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Cervical cancer (CC) is a global public health concern, primarily caused by persistent infection with oncogenic types of human papillomavirus (HPV). The World Health Organization (WHO) has established a plan to eliminate CC as a public health issue by the year 2100. However, the implementation of the HPV vaccine is impeded by vaccine restrictions and misinformation despite its demonstrated effectiveness. The CC treatment is influenced by the disease stage, with an unfavorable prognosis for those in advanced stages. This study aimed to investigate the potential of long non-coding RNAs (lncRNAs) in CC by identifying and characterizing related lncRNAs, elucidating their regulatory mechanisms and molecular interactions, and analyzing their expression patterns in patients with diverse responses to chemoradiotherapy. Non-stem cells from CC were isolated using flow cytometry sorting and used for total RNA extraction. The RNA was used to build libraries that were subsequently sequenced using the Illumina Nextseq 550.417 lncRNAs that showed differentially expressed between CC patients who responded or not to treatment. Further analysis demonstrated that these lncRNAs significantly interact with several molecules, which play crucial roles in CC progression and therapeutic resistance. Statistical analysis correlated the expression profile of these lncRNAs with treatment efficacy. Three lncRNAs, ENSG00000267838 , ENSG00000266340 , and FRMD6-AS1 , were identified with positive expression related to non-response to chemoradiotherapy and worse progression-free survival in CC patients. Specifically, lncRNA ENSG00000267838 has its up-regulation related to non-response and down-regulation to response to chemoradiotherapy treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Aim: This study investigated RAP1 immunostaining variation in different cell types during CC progression. Methods: Paraffin-embedded cervical tissues from 101 patients were categorized into control, pre-neoplastic and neoplastic groups. RAP1 immunolocalization, HPV detection and genotyping were performed. A semiquantitative immunoreactive score was employed to compare labeling intensity, cellular localization, nuclear labeling, percentage and distribution of reactive cells. Results: 73% (72/99) of cervical specimens were HPV+. RAP1 was localized in the nucleus and cytoplasm of all samples. Cytoplasmic RAP1 immunoscore was higher than nuclear score in all CC groups. RAP1 intensity increased with lesion severity. SCC samples exhibited predominantly intense RAP1 immunostaining. Conclusion: RAP1 is an efficient biomarker for detecting invasive CC lesions but has limited utility in distinguishing SCC grades.

Cervical cancer (CC) is a major cause of death and suffering to women globally with 570,000 new cases in 2017. It disproportionately affects those living in resource-constrained countries such as Brazil, with 90% of the deaths from CC happening in low and middle-income countries. Early detection is still the best strategy for improving response to therapy and survival and cases detected in advanced stages show variable response rates to the standard chemoradiation therapy protocols. Both the genetic landscape and the immune status of patients can dramatically affect cancer progression and response to therapy, as well as disease recurrence. Here we performed a comprehensive sequencing analysis using the cancer gene panel - Ion AmpliSeq™ Cancer hotspot Panel V2 CHPv2, as well as determined the immune infiltrate composition of a group of locally advanced CC patients with the goal of identifying genetic and immune characteristics associated with a clinical response to therapy. The expression levels of CD68 + tumor-associated macrophages (TAMs) and CD8 + tumor-infiltrating lymphocytes (TILs), as well as the immune checkpoint molecules PD-1, PD-L1 and PD-L2 in stroma and in tumor regions were analyzed by immunohistochemistry (IHC). The HPV infection status with high-risk strains was also determined. Twenty-one samples from patients with squamous cell carcinoma segregated into responder (11) and non-responder (10) groups according to standard chemoradiation therapy response were studied. Our findings indicate that responder patients showed an increase of an inflammatory tumor microenvironment as indicated by higher numbers of CD8 + and PD-L2 + TILs, as well as higher expression of PD-L1 immunoreactive area, as compared to the non-responder group. Additionally, our results demonstrate a correlation between the number of gene mutations and PD-L2 + TILs in the responder group. The genes PIK3CA and KDR/VEGFR were the most mutated genes, corroborating past findings. Together, these findings indicate an inflammatory tumor microenvironment present in patients that will respond to future chemoradiation treatment as compared to those that will not. This points to possible future predictors of response to therapy in CC patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Renal medullary carcinomas (RMCs) and collecting duct carcinomas (CDCs) are rare subsets of lethal high-stage, high-grade distal nephron-related adenocarcinomas with a predilection for the renal medullary region. Recent findings have established an emerging group of fumarate hydratase (FH)-deficient tumors related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC-RCCs) syndrome within this morphologic spectrum. Recently developed, reliable ancillary testing has enabled consistent separation between these tumor types. Here, we present the clinicopathologic features and differences in the morphologic patterns between RMC, CDC, and FH-deficient RCC in consequence of these recent developments. This study included a total of 100 cases classified using contemporary criteria and ancillary tests. Thirty-three RMCs (SMARCB1/INI1-deficient, hemoglobinopathy), 38 CDCs (SMARCB1/INI1-retained), and 29 RCCs defined by the FH-deficient phenotype (FH/2SC or FH/2SC with FH mutation, regardless of HLRCC syndromic stigmata/history) were selected. The spectrum of morphologic patterns was critically evaluated, and the differences between the morphologic patterns present in the 3 groups were analyzed statistically. Twenty-five percent of cases initially diagnosed as CDC were reclassified as FH-deficient RCC on the basis of our contemporary diagnostic approach. Among the different overlapping morphologic patterns, sieve-like/cribriform and reticular/yolk sac tumor-like patterns favored RMCs, whereas intracystic papillary and tubulocystic patterns favored FH-deficient RCC. The tubulopapillary pattern favored both CDCs and FH-deficient RCCs, and the multinodular infiltrating papillary pattern favored CDCs. Infiltrating glandular and solid sheets/cords/nested patterns were not statistically different among the 3 groups. Viral inclusion-like macronucleoli, considered as a hallmark of HLRCC-RCCs, were observed significantly more frequently in FH-deficient RCCs. Despite the overlapping morphology found among these clinically aggressive infiltrating high-grade adenocarcinomas of the kidney, reproducible differences in morphology emerged between these categories after rigorous characterization. Finally, we recommend that definitive diagnosis of CDC should only be made if RMC and FH-deficient RCC are excluded.

The common histopathologic subtypes of renal epithelial neoplasms include conventional, or clear cell, renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, and renal oncocytoma. These subtypes differ clinically and pathologically, making accurate classification important. However, this differential diagnosis can be challenging because of overlapping morphology, suggesting a potential utility for ancillary immunohistochemical markers. We used cDNA microarrays to identify candidate markers for distinguishing renal tumor subtypes. In this report we validated differential expression of three candidate markers, beta defensin-1, parvalbumin, and vimentin, and evaluated the use of this immunohistochemical panel as a potential diagnostic tool. Consistent with our cDNA microarray data, chromophobe RCCs and oncocytomas exhibited similar expression profiles: 8 of 8 examples of each subtype were immunohistochemically positive for beta defensin-1 and parvalbumin and negative for vimentin (sensitivity 100%, specificity 100%); 4 of 7 papillary RCCs were positive for beta defensin-1, parvalbumin, and vimentin (sensitivity 57%, specificity 97%); and 22 of 23 conventional RCCs were negative for beta defensin-1, parvalbumin, or both markers (sensitivity 96%, specificity 96%) as well as positive for vimentin (sensitivity 83%). The immunohistochemical panel distinguished renal tumor subtypes with greater specificity than any marker used alone. This work demonstrates that a useful panel of immunohistochemical markers can be derived from differential gene expression profiles determined using cDNA microarrays.