -related disorders include vascular malformations, potential overgrowth of various tissues, limb abnormalities, disordered soft tissue, and/or fatty hyperplasia that often leads to significant morbidity. Alpelisib, a targeted inhibitor of p110α, an enzyme encoded by the PIK3CA gene, has demonstrated success in a cohort of patients with PIK3CA -driven overgrowth syndromes. We describe the clinical course of 2 pediatric patients treated with alpelisib under the Novartis Managed Access Program. Both patients, though clinically distinct, demonstrate improvements in overgrowth volumes/extent, function of their affected limb, and quality of life, without significant adverse effects after prolonged treatment.

A severe presentation of acute generalized exanthematous pustulosis with non-infectious circulatory shock in an adolescent.

We present a severe case of acute generalized exanthematous pustulosis (AGEP) secondary to trimethoprim-sulfamethoxazole complicated by non-infectious circulatory shock in a 16-year-old boy. Hemodynamic instability has been reported as a complication of AGEP in adults, but is rarely observed in pediatric patients. The patient we present demonstrated characteristic cutaneous findings of AGEP including isolated non-follicular, sterile pustules on a background of erythema with involvement at intertriginous areas and subsequently developed non-infectious circulatory shock. This case expands the spectrum of possible clinical presentations for AGEP in pediatric patients.

Basal cell carcinoma histopathologic upgrading and Mohs micrographic surgery: a single institution, retrospective review.

Basal cell carcinoma (BCC) histopathology can differ between original biopsy and wide local excision or Mohs micrographic surgery (MMS). We aimed to analyze the rate of difference in BCC subtypes between the original biopsy and MMS frozen section to determine the rate of histopathological upgrading and also to identify risk factors for upgrading. A single institution, retrospective cohort study of patients with BCC treated with MMS was performed at the University of Texas Southwestern. Screening criteria identified 3235 BCCs. Of these, 1289 tumors were identified as having lower-grade pathology on initial biopsy. 291 (22.6%) of the lower-grade pathology tumors were upgraded to a higher-grade pathology. Tumors with an upgraded pathology had significantly greater number of stages performed [mean of 2.5 vs 2.3, p < 0.001], pre-operative size [median of 1.0 cm vs 0.8 cm, p < 0.001], and post-operative size [median of 2.0 cm vs 1.7 cm, p < 0.001]. These tumors were significantly more likely to require more advanced repairs [36.8% (107/291) vs 29.8% (297/998), p = 0.03] and be referred for post-operative radiation [1.7% (5/291) vs 0.0% (0/998), p < 0.001]. In addition, there were a significantly greater number of tumors considered recurrent (received prior surgical or non-surgical treatment) in the upgraded pathology group [8.6% (25/291) vs 3.9% (39/998), p < 0.01]. Our study highlights that a significant proportion of these patients are under-graded on initial biopsy and would benefit from more definitive intervention, such as MMS.

UV Exposure and the Risk of Keratinocyte Carcinoma in Skin of Color: A Systematic Review.

Importance: Ultraviolet radiation exposure is an important modifiable risk factor for keratinocyte carcinoma (KC) in fair-skinned non-Hispanic White populations; however, the evidence for this relationship in darker-skinned populations is less certain. Objective: To assess and synthesize the published data concerning the association between UV exposure and the risk of KC in individuals with skin of color. Evidence Review: PubMed, Cochrane, and Web of Science databases were searched from database origin through January 2022. Studies deemed eligible included UV exposure as a risk factor for KC in individuals with skin of color, defined as any race other than non-Hispanic White, Fitzpatrick skin types IV to VI, or tanning ability of rarely or never burns. The UV index, irradiance, latitude, history of phototherapy, history of sunburn, or occupational exposure were used as measures of exposure. The Oxford Centre for Evidence-Based Medicine guidelines were used to assess evidence quality. Findings: A total of 72 716 articles appeared in the search. After duplicate removal, 29 393 database records were screened, 454 full-text articles were assessed, a forward and reverse citation search was performed, and 12 articles, with clinical data spanning the years 1990 to 2019, met inclusion criteria. More than 32 970 KCs in individuals with skin of color were included. Eight studies found no association between UV exposure and KC, while 4 studies showed a positive association. Study types included 1 ecological study, 9 cohort studies, and 2 case-control studies. The quality of the studies was rated from moderate to low (2b to 4). Conclusions and Relevance: Results of this systematic review show that the evidence assessing the association of UV exposure with KC is of moderate to low quality. The studies that found no association were among patients receiving phototherapy. Studies assessing nonphototherapy-related UV exposure, such as geographic location or occupation, found small positive associations in primarily East Asian individuals. There were no studies performed in the US, no studies among Black individuals, and only 1 study among a Hispanic population. Further research is required to better assess whether these associations exist across populations of patients with darker skin types.

Human Papillomavirus‒Positive and ‒Negative Vulvar Squamous Cell Carcinoma Are Biologically but Not Clinically Distinct.

Vulvar squamous cell carcinoma pathogenesis is traditionally defined by the presence or absence of human papillomavirus (HPV), but the definition of these groups and their molecular characteristics remain ambiguous across studies. In this study, we present a retrospective cohort analysis of 36 patients with invasive vulvar squamous cell carcinoma where HPV status was determined using RNA in situ hybridization and PCR. Clinical annotation, p16 immunohistochemistry, PD-L1 immunohistochemistry, HPV16 circular E7 RNA detection, and RNA sequencing of the cases were performed. A combination of in situ hybridization and PCR identified 20 cases (55.6%) as HPV positive. HPV status did not impact overall survival (hazard ratio: 1.36, 95% confidence interval = 0.307-6.037, P = 0.6857) or progression-free survival (hazard ratio: 1.12, 95% confidence interval = 0.388-3.22, P = 0.8367), and no significant clinical differences were found between the groups. PD-L1 expression did not correlate with HPV status, but increased expression of PD-L1 correlated with worse overall survival. Transcriptomic analyses (n = 23) revealed distinct groups, defined by HPV status, with multiple differentially expressed genes previously implicated in HPV-induced cancers. HPV-positive tumors showed higher global expression of endogenous circular RNAs, including several circular RNAs that have previously been implicated in the pathogenesis of other cancers.

Vulvar lichen sclerosus in women of reproductive age.

Vulvar lichen sclerosus (vLS) is an inflammatory skin condition that predominantly affects the vulvar and perianal regions. Approximately 50% of cases present prior to menopause; however, there is a paucity of data on vLS in women of reproductive age as well as during their pregnancies. A retrospective review was performed at two tertiary referral centers to better describe cases of vLS in women of reproductive age. Thirty-three patients with a mean age of 40 years met inclusion criteria. In this group, vulvar pruritus was the most common presenting symptom (52%); 61% had biopsy-proven vLS, 42% had at least one autoimmune condition, 21% had comorbid depression or anxiety, 33% were given an incorrect diagnosis prior to vLS, and 42% had documented nonadherence to topical steroids. Among the eight patients who became pregnant, four had cesarean deliveries and 63% were symptomatic during pregnancy. When treating a woman who presents with vulvar pruritus or skin changes, vLS should be considered.

A lobulated mass on the upper back with prominent vasculature: A giant basal cell carcinoma.

Basal cell carcinoma (BCC) is characterized by slow but locally invasive growth. Although there is low metastatic potential, if not treated early, these skin cancers can lead to significant morbidity and mortality. In this case report, we present a man with a neglected BCC that developed into what is termed a giant BCC or one that is greater than 5 cm. This tumor was discovered only upon workup of orthostatic lightheadedness and iron deficiency anemia. Although rare, basal cell carcinoma must be included on the differential of a large cutaneous lesion and may be a source of significant blood loss.

Dual-layer spectral detector CT: non-inferiority assessment compared to dual-source dual-energy CT in discriminating uric acid from non-uric acid renal stones ex vivo.

PURPOSE: To assess the non-inferiority of dual-layer spectral detector CT (SDCT) compared to dual-source dual-energy CT (dsDECT) in discriminating uric acid (UA) from non-UA stones. METHODS: Fifty-seven extracted urinary calculi were placed in a cylindrical phantom in a water bath and scanned on a SDCT scanner (IQon, Philips Healthcare) and second- and third-generation dsDECT scanners (Somatom Flash and Force, Siemens Healthcare) under matched scan parameters. For SDCT data, conventional images and virtual monoenergetic reconstructions were created. A customized 3D growing region segmentation tool was used to segment each stone on a pixel-by-pixel basis for statistical analysis. Median virtual monoenergetic ratios (VMRs) of 40/200, 62/92, and 62/100 for each stone were recorded. For dsDECT data, dual-energy ratio (DER) for each stone was recorded from vendor-specific postprocessing software (Syngo Via) using the Kidney Stones Application. The clinical reference standard of X-ray diffraction analysis was used to assess non-inferiority. Area under the receiver-operating characteristic curve (AUC) was used to assess diagnostic performance of detecting UA stones. RESULTS: Six pure UA, 47 pure calcium-based, 1 pure cystine, and 3 mixed struvite stones were scanned. All pure UA stones were correctly separated from non-UA stones using SDCT and dsDECT (AUC = 1). For UA stones, median VMR was 0.95-0.99 and DER 1.00-1.02. For non-UA stones, median VMR was 1.4-4.1 and DER 1.39-1.69. CONCLUSION: SDCT spectral reconstructions demonstrate similar performance to those of dsDECT in discriminating UA from non-UA stones in a phantom model.