Search

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., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

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., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

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., Competing Interests: The authors have declared that no competing interests exist.

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., (Copyright © 2021 Baylor University Medical Center.)

Introduction: Despite proven effectiveness of medications in preventing stone recurrence, compliance with pharmacotherapy (PT) is often poor because of cost, side effects, and impact on lifestyle. We sought to compare the risk of stone recurrence between patients managed with conservative therapy (CT) vs PT controlling for aggressiveness of stone disease. Materials and Methods: The Multi-center collaboration to Study Treatment Outcomes in Nephrolithiasis Evaluation (MSTONE) database contains patient data and outcomes from July 2001 to April 2015 across four centers. The database was queried for patients whose stone disease was managed with CT alone (fluid and dietary recommendations) vs PT. Patients were risk stratified according to number of previous passed stones. Within each risk group, we compared CT vs PT with respect to 2-year stone event rate and stone event-free survival (SEFS) using the Kaplan-Meier method. Results: A total of 245 patients, with a median follow-up of 29 months (interquartile range = 16-44), were identified, including 93 on CT and 152 on PT. The overall 2-year stone event rate was 38% for all patients. Stone events at 2 years occurred less frequently in the PT group compared with the CT group (31% vs 44%, p  = 0.043), with the difference most pronounced in the high-risk group (71% vs 32% for CT and PT, respectively, p  = 0.058). The 30-month SEFS was significantly higher for PT (58%) than CT (46%) overall. When stratified by risk group, 30-month SEFS was statistically significantly higher for PT than CT in the intermediate risk group (65% vs 45% for PT and CT, respectively). Conclusion: Controlling for aggressiveness of stone disease, PT was more effective than CT in reducing and delaying stone-related events. However, CT appeared to be as effective as PT in low-risk patients. PT is best reserved for recurrent stone formers, regardless of metabolic background.

AMPA receptor GluA2 subunits are strongly implicated in cognition, and prior work suggests that these subunits may be regulated by atypical protein kinase C (aPKC) isoforms. The present study assessed whether hippocampal and cortical AMPA receptor GluA2 subunit regulation may be an underlying factor in known age-related differences to cognitive-impairing doses of ethanol, and if aPKC isoforms modulate such responses. Hippocampal AMPA receptor GluA2 subunit, protein kinase Mζ (PKMζ), and PKCι/λ expression were elevated during adolescence compared to adults. 1 h following a low-dose (1.0-g/kg) ethanol exposure, hippocampal AMPA receptor GluA2 subunit serine 880 phosphorylation was decreased in adolescents, but was increased in adults. Age-dependent changes in GluA2 subunit phosphorylation were paralleled by alterations in aPKC isoforms, and zeta inhibitory peptide (ZIP) administration prevented ethanol-induced increases in both in adults. Ethanol-induced changes in GluA2 subunit phosphorylation were associated with delayed regulation in synaptosomal GluA2 subunit expression 24 h later. A higher ethanol dose (3.5-g/kg) failed to elicit changes in most measures in the hippocampus at either age. Similar to the hippocampus, analysis of cerebral cortical tissue also revealed age-related declines. However, no demonstrable effects were found following a low-dose ethanol exposure at either age. High-dose ethanol exposure reduced adolescent GluA2 subunit phosphorylation and aPKC isoform expression that were again accompanied by delayed reductions in synaptosomal GluA2 subunit expression. Together, these results suggest that GluA2-containing AMPA receptor modulation by aPKC isoforms is age-, region- and dose-dependently regulated, and may potentially be involved in developmentally regulated ethanol-induced cognitive impairment and other ethanol behaviors., (Copyright © 2014 IBRO. All rights reserved.)