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Endocervical adenocarcinoma (ECA) is reported increasingly often in young women, and this aggressive disease lacks effective methods of targeted therapy. Since mismatch repair deficiency (dMMR) is an important biomarker for predicting response to immune checkpoint inhibitors, it is important to investigate the clinicopathological features and immune microenvironment of dMMR ECAs. We assessed 617 ECAs from representative tissue microarray sections, gathered clinicopathologic information, reviewed histological characteristics, and performed immunohistochemical staining for MMR, programmed cell death 1 (PD-L1), and other immune markers. Of 617 ECA samples, 20 (3.2%) cases had dMMR. Among them, loss of MMR-related proteins expression was observed in 17/562 (3.0%) human papilloma virus-associated (HPVA) adenocarcinoma and 3/55 (5.5%) non-HPV-associated (NHPVA) adenocarcinoma. In NHPVA cohort, dMMR status was observed in 3 (3/14, 15.0%) patients with clear cells. dMMR ECAs had a higher tendency to have a family history of cancer, larger tumor size, p16 negative, HPV E6/E7 mRNA in situ hybridization (HPV E6/E7 RNAscope) negative, and lower ki-67 index. Among the morphological variables evaluated, poor differentiation, necrosis, stromal tumor-infiltrating lymphocytes, peritumoral lymphocytes, and lymphoid follicles were easily recognized in the dMMR ECAs. In addition, dMMR ECAs had higher CD3+, CD8+, CD38+, CD68+ and PD-1+ immune cells. A relatively high prevalence of PD-L1 expression was observed in dMMR ECAs. dMMR ECAs were significantly more likely to present with a tumor-infiltrating lymphocytes -high/PD-L1-positive status. In conclusion, dMMR ECAs have some specific morphological features and a critical impact on the immune microenvironment, which may provide insights into improving responses to immunotherapy-included comprehensive treatment for ECAs in the future.
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Neoadjuvant chemotherapy (NACT) is a viable therapeutic option for women diagnosed locally advanced cervical cancer (LACC). However, the factors influencing pathological response are still controversial. We collected pair specimens of 185 LACC patients before and after receiving NACT and conducted histological evaluation. 8 fresh tissues pre-treatment were selected from the entire cohort to conducted immune gene expression profiling. A novel pathological grading system was established by comprehensively assessing the percentages of viable tumor, inflammatory stroma, fibrotic stroma, and necrosis in the tumor bed. Then, 185 patients were categorized into either the good pathological response (GPR) group or the poor pathological response (PPR) group post-NACT, with 134 patients (72.4%, 134/185) achieving GPR. Increasing tumor-infiltrating lymphocytes (TILs) and tumor-infiltrating lymphocytes volume (TILV) pre-treatment were correlated with GPR, with TILV emerging as an independent predictive factor for GPR. Additionally, CIBERSORT analysis revealed noteworthy differences in the expression of immune makers between cPR and non-cPR group. Furthermore, a significantly heightened density of CD8 + T cells and a reduced density of FOXP3 + T cells were observed in GPR than PPR. Importantly, patients exhibiting GPR or inflammatory type demonstrated improved overall survival and disease-free survival. Notably, stromal type was an independent prognostic factor in multivariate analysis. Our study indicates the elevated TILV in pre-treatment specimens may predict a favorable response to NACT, while identifying stromal type in post-treatment specimens as an independent prognostic factor. Moreover, we proposed this pathological grading system in NACT patients, which may offer a more comprehensive understanding of treatment response and prognosis.
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Linfocitos Infiltrantes de Tumor , Terapia Neoadyuvante , Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Persona de Mediana Edad , Linfocitos Infiltrantes de Tumor/inmunología , Adulto , Resultado del Tratamiento , Anciano , Supervivencia sin EnfermedadRESUMEN
BACKGROUND: Uterine tumors resembling ovarian sex cord tumor (UTROSCT) is a rare neoplasm of unknown etiology and has undetermined malignant potential. The emergence of recurrent UTROSCT case reports has led to its initial identification as a tumor of low malignancy potential. Owing to its low incidence, we currently lack any in-depth studies regarding the subset of UTROSCTs that may be aggressive in nature. Here, we sought to identify unique characteristics in aggressive UTROSCT. METHODS: 19 cases of UTROSCT were collected. Their histologic and tumor immune microenvironment were evaluated by three gynecologic pathologists. The gene alteration was also detected by RNA sequencing. For later analyses regarding differences between benign and malignant tumors, we supplemented our 19 included cases with additional reports from the literature. RESULTS: Interestingly, we found PD-L1 expression in stromal tumor-infiltrating immune cells (stromal PD-L1) was markedly higher in aggressive UTROSCT. Patients with high stromal PD-L1 (≥ 22.5 cells/mm2) had worse prognosis. When our cases were added with previous cases identified in the literature, we discovered that aggressive UTROSCT was more likely to have significant mitotic activity and NCOA2 gene alterations than benign UTROSCT. Consistence with those results, patients with significant mitotic activity and gene alteration of NCOA2 had worse prognoses. CONCLUSIONS: Collectively, high expression of stromal PD-L1, significant mitotic activity, and gene alteration of NCOA2 may be useful markers to predict aggressive UTROSCT.
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Tumores de los Cordones Sexuales y Estroma de las Gónadas , Neoplasias Uterinas , Humanos , Femenino , Antígeno B7-H1 , Recurrencia Local de Neoplasia , Útero , Microambiente TumoralRESUMEN
Endocervical adenocarcinoma (ECA), harboring poor prognosis, is divided into human papilloma virus (HPV)-associated adenocarcinoma (HPVA) and non-HPVA (NHPVA), each consisting of a heterogeneous immune microenvironment. We aim to examine the effect of CKLF-like MARVEL transmembrane domain 6 (CMTM6), a key regulator of PD-L1, on ECA. Immunohistochemistry and RNA-sequencing (RNA-seq) were used to detect CMTM6, Programmed death ligand 1 (PD-L1), and immune cells biomarkers levels in tumors. RT-qPCR and Western Blotting were used to detect the mRNA and protein level changed in cells. The expression of CMTM6 in ECA is upregulated compared to cervical squamous cell carcinoma tissues. More infiltrating T cells were observed in CMTM6high ECA tissues, especially in CMTM6high HPVA. Higher expression of CMTM6 is associated with a higher rate of infiltrating CD8+ T cells in HPVA, but not in NHPVA. ECA patients were divided into three groups according to the co-expression status of CMTM6 and PD-L1(CPS) . Patients with CMTM6high /PD-L1(CPS+) had the longest OS and DFS, especially in NHPVA patients. Moreover, knock down of CMTM6 promotes ECA cell proliferation via the p53 pathway. CMTM6 recruits T cells, suppresses ECA cell proliferation via the p53 pathway and can be used as a novel prognostic indicator for ECA patients.
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Adenocarcinoma , Neoplasias del Cuello Uterino , Femenino , Humanos , Antígeno B7-H1/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/análisis , Linfocitos T CD8-positivos , Proliferación Celular , Microambiente TumoralRESUMEN
BACKGROUND: Immune-related adverse events (irAEs) are side effects that reflect the activation of patients' immune systems after treatment with immune checkpoint inhibitors (ICIs). However, there is no meta-analysis on the effect of early irAEs on patient survival. Thus, we assessed the association between early irAEs and the survival of patients treated with ICIs. METHODS: PubMed, Embase, and Web of Science were searched from May 2010 to May 2020 for all the retrospective and prospective comparative studies to evaluate the hazard ratios (HRs) for death. A random-effects model was used to calculate the pooled HR for death, and heterogeneity was assessed using I² statistics. The main outcomes were overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 11 reports with 2077 patients were included. A significant association was observed between early irAEs and a favorable clinical outcome. Patients with early irAEs had prolonged OS (HR: 0.62, 95% confidence interval (CI): 0.53-0.74, p < 0.001) and PFS (HR: 0.53, 95% CI: 0.41-0.66, p < 0.001) compared to those without; these results were confirmed using a sensitivity analysis. The irAE types, malignancy types, and sample size were correlated with patients' clinical outcomes. CONCLUSIONS: Early irAEs, especially cutaneous irAEs, correlated with a better clinical outcome in patients treated with ICIs.
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AIMS: To develop and verify pathological models using pathological features basing on HE images to predict survival invasive endocervical adenocarcinoma (ECA) postoperatively. METHODS: There are 289 ECA patients were classified into training and validation cohort. A histological signature was produced in 191 patients and verified in the validation groups. Histological models combining the histological features were built, proving the incremental value of our model to the traditional staging system for individualised prognosis estimation. RESULTS: Our model included five chosen histological characteristics and was significantly related to overall survival (OS). Our model had AUC of 0.862 and 0.955, 0.891 and 0.801 in prognosticating 3-year and 5 year OS in the training and validation cohort, respectively. In training cohorts, our model had better performance for evaluation of OS (C-index: 0.832; 95% CI 0.751 to 0.913) than International Federation of Gynecology and Obstetrics (FIGO) staging system (C-index: 0.648; 95% CI 0.542 to 0.753) and treatment (C-index: 0.687; 95% CI 0.605 to 0.769), with advanced efficiency of the classification of survival outcomes. Furthermore, in both cohorts, a risk stratification system was built that was able to precisely stratify stage I and II ECA patients into high-risk and low-risk subpopulation with significantly different prognosis. CONCLUSIONS: A nomogram with five histological signatures had better performance in OS prediction compared with traditional staging systems in ECAs, which might enable a step forward to precision medicine.
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Adenocarcinoma , Nomogramas , Humanos , Pronóstico , Estadificación de Neoplasias , Factores de Riesgo , Adenocarcinoma/patologíaRESUMEN
The metastatic or recurrent potential of localized human papillomavirus-associated endocervical adenocarcinoma (HPVA EAC) is difficult to predict, especially based upon biopsy alone. Recent analyses of small cohorts indicate that high tumor nuclear grade (TNG) and the presence of necrotic tumor debris (NTD) from HPVA EACs in cervical biopsy specimens are highly predictive of nodal metastasis (NM). In the present study, we aimed to investigate how reliably tumoral morphologic features from cervical biopsy specimens predict NM or tumor recurrence (TR) and patient outcomes in a large cohort of endocervical adenocarcinoma patients. A cohort comprised of 397 patients with HPVA EAC treated at 18 institutions was identified, and cervical biopsies were paired with their associated complete tumor resections for a total of 794 specimens. A variety of tumoral histologic features were examined for each paired specimen, including TNG (assessed on a 3-tiered scale of increasing abnormalities-TNG1, TNG2, TNG3) and NTD (defined by the presence of necrotic and apoptotic tumor cells within tumor glandular lumens admixed with granular and eosinophilic amorphous material and inflammatory cells), which were correlated with outcomes. The distribution of TNG in biopsies was as follows: 86 (21.7%) TNG1, 223 (56.2%) TNG2, and 88 (22.2%) TNG3. NTD was identified in 176 (44%) of the biopsy specimens. The sensitivity, specificity, positive predictive value, and negative predictive value of a TNG1 assignment in the biopsy being predictive of the same assignment in the full resection were 0.82 (95% confidence interval [CI]: 0.7-0.9), 0.895 (0.86-0.93), 0.593 (0.48-0.696), and 0.96 (0.94-0.98), respectively. Respective values for an NTD-negative status were 0.89 (95% CI: 0.83-0.92), 0.715 (0.64-0.77), 0.72 (0.65-0.77), and 0.89 (0.83-0.93), respectively. Compared with the other cases in each category, both TNG1 and an NTD-negative status were each significantly associated with lower rates of NM (odds ratio for TNG1=0.245, 95% CI: 0.070-0.857, P=0.0277; for NTD=0.199, 95% CI: 0.094-0.421, P<0.0001) and TR (odds ratio for TNG1=0.225, 95% CI: 0.051-0.987, P=0.0479; for NTD=0.367, 95% CI: 0.171-0.786, P=0.0099) independent of depth of stromal invasion, lymphovascular invasion, tumor size, FIGO stage, and Silva pattern. Overall, 73/379 (19%) cases were both TNG1 and NTD-negative on the biopsy, and none of these 73 cases showed NM (0%), but a single case (1.4%) showed TR. In contrast, among the 324 biopsies with TNG2/3 and/or presence of NTD, 62 (19.1%) had NM, and 41 (12.9%) had TR. In summary, 2 variables in combination (ie, TNG1 and NTD-negative) identified a subset of HPVA EAC patients-â¼19%-with a 0% frequency of nodal metastases and only 1.4% frequency of recurrence. Biopsies highly but imperfectly predicted these features. Nonetheless, these findings may potentially be of clinical utility in the risk stratification of patients with HPVA EACs. This may allow some patients with a minimal risk of nodal metastases and TR to be identified at the biopsy phase, thereby facilitating more personalized, possibly less aggressive treatment.
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Adenocarcinoma , Carcinoma , Neoplasias del Cuello Uterino , Adenocarcinoma/patología , Biopsia , Femenino , Humanos , Recurrencia Local de Neoplasia/patología , Papillomaviridae , Neoplasias del Cuello Uterino/patologíaRESUMEN
BACKGROUND: Human papillomavirus (HPV) E6/E7 mRNA in situ hybridization (HPV E6/E7 RNAscope) appears to be a sensitive and specific technique in detecting transcriptionally active HPV. We aimed to examine the diagnostic utility of this technique in endocervical adenocarcinoma (ECA), to explore the prognostic factors for ECA patients and develop a clinically useful nomogram based on clinicopathological parameters to predict it. METHODS: We retrospectively analyzed 200 patients with ECA who had undergone surgery at Sun Yat-sen University Cancer Center from 2010 and 2014. The diagnostic performance of HPV E6/E7 RNAscope were evaluated by receiver operating characteristic (ROC) curve. A prognostic nomogram model including HPV E6/E7 RNAscope was generated based on multivariate Cox regression analysis, then we compared the predictive accuracy of the prognostic model with FIGO staging and treatment using concordance index (C-index), time-dependent ROC (tdROC), and decision curve analysis (DCA). RESULTS: The sensitivity and specificity of HPV E6/E7 RNAscope for distinguishing HPV-associated adenocarcinoma (HPVA) from non-HPV-associated adenocarcinoma (NHPVA) in the whole cohort were 75.8% and 80%, respectively. According the univariate analysis and multivariate logistic regression analysis, age, lymphovascular invasion (LVI), lymph node involvement (LNI), and HPV E6/E7 RNAscope were valuable predictive factors for OS. These parameters were incorporated into the nomogram model (nomogram A) compared with FIGO stage and treatment. The C-index of nomogram A for predicting OS was 0.825, which was significantly higher than FIGO stage (C-index = 0.653, p = 0.002) and treatment (C-index = 0.578, p < 0.001). CONCLUSIONS: HPV E6/E7 RNAscope is highly specific for ECA, and the 4-variable nomogram showed more accurate prognostic outcomes in patients with ECA.
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RNA-binding proteins (RBPs) play crucial roles in the post-transcriptional regulation of mRNA during numerous physiological and pathological processes, including tumor genesis and development. However, the role of RNA-binding motif protein 43 (RBM43) in esophageal squamous cell carcinoma (ESCC) has not been reported so far. The current study was the first to evaluate RBM43 protein expression by immunohistochemistry (IHC) in an independent cohort of 207 patients with ESCC, to explore its potential prognostic value and clinical relevance in ESCC. The results indicated that RBM43 protein levels were significantly elevated in ESCC tissues and increased RBM43 expression was associated with age and N categories. In addition, ESCC patients with high expression of RBM43 had shorter overall survival (OS) and disease-free survival (DFS) than those with low RBM43 expression. Furthermore, when survival analyses were conducted at different clinical stages, overexpression of RBM43 was significantly correlated with shortened survival in patients with ESCC at early stages (TNM stage I-II and N0 stage). Cox regression analysis further proved that high RBM43 expression was an independent predictor of poor prognosis in ESCC patients. In conclusion, increased expression of RBM43 is correlated with malignant attributes to ESCC and predicts unfavorable prognosis, suggesting an effective prognostic biomarker and potential therapeutic target for ESCC.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Neoplasias de Cabeza y Cuello , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Pronóstico , Motivos de Unión al ARNRESUMEN
BACKGROUND AND AIM: To assess the profile of global histone modifications in small hepatocellular carcinoma (small HCC) and identify its prognostic value in predicting recurrence. METHODS: The expression profiles of global histone modifications, including H2AK5AC, H2BK20AC, H3K4me2, H3K9AC, H3K18AC, H4K12AC, and H4R3me2, were evaluated with immunohistochemistry in 335 HBV related small HCC patients. Two histone signature classifiers were then developed using least absolute shrinkage and selection operator Cox regression. A nomogram was built using the classifier and independent risk factors. The performances of the classifier and nomogram were assessed by receiver operating characteristic curves. RESULTS: Histone modifications were more pronounced in tumor tissues than in adjacent liver tissues. In tumor tissues, the risk score built based on the seven-histone signature exhibited satisfactory prediction efficiency, with an AUC = 0.71 (0.63-0.79) for 2-year survival in the training cohort. Patients with a high risk score had shorter recurrence-free survival than those with a low risk score (HR: 1.96, 95% CI: 1.24-3.08, p = 0.004; HR: 1.95, 95% CI: 1.12-3.42, p = 0.019; and HR: 1.97, 95% CI: 1.39-2.80, p < 0.001 for the training, validation and total cohorts, respectively). Furthermore, the statistical nomogram built using the histone classifier for early recurrence had a C-index = 0.68. In non-neoplastic liver tissues, the hepatic signature based on H3K4me2 and H4R3me2 was related to late recurrence (HR: 2.00, 95% CI: 1.15-3.48, p = 0.01). CONCLUSION: Global histone modifications in tumor and adjacent liver tissues are novel predictors of early and late recurrence, respectively, in HBV-related small HCC patients.
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BACKGROUND: Endocervical adenocarcinoma (ECA) is further classified as human papillomavirus (HPV)-associated (HPVA) or non-HPVA (NHPVA), per the International Endocervical Adenocarcinoma Criteria and Classification (IECC). HPVA is a glandular tumor with stromal invasion and/or exophytic expansile-type invasion, associated with the typical molecular characteristics of high-risk HPV (HR-HPV) infection. Transforming acidic coiled-coil protein-3 (TACC3),an oncogene that is frequently abnormally expressed,represents a vital biomarker for multiple human malignancies. This study aimed to examine the role of TACC3 in the diagnosis and prognosis of ECA. METHODS: We analyzed 264 patients with ECA who underwent surgical resection, classifying their tumors into HPVA and NHPVA subtypes. The expression levels of TACC3, P16, MLH1, PMS2, MSH2, MSH6 and Ki-67 in tumors were evaluated by tissue microarray using immunohistochemistry (IHC). HPV subtypes were identified in formalin-fixed paraffin-embedded (FFPE) ECA tissues by the polymerase chain reaction (PCR). RESULTS: ECA samples showed increased TACC3 expression relative to adjacent non-carcinoma samples. TACC3 expression was higher in HPVA than in NHPA. In the HPVA subtype, high TACC3 expression was significantly correlated with P16-positive, Ki-67-high expression. Furthermore, TACC3 levels were significantly related to tumor histological type (P = 0.006), nerve invasion (P = 0.003), differentiation (P = 0.004), surgical margin (P = 0.012), parametrium invasion (P = 0.040), P16 expression (P < 0.001), and Ki-67 (P = 0.004). Additionally, Kaplan-Meier analysis showed that TACC3 upregulation was associated with poor overall survival (OS, P = 0.001), disease-free survival (DFS, P < 0.001), and recurrence survival (P < 0.001). Multivariate analysis indicated that elevated TACC3 expression served as a marker to independently predict ECA prognosis. ROC curve analyses indicated that TACC3, P16, and HPV subtypes showed similar utility for distinguishing HPVA from NHPVA, with areas under the ROC curves of 0.640, 0.649, and 0.675, respectively. The combination of TACC3 and HPV subtypes improved the diagnostic performance of ECA compared with TACC3, P16, and HPV subtypes alone. CONCLUSIONS: Taken together, our findings identify that TACC3 is a promising complementary biomarker for diagnosis and prognosis for patients with ECA.
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Biomarcadores , Carcinoma in Situ/diagnóstico , Carcinoma in Situ/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/metabolismo , Adulto , Carcinoma in Situ/etiología , Carcinoma in Situ/mortalidad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Papillomaviridae , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/virología , Pronóstico , Curva ROC , Análisis de Matrices Tisulares , Neoplasias del Cuello Uterino/etiología , Neoplasias del Cuello Uterino/mortalidad , Adulto JovenRESUMEN
Centrosomal protein 55 (CEP55) is a centrosome- and midbody-associated protein that is overexpressed in several cancers. However, the underlying molecular mechanism of CEP55-mediated progression and metastasis of esophageal squamous cell carcinoma (ESCC) is not clear. In the current study, we detected CEP55 mRNA by qRT-PCR while protein expression was detected by western blot analysis and immunohistochemistry (IHC). In addition, we knocked down CEP55 and investigated the ability of CEP55 to affect colony formation and migration. Here, we report that CEP55 mRNA and protein expression was significantly increased in ESCC. IHC staining showed that CEP55 expression correlated with TNM stage (p=0.046) and lymph node metastases (p=0.024). According to overall survival (OS) and disease-free survival (DFS), patients whose tumors expressed a higher level of CEP55 had a poorer prognosis than those with low expression level of CEP55. A multivariate analysis revealed that CEP55 expression was an independent prognostic indicator for patients with ESCC. Knockdown of CEP55 decreased the colony formation ability and migration of ESCC cells and also reduced the phosphorylation of Src, FAK, and ERK. Therefore, our study implied that CEP55 may be a valuable biomarker and a potential target in the treatment of patients with ESCC.
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BACKGROUND: Small cell neuroendocrine carcinoma of the uterine cervix (SCNEC) is a rare cancer involving the human papilloma virus (HPV), and has few available treatments. The present work aimed to assess the feasibility of SOX2 and HPV statuses as predictive indicators of SCNEC prognosis. METHODS: The associations of SOX2 and/or high-risk (HR)-HPV RNA in situ hybridization (RISH) levels with clinicopathological characteristics and prognostic outcomes for 88 neuroendocrine carcinoma (NEC) cases were analyzed. RESULTS: Among these patients with SCNEC, SOX2, P16INK4A and HR-HPV RISH expression and SOX2/HR-HPV RISH co-expression were detected in 68(77.3%), 76(86.4%), 73(83.0%), and 48(54.5%), respectively. SOX2-positive and HR-HPV RISH-positive SCNEC cases were associated with poorer overall survival (OS, P = 0.0170, P = 0.0451) and disease-free survival (DFS, P = 0.0334, P = 0.0309) compared with those expressing low SOX2 and negative HR-HPV RISH. Alternatively, univariate analysis revealed that SOX2 and HR-HPV RISH expression, either separately or in combination, predicted the poor prognosis of SCNEC patients. Multivariate analysis revealed that the co-expression of SOX2 with HR-HPV RISH may be an independent factor of OS [hazard ratio = 3.597; 95% confidence interval (CI): 1.085-11.928; P = 0.036] and DFS [hazard ratio = 2.880; 95% CI: 1.199-6.919; P = 0.018] prediction in SCNEC. CONCLUSIONS: Overall, the results of the present study suggest that the co-expression of SOX2 with HR-HPV RISH in SCNEC may represent a specific subgroup exhibiting remarkably poorer prognostic outcomes compared with the expression of any one marker alone.
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Carcinoma Neuroendocrino/metabolismo , Carcinoma Neuroendocrino/virología , Carcinoma de Células Pequeñas/genética , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/metabolismo , Factores de Transcripción SOXB1/biosíntesis , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/virología , Adulto , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/patología , Carcinoma de Células Pequeñas/patología , Femenino , Humanos , Hibridación in Situ , Persona de Mediana Edad , Estadificación de Neoplasias , Nomogramas , Papillomaviridae/genética , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Pronóstico , ARN Viral/genética , Estudios Retrospectivos , Factores de Transcripción SOXB1/metabolismo , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patologíaRESUMEN
OBJECTIVE: Esophageal spindle cell squamous cell carcinoma (ESCSCC) is a distinct subtype of esophageal carcinoma with unique morphologic and clinicopathologic features. This study aimed to characterize the clinicopathologic manifestations and postoperative prognostic factors of ESCSCC. METHODS: In this study, 43 ESCSCC patients who underwent esophagectomy at Sun Yat-sen University Cancer Center between January 2001 and December 2014 were identified. 200 patients with conventional squamous cell carcinoma during the same period were sampled as a control. Hematoxylin and eosin-stained slides and available data were reviewed, and pertinent clinicopathologic features were retrospectively analyzed. RESULTS: Among the ESCSCC patients, the median age was 60.5 years, with a male-to-female ratio of 2.58:1. The five-year disease-free survival and cancer-specific survival rates were 51.6 and 55.5%, respectively. In the univariate analysis, drinking abuse, tumor size, macroscopic type, perineural invasion, pT, preoperative blood white blood cell count, preoperative blood neutrophil count, and preoperative blood neutrophil to lymphocyte ratio were significantly correlated with the cancer-specific survival and disease-free survival of the ESCSCC patients. The multivariate analysis showed that macroscopic type, perineural invasion, and preoperative blood neutrophil to lymphocyte ratio were independent prognostic factors for cancer-specific survival; macroscopic type, perineural invasion, tumor size, and pT were independent prognostic factors for disease-free survival. Moreover, the combined prognostic model for cancer-specific survival (including macroscopic type, perineural invasion, and preoperative blood neutrophil to lymphocyte ratio), the combined prognostic model for disease-free survival (including macroscopic type, perineural invasion, and tumor size) significantly stratified patients according to risk (low, intermediate, and high) to predict cancer-specific survival, disease-free survival, respectively. In terms of esophageal conventional squamous cell carcinoma cohort, there was no significant difference in long-term outcome when compared with ESCSCC. Though five independent prognostic variables (macroscopic type, perineural invasion, preoperative blood neutrophil to lymphocyte ratio, tumor size, and pT) were indentified in ESCSCC, univariate analysis demonstrated that perineural invasion, preoperative blood neutrophil to lymphocyte ratio were correlated with esophageal conventional squamous cell carcinoma on cancer-specific survival; whereas only perineural invasion on disease-free survival. CONCLUSIONS: The proposed two new prognostic models might aid in risk stratification and personalized management for patients with esophageal spindle cell squamous cell carcinoma who received radical surgery.
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The "macrotrabecular-massive" (MTM) pattern of hepatocellular carcinoma (HCC) has been suggested to represent a distinct HCC subtype and is associated with specific molecular features. Since the immune microenvironment is heterogenous in HCC, it is important to evaluate the immune microenvironment of this novel variant. CMTM6, a key regulator of PD-L1, is an important immunocheckpoint inhibitor. This study aimed to evaluate the prognostic effect of CMTM6/PD-L1 coexpression and its relationship with inflammatory cells in HCC. We analyzed 619 HCC patients and tumors were classified into MTM and non-MTM HCC subtypes. The expression levels of CMTM6 and PD-L1 in tumor and inflammatory cells were evaluated by immunohistochemistry. The density of inflammatory cells in the cancer cell nest was calculated. Tumoral PD-L1 expression and inflammatory cell density were higher in the MTM type than in the non-MTM type. CMTM6-high expression was significantly associated with shorter OS and DFS than CMTM6-low expression in the whole HCC patient population and the MTM HCC patient population. Moreover, MTM HCC patients with CMTM6/PD-L1 coexpression experienced a higher risk of HCC progression and death. In addition, CMTM6/PD-L1 coexpression was shown to be related to a high density of inflammatory cells. Notably, a new immune classification, based on CMTM6/PD-L1 coexpression and inflammatory cells, successfully stratified OS and DFS in MTM HCC. CMTM6/PD-L1 coexpression has an adverse effect on the prognosis of HCC patients, especially MTM HCC patients. Our study provides evidence for the combination of immune status assessment with anti-CMTM6 and anti-PD-L1 therapy in MTM HCC patients.
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Antígeno B7-H1/biosíntesis , Carcinoma Hepatocelular/inmunología , Neoplasias Hepáticas/inmunología , Proteínas con Dominio MARVEL/inmunología , Proteínas de la Mielina/inmunología , Adolescente , Adulto , Anciano , Antígeno B7-H1/inmunología , Carcinoma Hepatocelular/patología , Femenino , Humanos , Inmunofenotipificación , Proteínas con Dominio MARVEL/biosíntesis , Masculino , Persona de Mediana Edad , Proteínas de la Mielina/biosíntesis , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Cancer metastasis is the major reason for cancer-related deaths, but the mechanism of cancer metastasis still unclear. Adrenomedullin (ADM), a peptide hormone, functions as a local paracrine and autocrine mediator with multiple biological activities, such as angiogenesis, cell proliferation, and anti-inflammation. However, the expression and potential function of ADM in triple-negative breast cancer (TNBC) remain unclear. METHODS: Real-time polymerase chain reaction and western blotting were performed to examine the expression of ADM in TNBC tissues and cell lines. A total of 458 TNBC tissue samples and adjacent nontumor tissue samples were detected by immunochemistry to determine the correlation between ADM expression and clinicopathological characteristics. We determined the role and mechanistic pathways of ADM in tumor metastasis in cell lines. RESULTS: Our data showed that ADM expression was noticeably decreased in TNBC samples and cell lines. Low expression levels correlate with an increased risk of recurrence and metastasis. Furthermore, low ADM expression was associated with poor prognosis and was an independent marker for TNBC. In vitro, ADM may decrease cancer cell invasion, which is likely the result of its effect on the cancer cell epithelial-mesenchymal transition. CONCLUSIONS: Our findings suggest that ADM is a valuable biomarker for TNBC prognosis and an anti-metastasis candidate therapeutic target in triple-negative breast cancer.
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Deregulation of alternative splicing contributes to the malignant progression of cancer. Little is known about the significant alternative splicing events in hepatocellular carcinoma (HCC). High-throughput sequencing revealed that coiled-coil domain containing 50 (CCDC50) pre-mRNA is aberrantly spliced in 50% of our HCC cases. A BaseScope assay was performed to examine the expression of CCDC50S (a truncated oncogenic splice variant) in HCC tissues. Compared with benign liver tumors and several other types of solid tumors, CCDC50S mRNA was up-regulated in HCC, with a diagnostic potential (sensitivity, 0.711; specificity, 0.793). High expression of CCDC50S mRNA in HCC was significantly correlated with poor tumor differentiation, advanced tumor node metastasis (TNM) stage, and unfavorable prognosis. Overexpression of CCDC50S exerted tumorigenic activities that promoted HCC growth and metastasis by activation of Ras/forkhead box protein O4 (Foxo4) signaling. Either suppression of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation or overexpression of Foxo4 markedly attenuated CCDC50S-mediated phenotypes. Furthermore, serine- and arginine-rich splicing factor 3 (SRSF3) directly bound to CCDC50S mRNA to maintain its stability in the cytoplasm. The cytosolic retention of SRSF3 was mediated by the interaction of hepatitis B virus-encoded X protein (HBx) and 14-3-3ß. Ectopic HBx expression induced expression of cytosolic SRSF3 and CCDC50S. Conclusion: Our study provided compelling evidence that up-regulation of CCDC50S was modulated by HBx/SRSF3/14-3-3ß complex and enhanced oncogenic progression of HCC through the Ras/Foxo4 signaling pathway. These data suggest that CCDC50S may serve as a diagnostic and prognostic biomarker and probably a promising therapeutic target in HCC.
Asunto(s)
Carcinoma Hepatocelular/etiología , Neoplasias Hepáticas/etiología , Proteínas Proto-Oncogénicas p21(ras)/fisiología , Factores de Empalme Serina-Arginina/fisiología , Transducción de Señal/fisiología , Animales , Masculino , Ratones , Ratones Endogámicos BALB CRESUMEN
Myosin light chains (MLC) serve important regulatory functions in a wide range of cellular and physiological processes. Recent research found that MLC are also chromatin-associated nuclear proteins which regulate gene transcription. In this study, the MLC member myosin regulatory light chain 5 (MYL5) expression was upregulated in late stage cervical cancer patients, positively correlated with pelvic lymph node metastasis, and identified as a poor survival indicator. MYL5 overexpression promoted metastasis in cervical cancer in vitro and in vivo models, whereas MYL5 silencing had the converse effect. We demonstrated a bidirectional regulation between MYL5 and hypoxia inducible factor-1α (HIF-1α). HIF-1α activates MYL5 via binding to the hypoxia response element (HRE) in the promoter of MYL5, and MYL5 could sustain HIF-1α expression by tethering to recognition sequence AGCTCC in the HIF-1α promoter region. Clinical data confirmed a positive correlation between MYL5 and HIF-1α. In summary, our data show that MYL5 may act as a prognosis predictive factor in cervical carcinoma, and strategies that inhibit the interaction of MYL5 and HIF-1α may benefit the cervical carcinoma patients with metastasis.
Asunto(s)
Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Cadenas Ligeras de Miosina/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Animales , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Regiones Promotoras Genéticas/genéticaRESUMEN
OBJECTIVE: The objective of this study was to evaluate the diagnostic performance of contrast-enhanced ultrasound (CEUS) in differentiating combined hepatocellular cholangiocarcinomas (CHCs) from hepatocellular carcinomas (HCCs) and intrahepatic cholangiocarcinomas (ICCs). MATERIALS AND METHODS: Thirty-three patients with pathologically confirmed CHC and matched control subjects with pathologically confirmed HCC (n = 30) or ICC (n = 32) who underwent preoperative CEUS from January 2005 to December 2015 were enrolled in this study. The CEUS images of the hepatic lesions were subjectively analyzed in consensus by two radiologists. The diagnostic performances were evaluated by ROC analysis. RESULTS: In the arterial phase, hyperenhancement was more common in CHCs (76%) and HCCs (100%) than in ICCs (22%), whereas in the late phase marked washout was more common in CHCs (76%) and ICCs (100%) than in HCCs (10%). Using marked washout in the late phase to differentiate CHC from HCC, the area under the ROC curve (AUC) was 0.829, and the sensitivity, specificity, and accuracy were 78%, 90%, and 83%, respectively. Using hyperenhancement in the arterial phase followed by marked washout in the late phase to distinguish CHC from ICC, the AUC value was 0.663, and the sensitivity, specificity, and accuracy were 55%, 78%, and 66%. CONCLUSION: Although the imaging features of CHC, HCC, and ICC on CEUS may overlap, CEUS could be used in the differential diagnosis of CHC from HCC and ICC.