Pelvic floor symptoms among premenopausal women with pelvic organ prolapse in the Democratic Republic of the Congo.

INTRODUCTION AND HYPOTHESIS: Most of the literature on pelvic organ prolapse (POP) has been generated from postmenopausal patients in high-income countries. In the Democratic Republic of the Congo (DRC), a significant proportion of patients who present for surgical management of POP are premenopausal. Little is known about the impact of POP on pelvic floor symptoms in this population. The objective was to describe pelvic floor symptoms and sexual function among premenopausal patients presenting for POP surgery in DRC. METHODS: We performed a prospective cohort study of symptomatic premenopausal patients undergoing fertility-sparing POP surgery at a large referral hospital in the DRC. Pelvic floor symptoms were evaluated with the Pelvic Floor Distress Inventory Questionnaire and sexual function with the Pelvic organ prolapse/urinary Incontinence Sexual Questionnaire. Data are presented as means with standard deviations or counts with percentages. RESULTS: A total of 107 patients were recruited between April 2019 and December 2021. All had either stage III (95.3%) or stage IV (4.7%) prolapse. Ages were 34.2 ± 6.7 years; 78.5% were married. A majority of patients experienced low abdominal pain (82.2%), heaviness or dullness (95.3%), and bulging or protrusion of the prolapse (92.5%). Almost two-thirds of patients reported no longer being sexually active, and 80% stated that they were not sexually active because of POP. Of the 37 sexually active patients (34.6%), nearly all reported significant sexual impairment because of the prolapse, with only 4 reporting no sexual impairment. CONCLUSIONS: This study represents one of the largest prospective series of patients with premenopausal POP. Our results highlight the severity of pelvic floor symptoms and the negative effects on sexual function among this patient population with POP.

The impact of hormones in autoimmune cutaneous diseases.

INTRODUCTION: Dermatomyositis, systemic and cutaneous lupus erythematosus have a significantly higher prevalence in women than men, emphasizing the relevance of exploring the relationship between sex hormones and autoimmune skin diseases. This review analyzes the interplay between sex hormones and these two skin diseases. MATERIALS AND METHODS: We performed an extensive literature search using the PubMed database from July to August 2023. Search terms included 'contraceptives', 'pregnancy', 'hormone replacement', 'tamoxifen', and 'aromatase inhibitors'. RESULTS AND DISCUSSION: This comprehensive literature review shows that there remains considerable debate regarding the use of hormonal contraceptives and hormonal replacement therapy in individuals with autoimmune skin conditions. Nonetheless, it is well established that their use is contraindicated in patients with antiphospholipid syndrome or when antiphospholipid antibodies are positive. Individuals experiencing disease flares and uncontrolled symptoms should also avoid these interventions. Pregnancy planning should be timed to coincide with well-managed disease states to minimize obstetric and neonatal complications. Hormonal breast cancer treatment requires close skin monitoring. CONCLUSION: Pregnancy, menopause, contraceptive use, hormone replacement therapy, and breast cancer treatment drugs result in substantial shifts in hormone levels. Additionally, hormone levels are altered by aromatase inhibitors and anti-estrogen medications. These fluctuations can modulate mechanisms influencing autoimmune skin abnormalities.

HPV51-associated Leiomyosarcoma: A Novel Class of TP53/RB1-Wildtype Tumor With Predilection for the Female Lower Reproductive Tract.

Inactivating mutations in tumor suppressor genes TP53 and RB1 are considered central drivers in leiomyosarcomas (LMSs). In high-risk human papillomavirus (HPV)-related tumors, a similar functional outcome is achieved through oncoproteins E6 and E7, which inactivate the p53 and RB1 proteins, respectively. Here, we hypothesized that HPV infection could provide an alternative mechanism for tumorigenesis in a subset of TP53/RB1-wildtype LMS. We evaluated tumor samples from 2585 consecutive unique patients carrying a diagnosis of gynecologic or soft tissue LMS. Tumor DNA and available RNA were analyzed by hybrid-capture-based next-generation sequencing/comprehensive genomic profiling of 406 genes and transcripts (FoundationOneHeme). Of the initial 2585 cases, we excluded 16 based on the presence of molecular alterations that are considered defining for sarcomas other than LMS. In the remaining 2569 cases, we searched for LMS that were TP53/RB1-wildtype (n=486 of 2569; 18.9%). We also searched LMS tumors for HPV sequences that we then classified into genotypes by de novo assembly of nonhuman sequencing reads followed by alignment to the RefSeq database. Among TP53/RB1-wildtype LMS, we identified 18 unique cases harboring HPV sequences. Surprisingly, most (n=11) were HPV51-positive, and these 11 represented all HPV51-positive tumors in our entire LMS database (n=11 of 2569; 0.4%). The absence of genomic alterations in TP53 or RB1 in HPV51-positive LMS represented a marked difference from HPV51-negative LMS (n=2558; 0% vs. 72% [P<0.00001], 0% vs. 53% [P=0.0002]). In addition, compared with HPV51-negative LMS, HPV51-positive LMS were significantly enriched for genomic alterations in ATRX (55% vs. 24%, P=0.027) and TSC1 (18% vs. 0.6%, P=0.0047). All HPV51-positive LMS were in women; median age was 54 years at surgery (range: 23 to 74 y). All known primary sites were from the gynecologic tract or adjacent anogenital area, including 5 cases of vaginal primary site. Histology was heterogeneous, with evaluable cases showing predominant epithelioid (n=5) and spindle (n=5) morphology. In situ hybridization confirmed the presence of high-risk HPV E6/E7 mRNA in tumor cells in three of three evaluable cases harboring HPV51 genomic sequences. Overall, in our pan-LMS analysis, HPV reads were identified in a subset of TP53/RB1-wildtype LMS. For all HPV51-associated LMS, the striking absence of any detectable TP53 or RB1 mutations and predilection for the female lower reproductive tract supports our hypothesis that high-risk HPV can be an alternative tumorigenic mechanism in this distinct class of LMS.

CDKN2C-Null Leiomyosarcoma: A Novel, Genomically Distinct Class of TP53/RB1-Wild-Type Tumor With Frequent CIC Genomic Alterations and 1p/19q-Codeletion.

PURPOSE: Leiomyosarcoma (LMS) harbors frequent mutations in TP53 and RB1 but few actionable genomic alterations. Here, we searched for recurrent actionable genomic alterations in LMS that occur in the absence of common untreatable oncogenic drivers. METHODS: Tissues from 276,645 unique advanced cancers, including 2,570 uterine and soft tissue LMS, were sequenced by hybrid-capture-based next-generation DNA and RNA sequencing/comprehensive genomic profiling of up to 406 genes. We characterized clinicopathologic features of relevant patient cases. RESULTS: Overall, 77 LMS exhibited homozygous copy loss of CDKN2C at chromosome 1p32.3 (3.0% of LMS). Genomic alterations (GAs) in TP53, RB1, and ATRX were rare compared with the remainder of the LMS cohort (11.7% v 73.4%, 0% v 54.5%, 2.6% v 24.5%, respectively; all P < .0001). CDKN2C-null LMS patient cases were significantly enriched for GAs in CIC (40.3% v 1.4%) at 19q13.2, CDKN2A (46.8% v 7.0%), and RAD51B (16.9% v 1.7%; all P < .0001). Chromosome arm-level aneuploidy analysis of available LMS patient cases (n = 1,284) found that 81% (58 of 72) of CDKN2C-null LMS exhibited 1p/19q-codeletion, a significant enrichment compared with 5.1% in the remainder of the LMS cohort (P < .0001). In total, 99% of CDKN2C-null LMS were in women; the median age was 61 years at surgery (range, 36-81 years). Fifty-five patient cases were uterine primary, four were nonuterine, and the remaining 18 were of uncertain primary site. Sixty percent of cases showed at least focal epithelioid variant histology. Most patients had advanced-stage disease, with 62% of confirmed uterine primary LMS at International Federation of Gynecology and Obstetrics stage IVB. We further validated our findings in two publicly available datasets: The Cancer Genome Atlas and the Project GENIE initiative. CONCLUSION: CDKN2C-null LMS defines a genomically distinct tumor that may have prognostic and/or therapeutic clinical implications, including possible use of specific cyclin-dependent kinase inhibitors.

Vulvar Squamous Cell Carcinoma: Comprehensive Genomic Profiling of HPV+ Versus HPV- Forms Reveals Distinct Sets of Potentially Actionable Molecular Targets.

PURPOSE: Vulvar squamous cell carcinoma (vSCC) encompasses two predominant variants: one associated with detectable high-risk strains of human papillomavirus (hrHPV) and a second form often occurring in the context of chronic dermatitis in postmenopausal women. Genomic assessment of a large-scale cohort of patients with aggressive vSCC may identify distinct mutational signatures. MATERIALS AND METHODS: Tumor samples from a total of 280 patients with vSCC underwent hybridization capture with analysis of up to 406 cancer-related genes. Human papillomavirus (HPV) sequences were detected by de novo assembly of nonhuman sequencing reads and aligned to the RefSeq database. Immunohistochemistry for programmed death-ligand 1 (PD-L1) was assessed. RESULTS: One hundred two of 280 vSCCs (36%) contained hrHPV sequences, predominantly HPV 16 (88%). The HPV-positive (HPV+) group was significantly younger (median age, 59 v 64 years; P = .001). Compared with HPV-negative (HPV-) vSCCs, HPV+ tumors showed more frequent pathogenic alterations in PIK3CA (31% v 16%; P = .004), PTEN (14% v 2%; P < .0001), EP300 (14% v 1%; P < .0001), STK11 (14% v 1%; P < .0001), AR (5% v 0%; P = .006), and FBXW7 (10% v 3%; P = .03). In contrast, HPV- vSCCs showed more alterations in TP53 (83% v 6%; P < .0001), TERTp (71% v 9%; P < .0001), CDKN2A (55% v 2%; P < .0001), CCND1 amplification (22% v 2%; P < .0001), FAT1 (25% v 4%; P < .0001), NOTCH1 (19% v 6%; P = .002), and EGFR amplification (11% v 0%; P < .0001), as well as a higher rate of 9p24.1 (PDL1/PDL2) amplification (5% v 1%) and PD-L1 immunohistochemistry high-positive tumor staining (33% v 9%; P = .04). CONCLUSION: Comprehensive molecular profiles of vSCC vary considerably with hrHPV status and may inform patient selection into clinical trials. Sixty-one percent of HPV+ vSCCs had a pathogenic alteration in the PI3K/mTOR pathway, whereas HPV- vSCCs showed alterations in TP53, TERTp, CDKN2A, CCND1, and EGFR, and biomarkers associated with responsiveness to immunotherapy.

CD164 identifies CD4+ T cells highly expressing genes associated with malignancy in Sézary syndrome: the Sézary signature genes, FCRL3, Tox, and miR-214.

Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), is associated with a significantly shorter life expectancy compared to skin-restricted mycosis fungoides. Early diagnosis of SS is, therefore, key to achieving enhanced therapeutic responses. However, the lack of a biomarker(s) highly specific for malignant CD4+ T cells in SS patients has been a serious obstacle in making an early diagnosis. We recently demonstrated the high expression of CD164 on CD4+ T cells from Sézary syndrome patients with a wide range of circulating tumor burdens. To further characterize CD164 as a potential biomarker for malignant CD4+ T cells, CD164+ and CD164-CD4+ T cells isolated from patients with high-circulating tumor burden, B2 stage, and medium/low tumor burden, B1-B0 stage, were assessed for the expression of genes reported to differentiate SS from normal controls, and associated with malignancy and poor prognosis. The expression of Sézary signature genes: T plastin, GATA-3, along with FCRL3, Tox, and miR-214, was significantly higher, whereas STAT-4 was lower, in CD164+ compared with CD164-CD4+ T cells. While Tox was highly expressed in both B2 and B1-B0 patients, the expression of Sézary signature genes, FCRL3, and miR-214 was associated predominantly with advanced B2 disease. High expression of CD164 mRNA and protein was also detected in skin from CTCL patients. CD164 was co-expressed with KIR3DL2 on circulating CD4+ T cells from high tumor burden SS patients, further providing strong support for CD164 as a disease relevant surface biomarker.

Srcasm inhibits Fyn-induced cutaneous carcinogenesis with modulation of Notch1 and p53.

Src family tyrosine kinases (SFK) regulate cell proliferation, and increased SFK activity is common in human carcinomas, including cutaneous squamous cell carcinomas (SCC) and its precursors. The elevated SFK activity in cutaneous SCCs was modeled using K14-Fyn Y528F transgenic mice, which spontaneously form punctate keratotic lesions, scaly plaques, and large tumors resembling actinic keratoses, SCC in situ, and SCCs, respectively. Lesional tissue showed increased levels of activated SFKs, PDK1, STAT3, and ERK1/2, whereas Notch1/NICD protein and transcript levels were decreased. p53 levels also were decreased in SCC in situ and SCCs. Increasing Srcasm levels using a K14-Fyn Y528F/K14-Srcasm double transgenic model markedly inhibited cutaneous neoplasia. In contrast, increased expression of a nonphosphorylatable Srcasm mutant maintained the neoplastic phenotype. Increasing Srcasm levels decreased levels of Fyn, activated SFKs, ERK1/2, PDK1, and phospho-STAT3, and increased Notch1/NICD and p53 levels. Analysis of human specimens revealed that levels of Fyn and activated SFKs were elevated in SCCs compared with adjacent nonlesional epidermis. In addition, Notch1 and Srcasm protein and transcript levels were decreased in human SCCs compared with nonlesional epidermis. Therefore, the SCCs produced by the Fyn Y528F mice resemble their human counterparts at the molecular level. K14-Fyn Y528F mice represent a robust model of cutaneous carcinogenesis that manifests precancerous lesions and SCCs resembling human disease. The Fyn/Srcasm signaling nexus modulates activity of STAT3, PDK1, ERK1/2, Notch1, and p53. Further study of Fyn and Srcasm should provide insights into the mechanisms regulating keratinocyte proliferation and skin carcinogenesis.