Exploration of MELK as a downstream of Del-1 and druggable targets in triple-negative breast cancer.

PURPOSE: In our previous study, Developmental endothelial locus-1 (Del-1) was a promising predictive marker for breast cancer. However, the downstream targets of Del-1 remain unknown. Here, we sought to discover a druggable target downstream of Del-1 and investigate the mechanism by which it regulates the course of breast cancer. METHODS: To investigate Del-1 downregulation effect on breast cancer, we performed transcriptome analysis using RNA sequencing of Del-1 knockdowned MDA-MB-231 cell line Plus, to investigate the expression of Del-1 and Maternal embryonic leucine zipper kinase (MELK), mRNA levels in eight different triple-Negative Breast Cancer (TNBC) cell lines were analyzed. High-throughput sequencing was performed on total RNA isolated. OTS167 was used for MELK inhibition. The effects of MELK on cell proliferation and invasion were determined using the MTT and Matrigel transwell assays. Furthermore, we examined MELK expression in breast cancer tissue. RESULTS: Del-1 and MELK mRNA expression levels were significantly higher in the TNBC cell lines, MDA-MB-468, HCC-1806, and MBA-MB-231. Knocking down Del-1 with siRNA in HCC-1806 and MBA-MB-231 cells significantly decreased MELK expression and thus suggested a possible relationship between Del-1 and MELK. In MDA-MB-468 cells, a basal-like 1 TNBC cell line, OTS167 significantly inhibited breast cancer cell proliferation and promoted cell apoptosis. To further investigate the relationship between Del-1 and MELK, dual inhibition of both Del-1 and MELK was performed, which significantly reduced the viability of MDA-MB-468 and MBA-MB-231 cells. CONCLUSION: We found that MELK acts downstream of Del-1 and is a promising druggable target, especially in basal-like and mesenchymal stem-like subtype.

Ten-Year Oncologic Outcomes in T1-3N1 Breast Cancer After Targeted Axillary Sampling: A Retrospective Study.

BACKGROUND: Targeted axillary sampling (TAS) is a new surgical concept for the assessment of axillary lymph node status in breast cancer that is hypothesized to be more effective at minimizing postoperative morbidities than axillary lymph node dissection (ALND), provided the metastatic axillary lymph node can be accurately detected without missing data; however, the oncologic outcomes over long-term follow-up have not been sufficiently investigated. This was a retrospective analysis to evaluate the 10-year oncologic outcomes in T1-3N1 breast cancer after TAS. METHODS: Between 2008 and 2013, 230 female patients with cT1-3N1 breast cancer underwent breast and axillary surgery (ALND, n = 171; TAS, n = 59) at our institute. After TAS was applied, additional axillary radiotherapy was performed. Various postoperative complications, including postoperative seroma, lymphedema, and 10-year oncological outcomes, were evaluated and compared between the ALND and TAS groups. RESULTS: Although overall survival during the 10-year follow-up period was better in the TAS group, there was no statistically significant difference in oncologic outcomes, including locoregional recurrence, distant metastasis, and overall survival (p = 0.395, 0.818, and 0.555, respectively). Furthermore, the incidence of lymphedema on the ipsilateral arm was significantly higher in the ALND group (p < 0.001). CONCLUSIONS: The 10-year oncological outcomes of TAS were not inferior to those of conventional ALND in T1-3N1 breast cancers; however, the incidence of lymphedema was significantly higher in the ALND group.

Pellino-1 expression is associated with epidermal proliferation and enhanced Th17 cell infiltration in psoriatic lesions.

Pellino-1 plays a crucial role in cellular proliferation and regulates inflammatory processes. This study investigated Pellino-1 expression patterns and their relationship with CD4+ T-cell subsets in psoriasis patients. Group 1 comprised primarily biopsied psoriasis lesions from 378 patients, multiplex-immunostained for Pellino-1, CD4 and representative T helper (Th) cells (T-bet [Th1], GATA3 [Th2], and RORγt [Th17] and regulatory T cell [FoxP3] markers). Ki-67 labeling was evaluated in the epidermis. Group 2 comprised 43 Pellino-1-positive cases immunostained for Pellino-1 in both lesion and non-lesion skin biopsy samples. Five normal skin biopsies served as controls. Among 378 psoriasis cases, 293 (77.5%) were positive for Pellino-1 in the epidermis. Pellino-1-positivity was higher in psoriasis lesions than in non-lesions and normal skin (52.55% vs. 40.43% vs. 3.48%, p < 0.001; H-score, 72.08 vs. 47.55 vs. 4.40, p < 0.001, respectively). Pellino-1-positive cases also had a significantly higher Ki-67 labeling index (p < 0.001). Epidermal Pellino1-positivity was significantly associated with higher RORγt+ (p = 0.001) and FoxP3+ (p < 0.001) CD4+ T cell ratios but not T-bet+ and GATA3+ CD4+ T cell ratios. Among the CD4+ Pellino-1+ T-cell subsets, the CD4+ Pellino-1+ RORγt+ ratio was significantly associated with epidermal Pellinio-1 expression (p < 0.001). Pellino-1 expression is thus increased in psoriasis lesions and associated with increased epidermal proliferation and CD4+ T-cell subset infiltration, especially Th17 cells. This suggests that Pellino-1 could be a therapeutic target that simultaneously regulates psoriasis epidermal proliferation and immune interactions.

Deep Learning Prediction of TERT Promoter Mutation Status in Thyroid Cancer Using Histologic Images.

Background and objectives: Telomerase reverse transcriptase (TERT) promoter mutation, found in a subset of patients with thyroid cancer, is strongly associated with aggressive biologic behavior. Predicting TERT promoter mutation is thus necessary for the prognostic stratification of thyroid cancer patients. Materials and Methods: In this study, we evaluate TERT promoter mutation status in thyroid cancer through the deep learning approach using histologic images. Our analysis included 13 consecutive surgically resected thyroid cancers with TERT promoter mutations (either C228T or C250T) and 12 randomly selected surgically resected thyroid cancers with a wild-type TERT promoter. Our deep learning model was created using a two-step cascade approach. First, tumor areas were identified using convolutional neural networks (CNNs), and then TERT promoter mutations within tumor areas were predicted using the CNN-recurrent neural network (CRNN) model. Results: Using the hue-saturation-value (HSV)-strong color transformation scheme, the overall experiment results show 99.9% sensitivity and 60% specificity (improvements of approximately 25% and 37%, respectively, compared to image normalization as a baseline model) in predicting TERT mutations. Conclusions: Highly sensitive screening for TERT promoter mutations is possible using histologic image analysis based on deep learning. This approach will help improve the classification of thyroid cancer patients according to the biologic behavior of tumors.

Immune Pathway and Gene Database (IMPAGT) Revealed the Immune Dysregulation Dynamics and Overactivation of the PI3K/Akt Pathway in Tumor Buddings of Cervical Cancer.

Tumor budding (TB) is a small cluster of malignant cells at the invasive front of a tumor. Despite being an adverse prognosis marker, little research has been conducted on the tumor immune microenvironment of tumor buddings, especially in cervical cancer. Therefore, RNA sequencing was performed using 21 formalin-fixed, paraffin-embedded slides of cervical tissues, and differentially expressed genes (DEGs) were analyzed. Immune Pathway and Gene Database (IMPAGT) was generated for immune profiling. "Pathway in Cancer" was identified as the most enriched pathway for both up- and downregulated DEGs. Kyoto Encyclopedia of Genes and Genomes Mapper and Gene Ontology further revealed the activation of the PI3K/Akt signaling pathway. An IMPAGT analysis revealed immune dysregulation even at the tumor budding stage, especially in the PI3K/Akt/mTOR axis, with a high efficiency and integrity. These findings emphasized the clinical significance of tumor buddings and the necessity of blocking the overactivation of the PI3K/Akt/mTOR pathway to improve targeted therapy in cervical cancer.

Transitional cell metaplasia of the uterine cervix: A histopathological and immunohistochemical analysis suggesting a possible role of androgenic conversion during urothelial-like differentiation in peri/postmenopausal women.

Transitional cell metaplasia (TCM) of the uterine cervix and vagina is typically seen in patients with adrenogenital syndrome with high serum androgen levels and in those under androgen treatment as well as in some peri/postmenopausal women. Considering that TCM occurs in patients with increased serum androgen levels, a microenvironment with altered sex hormones might be involved in the urothelial-like differentiation observed in TCM. To investigate a histogenetic role of androgen in TCM development, we compared the distribution patterns and intensity of androgen receptor (AR), estrogen receptor (ER), GATA3 (a transcription factor involved in androgen regulation), Ki-67, and AKR1C3 (an enzyme involved in androgen biosynthesis) expression in normal exocervical mucosa in young women (n = 25), senile atrophy (n = 23), and TCM (n = 29). In TCM, AR, ER, AKR1C3, and GATA3, expression was stronger and significantly increased upward into the intermediate and superficial layers compared with the senile atrophic mucosa and normal mucosa in young women. The epithelial layer in TCM is thicker than that in senile atrophic mucosa, although both conditions may occur in the same age group. Proliferation in TCM was significantly lower than that in young women but slightly higher than that in senile atrophy. Considering the conversion activity of AKR1C3, thicker epithelial layers in TCM compared with those in senile atrophy might be due to increased conversion of androstenedione to testosterone via increased AKR1C3 activity, increased conversion of testosterone to 17ß-estradiol by aromatization, and AR activation.

Toward Interpretable Cell Image Representation and Abnormality Scoring for Cervical Cancer Screening Using Pap Smears.

Screening is critical for prevention and early detection of cervical cancer but it is time-consuming and laborious. Supervised deep convolutional neural networks have been developed to automate pap smear screening and the results are promising. However, the interest in using only normal samples to train deep neural networks has increased owing to the class imbalance problems and high-labeling costs that are both prevalent in healthcare. In this study, we introduce a method to learn explainable deep cervical cell representations for pap smear cytology images based on one-class classification using variational autoencoders. Findings demonstrate that a score can be calculated for cell abnormality without training models with abnormal samples, and we localize abnormality to interpret our results with a novel metric based on absolute difference in cross-entropy in agglomerative clustering. The best model that discriminates squamous cell carcinoma (SCC) from normals gives 0.908±0.003 area under operating characteristic curve (AUC) and one that discriminates high-grade epithelial lesion (HSIL) 0.920±0.002 AUC. Compared to other clustering methods, our method enhances the V-measure and yields higher homogeneity scores, which more effectively isolate different abnormality regions, aiding in the interpretation of our results. Evaluation using an external dataset shows that our model can discriminate abnormality without the need for additional training of deep models.

The Mclust Analysis of Tumor Budding Unveils the Role of the Collagen Family in Cervical Cancer Progression.

In RNA-seq data analysis, condensing the gene count matrix size is pivotal for downstream investigations, particularly pathway analysis. For this purpose, harnessing machine learning attracts increasing interest, while conventional methodologies depend on p-value comparisons. In this study, 20 tissue samples from real-world cervical cancers were subjected to sequencing, followed by the application of the Mclust algorithm to delineate an optimal cluster. By stratifying tumor budding into high and low groups and quantifying the epithelial-to-mesenchymal transition (EMT) score to scrutinize tumor budding, we discerned 24 EMT-related genes, with 5 showing strong associations with cervical cancer prognosis. Our observations elucidate a biological flow wherein EMT, Matrix Metallopep-tidase 2 (MMP2), and extracellular matrix (ECM) degradation are interconnected, ultimately leading to collagen type VI and exacerbating the prognosis of cervical cancer. The present study underscores an alternative method for selecting useful EMT-related genes by employing an appropriate clustering algorithm, thereby avoiding classical methods while unveiling novel insights into cervical cancer etiology and prognosis. Moreover, when comparing high and low tumor budding, collagen type VI emerges as a potential gene marker for the prognosis of cervical cancer.

Improving Tumor-Infiltrating Lymphocytes Score Prediction in Breast Cancer with Self-Supervised Learning.

Tumor microenvironment (TME) plays a pivotal role in immuno-oncology, which investigates the intricate interactions between tumors and the human immune system. Specifically, tumor-infiltrating lymphocytes (TILs) are crucial biomarkers for evaluating the prognosis of breast cancer patients and have the potential to refine immunotherapy precision and accurately identify tumor cells in specific cancer types. In this study, we conducted tissue segmentation and lymphocyte detection tasks to predict TIL scores by employing self-supervised learning (SSL) model-based approaches capable of addressing limited labeling data issues. Our experiments showed a 1.9% improvement in tissue segmentation and a 2% improvement in lymphocyte detection over the ImageNet pre-training model. Using these SSL-based models, we achieved a TIL score of 0.718 with a 4.4% improvement. In particular, when trained with only 10% of the entire dataset, the SwAV pre-trained model exhibited a superior performance over other models. Our work highlights improved tissue segmentation and lymphocyte detection using the SSL model with less labeled data for TIL score prediction.

Role of Tumor-Associated Macrophages in Cervical Cancer: Integrating Classical Perspectives with Recent Technological Advances.

Tumor-associated macrophages (TAMs) play a pivotal role in the tumor microenvironment, influencing cancer progression and contributing to poor prognosis. However, in cervical cancer (CC), their significance and involvement are relatively less studied than in other gynecological cancers such as ovarian and endometrial cancer. This review aims to provide an overview of TAMs, covering their origins and phenotypes and their impact on CC progression, along with major TAM-targeted therapeutic approaches. Furthermore, we advocate for the integration of cutting-edge research methodologies, such as single-cell RNA sequencing and spatial RNA sequencing, to enable in-depth and comprehensive investigations into TAMs in CC, which would be beneficial in leading to more personalized and effective immunotherapy strategies for patients with CC.

Association of human papillomavirus 16 and 18 with ovarian cancer risk: Insights from a meta­analysis.

Ovarian cancer (OC) presents a global health challenge, with well-documented genetic aspects. However, to the best of our knowledge, the role of human papillomavirus (HPV) types 16 and 18 in OC remains unclear. The present meta-analysis assessed the prevalence of HPV in OC across 43 studies and included a comparative meta-analysis of 19 case-control studies to determine the association of HPV with OC risk. Subgroup analyses were performed based on geographic regions and histopathological types to explore heterogeneity, and publication bias was evaluated using funnel plots and statistical tests of asymmetry. The pooled prevalence of HPV was found to be 10% (95% CI, 5-18) and 7% (95% CI, 3-15) specifically for HPV 16/18. Case-control studies indicated an odds ratio (OR) of 4.92 (95% CI, 1.96-12.53) for HPV 16/18, with higher pooled prevalence rates of 17% for all HPV genotypes and 13% for HPV 16/18. Notably, Asian countries exhibited the highest HPV prevalence and OR in OC. These findings support the involvement of HPV, particularly HPV 16 and 18, in increasing the risk of OC, emphasizing the need for further research to confirm these associations and explore potential mechanisms.

Heterogeneity of gut microbiome compositions in the third decade of life in Japanese women: insights from a comparative analysis.

The reasons for sex-associated gut microbiota differences have not been determined, and although sex hormones, diet, and other factors are considered to contribute to them, many of these factors are age related. To shed light on this complex interplay, our study aimed to investigate and compare the gut microbial compositions of males and females across a broad range of ages, aiming to identify sex-associated disparities and potential causal factors. Our study encompassed a comprehensive analysis of gut microbiota data obtained from 444 Japanese individuals, ranging from newborns to centenarians, sourced from the DNA Data Bank of Japan. We categorized the subjects into 13 distinct age groups and examined their relative microbial abundances, as well as alpha and beta diversities, in relation to sex and age. No difference was observed between gut microbiota relative abundances or alpha diversities between men and women at any age. However, the study showed that the heterogeneity of gut microbiota among women in their 20s was greater than in men. To confirm the general occurrence of this difference, we conducted additional analyses using seven datasets: three from Japan and four from other countries. Interestingly, this variance was particularly noticeable within Japanese women. We also showed a potential link between the observed heterogeneity and dietary fiber intake. It is hoped this study will provide clues that aid in the identification of factors responsible for sex-associated differences in gut microbiota compositions.

Long non-coding RNA SOX2OT in tamoxifen-resistant breast cancer.

Hormone receptor (HR)-positive breast cancer can become aggressive after developing hormone-treatment resistance. This study elucidated the role of long non-coding RNA (lncRNA) SOX2OT in tamoxifen-resistant (TAMR) breast cancer and its potential interplay with the tumor microenvironment (TME). TAMR breast cancer cell lines TAMR-V and TAMR-H were compared with the luminal type A cell line (MCF-7). LncRNA expression was assessed via next-generation sequencing, RNA extraction, lncRNA profiling, and quantitative RT-qPCR. SOX2OT overexpression effects on cell proliferation, migration, and invasion were evaluated using various assays. SOX2OT was consistently downregulated in TAMR cell lines and TAMR breast cancer tissue. Overexpression of SOX2OT in TAMR cells increased cell proliferation and cell invasion. However, SOX2OT overexpression did not significantly alter SOX2 levels, suggesting an independent interaction within TAMR cells. Kaplan-Meier plot analysis revealed an inverse relationship between SOX2OT expression and prognosis in luminal A and B breast cancers. Our findings highlight the potential role of SOX2OT in TAMR breast cancer progression. The downregulation of SOX2OT in TAMR breast cancer indicates its involvement in resistance mechanisms. Further studies should explore the intricate interactions between SOX2OT, SOX2, and TME in breast cancer subtypes.

Comparison of immunohistochemistry and next-generation sequencing results in oncogenic PTEN missense mutations.

BACKGROUND: Phosphatase and tensin homolog (PTEN) is one of the most frequently mutated tumor suppressor genes in malignant tumors. Oncogenic PTEN mutations have diagnostic, prognostic, and therapeutic implications. Similar to TP53 mutations, oncogenic PTEN mutations can result from nonsynonymous missense mutations. However, there has been no detailed study on the immunostaining pattern of oncogenic PTEN missense mutations. METHODS: We retrospectively selected 18 cancers (13 endometrial cancers, 2 brain tumors, 1 ovarian cancer, 1 lung cancer, and 1 cancer of unknown origin) harboring oncogenic PTEN missense mutations, which were confirmed by targeted next-generation sequencing. PTEN immunohistochemistry was conducted for all cases, and the results were compared with sequencing results. RESULTS: The immunostaining results of PTEN missense mutations revealed a diverse pattern depending on the site of mutation and co-occurring mutation. The most frequent oncogenic PTEN mutations were R130G (4/18, 22.2 %) and R130Q (3/18, 16.7 %). Eleven cases harbored PTEN missense mutations only, whereas the remaining seven cases harbored PTEN truncating mutations and PTEN missense mutations. Complete loss of cytoplasmic expression were found in five cases, of which three had missense mutation only. PTEN R130 residue mutation alone did not showed altered PTEN immunostaining pattern in this study. CONCLUSIONS: PTEN missense mutation, which comprises a portion of oncogenic PTEN mutation, can manifest as a diverse immunostaining pattern. Complementary testing using both immunostaining and next-generation sequencing should be conducted to accurately evaluate the PTEN status in malignancy.

Validation and Clinical Application of ONCOaccuPanel for Targeted Next-Generation Sequencing of Solid Tumors.

PURPOSE: Targeted next-generation sequencing (NGS) is widely used for simultaneously detecting clinically informative genetic alterations in a single assay. Its application in clinical settings requires the validation of NGS gene panels. In this study, we aimed to validate a targeted hybridization capture-based DNA panel (ONCOaccuPanel) using the Illumina MiSeq sequencing platform. The panel allows the simultaneous detection of single-nucleotide variants (SNVs), insertions, deletions, and copy number changes of 323 genes and fusions of 17 genes in solid tumors. Materials and Methods: We used 16 formalin-fixed paraffin-embedded (FFPE) tumor samples with previously known genetic mutations and one reference material (HD827) for validation. Moreover, we sequenced an additional 117 FFPE tumor samples to demonstrate the clinical utility of this panel. RESULTS: Validation revealed a 100% positive percentage agreement and positive predictive value for the detection of SNVs, insertions, deletions, copy number changes, fusion genes, and microsatellite instability-high types. We observed high levels of reproducibility and repeatability (R2 correlation coefficients=0.96-0.98). In the limit of detection assessment, we identified all clinically relevant genes with allele frequencies > 3%. Furthermore, the clinical application of ONCOaccuPanel using 117 FFPE samples demonstrated robust detection of oncogenic alterations. Oncogenic alterations and targetable genetic alterations were detected in 98.2% and 27.4% cases, respectively. CONCLUSION: ONCOaccuPanel demonstrated high analytical sensitivity, reproducibility, and repeatability and is feasible for the detection of clinically relevant mutations in clinical settings.

Profiling of Lymphovascular Space Invasion in Cervical Cancer Revealed PI3K/Akt Signaling Pathway Overactivation and Heterogenic Tumor-Immune Microenvironments.

Lymphovascular space invasion (LVSI) is the presence of tumor emboli in the endothelial-lined space at the tumor body's invasive edge. LVSI is one of three Sedlis criteria components-a prognostic tool for early cervical cancer (CC)-essential for indicating poor prognosis, such as lymph node metastasis, distant metastasis, or shorter survival rate. Despite its clinical significance, an in-depth comprehension of the molecular mechanisms or immune dynamics underlying LVSI in CC remains elusive. Therefore, this study investigated tumor-immune microenvironment (TIME) dynamics of the LVSI-positive group in CC. RNA sequencing included formalin-fixed paraffin-embedded (FFPE) slides from 21 CC patients, and differentially expressed genes (DEGs) were analyzed. Functional analysis and immune deconvolution revealed aberrantly enriched PI3K/Akt pathway activation and a heterogenic immune composition with a low abundance of regulatory T cells (Treg) between LVSI-positive and LVSI-absent groups. These findings improve the comprehension of LSVI TIME and immune mechanisms, benefiting targeted LVSI therapy for CC.

Relationship between Human Papillomavirus Status and the Cervicovaginal Microbiome in Cervical Cancer.

Uterine cervical cancer (CC) is a complex, multistep disease primarily linked to persistent infection with high-risk human papillomavirus (HR-HPV). However, it is widely acknowledged that HR-HPV infection alone cannot account for the formation and progression of CC. Emerging evidence suggests that the cervicovaginal microbiome (CVM) also plays a significant role in HPV-related CC. Certain bacteria, such as Fusobacterium spp., Porphyromonas, Prevotella, and Campylobacter, are currently being considered as potential microbiomarkers for HPV-positive CC. However, the composition of the CVM in CC is inconsistent; thus, further studies are needed. This review comprehensively discusses the complex interplay between HPV and the CVM in cervical carcinogenesis. It is postulated that the dynamic interaction between HPV and the CVM creates an imbalanced cervicovaginal microenvironment that triggers dysbiosis, enhances HPV persistence, and promotes cervical carcinogenesis. Moreover, this review aims to provide updated evidence on the potential role of bacteriotherapy, particularly probiotics, in the treatment of CC.

Transcriptomic Network Analysis Using Exfoliative Cervical Cells Could Discriminate a Potential Risk of Progression to Cancer in HPV-related Cervical Lesions: A Pilot Study.

BACKGROUND/AIM: Cervical cancer is the fourth most common type of cancer in women worldwide and it is a major cause of cancer-related deaths in developing countries. Despite the marked reduction observed in the rates of the disease as a result of screening programs, it is necessary to develop robust biomarkers that can detect the neoplastic progression early in HPV-related cervical lesions. MATERIALS AND METHODS: We performed comparative mRNA sequencing from exfoliative cervical cytology samples from nine Korean women using the Illumina NovaSeq6000 platform. Each pathological tissue was matched to the corresponding cytological sample. The pathologic diagnosis was scrutinized with ancillary immunohistochemistry and was considered a confirmative (endpoint) diagnosis. The pathological diagnoses consisted of three cases of chronic cervicitis, 2 high-grade squamous intraepithelial lesions (HSILs), 2 squamous cell carcinomas in situ (CIS), and 2 invasive squamous cell carcinomas (SQCCs), respectively. Using bioinformatic analyses, differentially expressed genes (DEGs; fold change ≥1.5; p<0.05) were applied for Gene Ontology (GO), Gene Set Enrichment Analysis (GSEA), and protein-protein interaction (PPI) networks. RESULTS: From a total of 55,882 genes, 438 DEGs were pinpointed; 282 genes were up-regulated and 156 genes down-regulated. These transcriptomic profiles were clearly divided into neoplastic (HSIL, CIS, and SQCC; ≥HSILs) and non-neoplastic lesions. The up-regulated DEGs were HIF-1a, EDN1, PIK3R3, PPP1CA and AKR1C1. GO, GSEA, and PPI network analyses showed marked associations with metabolism, proteolysis, or proteoglycan process pathways in cervical carcinogenesis. CONCLUSION: The transcriptomic analysis using exfoliative cervical cells was more likely representative of its corresponding histopathological diagnosis, thus emphasizing its potential utility in clinical practice. This study provides comprehensive transcriptomic network analyses for robust biomarkers that might present a high potential risk of progression to cancer in the exfoliative cervical cytology; our findings support their clinical utility for improved cervical cancer screening.

PIK3CA Mutations as a Prognostic Factor in Patients With Residual Rectal Cancer After Neoadjuvant Chemoradiotherapy.

BACKGROUND/AIM: PIK3CA mediates various cellular processes, such as transformation, tumor initiation and proliferation, and resistance to apoptosis. This study was conducted to identify the clinical significance and prognostic effect of PIK3CA mutations in patients with residual rectal cancer who underwent surgery after neoadjuvant chemoradiotherapy (NACRT). PATIENTS AND METHODS: Formalin-fixed and paraffin-embedded surgical specimens were collected from 128 patients between January 2006 and December 2011 and analyzed using real-time polymerase chain reaction for hotspot mutations in exons 9 and 20 of the PIK3CA gene. RESULTS: Of the 128 patients, 109 were analyzed and 19 were excluded because of poor DNA quality. Mutations in PIK3CA were identified in three patients (2.8%), all of which were detected in exon 20 of the PIK3CA gene. PIK3CA mutations significantly correlated with lymphatic invasion (p=0.016), lymph node metastasis (p=0.034), and higher pathological disease stage (p=0.040). By univariate analysis, patients with PIK3CA mutations were observed to have significantly shorter cancer-specific survival (CSS) (p=0.001) and disease-free survival (DFS) (p=0.006) than PIK3CA wild-type patients. However, PIK3CA mutations were not an independent prognostic factor for CSS (p=0.319) or DFS (p=0.219) in multivariate modeling. CONCLUSION: Our findings indicate that PIK3CA mutation plays a role in oncogenesis in rectal cancer and may be considered as a candidate therapeutic approach targeting the PIK3/Akt/mTOR pathway in patients with residual rectal cancer after NACRT.