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Background: The aim was to investigate circ-HMGCS1 expression and its correlation with clinical features and survival in cervical cancer (CC) patients., Methods: This prospective study recruited 100 patients with CC who underwent surgical resection. Circ-HMGCS1 expression was measured by RT-qPCR. Disease-free survival (DFS) and overall survival (OS) were recorded., Results: Circ-HMGCS1 was upregulated in tumor tissues and had a good value in separating tumor tissues from normal tissues. Circ-HMGCS1 expression in tumor tissues was positively correlated with tumor size, lymph node metastasis, and FIGO stage. High circ-HMGCS1 expression predicted worse DFS and OS., Conclusions: circ-HMGCS1 serves as an indicator of survival and prognosis in CC patients.

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a poor clinical prognosis and unsatisfactory treatment options. We previously found that the transcription factor CCAAT/Enhancer-Binding Protein Delta (C/EBPδ) is lowly expressed in PDAC compared to healthy pancreas duct cells, and that patient survival and lymph node involvement in PDAC is correlated with the expression of C/EBPδ in primary tumor cells. C/EBPδ shares a homologous DNA-binding sequence with other C/EBP-proteins, leading to the presumption that other C/EBP-family members might act redundantly and compensate for the loss of C/EBPδ. This implies that patient stratification could be improved when expression levels of multiple C/EBP-family members are considered simultaneously. In this study, we assessed whether the quantification of C/EBPβ or C/EBPγ in addition to that of C/EBPδ might improve the prediction of patient survival and lymph node involvement using a cohort of 68 resectable PDAC patients. Using Kaplan-Meier analyses of patient groups with different C/EBP-expression levels, we found that both C/EBPβ and C/EBPγ can partially compensate for low C/EBPδ and improve patient survival. Further, we uncovered C/EBPβ as a novel predictor of a decreased likelihood of lymph node involvement in PDAC, and found that C/EBPβ and C/EBPδ can compensate for the lack of each other in order to reduce the risk of lymph node involvement. C/EBPγ, on the other hand, appears to promote lymph node involvement in the absence of C/EBPδ. Altogether, our results show that the redundancy of C/EBP-family members might have a profound influence on clinical prognoses and that the expression of both C/EPBβ and C/EBPγ should be taken into account when dichotomizing patients according to C/EBPδ expression.

Objective: Secretory carcinoma of the breast (SCB) is a rare low-grade often triple-negative breast carcinoma. We aim to analyze the pathological and molecular features of 21 SCBs, especially the SCBs with axillary lymph node metastasis., Methods: The clinicopathological characteristics of 21 SCBs were reviewed. Breast biomarkers, Pan-TRK and ETV6 break, and ETV6-NTRK3 fusion were performed on all cases. Next-Generation Sequencing (NGS) was performed on two cases with lymph node metastasis., Results: 21 SCBs consisted of 2 men and 19 women aged 5～73 years (median 43 years), with a mean 2.1 cm (range 0.5～3.5 cm) tumor size. 90.1% (19/21) cases had mixed microcystic, solid, tubular, and papillary patterns. Pan-TRK and S100 are positive in 95% (20/21) and 90% (19/21) of cases, respectively. Tumor markers ER, PR, and HER2 expressions were 62% (13/21), 33% (7/21), and 0% (0/21). All cases showed ETV6 (21/21) rearrangement and ETV6-NTRK3 (11/11) fusion. 57% (12/21) of the cases had a balanced translocation and 38% (8/21) with unbalanced signals of ETV6. There was no clinical difference between balanced and unbalanced translocations in histological morphology and other prognosis factors. Furthermore, one case (#4) had a duplication of the ETV6 gene and presented axillary lymph node metastasis. NGS analysis revealed simple genomes, low tumor mutation burden, stable microsatellite sites, and single nucleotide polymorphism (SNP) heterozygous mutation in both SCBs with nodal metastasis., Conclusion: SCB is an indolent invasive carcinoma, even the cases with axillary lymph node metastasis, presenting simple genomes. Duplication of ETV6 cases may indicate lymph node metastasis., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Background: Lymph node metastasis (LNM) is an important factor for both treatment and prognosis of early gastric cancer (EGC). Current methods are insufficient to evaluate LNM in EGC due to suboptimal accuracy. Herein, we aim to identify methylation signatures for LNM of EGC, facilitate precision diagnosis, and guide treatment modalities., Methods: For marker discovery, genome-wide methylation sequencing was performed in a cohort (marker discovery) using 47 fresh frozen (FF) tissue samples. The identified signatures were subsequently characterized for model development using formalin-fixed paraffin-embedded (FFPE) samples by qPCR assay in a second cohort (model development cohort, n = 302, training set: n = 151, test set: n = 151). The performance of the established model was further validated using FFPE samples in a third cohorts (validation cohort, n = 130) and compared with image-based diagnostics, conventional clinicopathology-based model (conventional model), and current standard workups., Results: Fifty LNM-specific methylation signatures were identified de novo and technically validated. A derived 3-marker methylation model for LNM diagnosis was established that achieved an AUC of 0.87 and 0.88, corresponding to the specificity of 80.9% and 85.7%, sensitivity of 80.6% and 78.1%, and accuracy of 80.8% and 83.8% in the test set of model development cohort and validation cohort, respectively. Notably, this methylation model outperformed computed tomography (CT)-based imaging with a superior AUC (0.88 vs. 0.57, p < 0.0001) and individual clinicopathological features in the validation cohort. The model integrated with clinicopathological features demonstrated further enhanced AUCs of 0.89 in the same cohort. The 3-marker methylation model and integrated model reduced 39.4% and 41.5% overtreatment as compared to standard workups, respectively., Conclusions: A novel 3-marker methylation model was established and validated that shows diagnostic potential to identify LNM in EGC patients and thus reduce unnecessary gastrectomy in EGC., (© 2022. The Author(s).)

It is unclear as to whether Wilms' tumor 1-associated protein (WTAP) promotes or suppresses breast cancer. This immunohistochemistry analysis explored levels of WTAP expression in 347 cases of breast cancer and analyzed the relationship between WTAP expression and the clinicopathological characteristics and prognosis of breast cancer patients. The rate of high WTAP expression was significantly higher in breast cancer tissue than in adjacent normal breast tissue (37.5% vs 0.0%; P < 0.001). WTAP expression was positively associated with tumor size and grade, and negatively associated with axillary lymph node metastasis, estrogen and progesterone receptor status. Rates of high WTAP expression were 66.1% in triple-negative breast cancer (TNBC) tissue and 31.3% in non-TNBC tissue. In multiple logistic regression analysis, independent predictors of WTAP expression in breast cancer included larger tumor size (odds ratio = 1.907; 95% confidence interval: 1.185-3.067; P = 0.008), lymph node metastasis (0.597; 0.373-0.956; P = 0.032) and TNBC status (3.735; 2.056-6.784; P < 0.001). No clear relationship was observed between patient prognosis and WTAP expression. We suggest that WTAP expression is upregulated in breast cancer and appears to both promote tumor growth and inhibit lymph node metastasis., (© 2022. The Author(s).)

Lymphatic metastasis is a common clinical symptom in nasopharyngeal carcinoma (NPC), the most common Epstein-Barr virus (EBV)-associated head and neck malignancy. However, the effect of EBV on NPC lymph node (LN) metastasis is still unclear. In this study, we demonstrated that EBV infection is strongly associated with advanced clinical N stage and lymphangiogenesis of NPC. We found that NPC cells infected with EBV promote LN metastasis by inducing cancer-associated lymphangiogenesis, whereas these changes were abolished upon clearance of EBV genomes. Mechanistically, EBV-induced VEGF-C contributed to lymphangiogenesis and LN metastasis, and PHLPP1, a target of miR-BART15, partially contributed to AKT/HIF1a hyperactivity and subsequent VEGF-C transcriptional activation. In addition, administration of anti-VEGF-C antibody or HIF1α inhibitors attenuated the lymphangiogenesis and LN metastasis induced by EBV. Finally, we verified the clinical significance of this prometastatic EBV/VEGF-C axis by determining the expression of PHLPP1, AKT, HIF1a, and VEGF-C in NPC specimens with and without EBV. These results uncover a reasonable mechanism for the EBV-modulated LN metastasis microenvironment in NPC, indicating that EBV is a potential therapeutic target for NPC with lymphatic metastasis. IMPLICATIONS: This research demonstrates that EBV induces lymphangiogenesis in NPC by regulating PHLPP1/p-AKT/HIF1a/VEGF-C, providing a new therapeutic target for NPC with lymphatic metastasis., (©2021 American Association for Cancer Research.)

Background: Gall bladder carcinoma (GBC) is a multi-factorial disease, involving multiple genetic alterations. The present pilot study aims to explore some of the molecular pathways, by studying immunohistochemical (IHC) expression of biomarkers (HER2/neu, KRAS, and VEGF) in GBC with their correlation with various clinicopathological parameters., Aim of the Study: To study the expression of prognostic biomarkers (HER2/neu, KRAS and VEGF-A) in GBC and their correlation with clinico-morphological parameters. Materials and., Methods: This prospective study was conducted over a period of 2 years. The study group included tissue of GBC (29) reported as malignant on histopathology and cholecystitis as a control group (29) for histopathological evaluation and IHC expression of above markers., Results: HER2/neu was expressed in 27.5% cases, and KRAS in 51.6%; however, both showed no association with tumor type, stage and grade. No association was found in KRAS expression and dysplasia. Vascular Endothelial Growth Factor - A (VEGF-A) was expressed in 86.1% cases, of which strong positivity was seen in 48.27%; it showed significant association with tumor stage (P value-0.027, Fishers' exact test), hence possibly suggesting its role in tumor progression; though no association was found in VEGF expression with tumor type and grade. No significant association was seen with vascular and tumor invasion also., Conclusion: The results suggest that the VEGF-A expression may be used as a potential prognostic biomarker in GBC.

Tumor-associated lymphatic vessels play an important role in tumor progression, mediating lymphatic dissemination of malignant cells to tumor-draining lymph nodes and regulating tumor immunity. An early, necessary step in the lymphatic metastasis cascade is the invasion of lymphatic vessels by tumor cell clusters or single tumor cells. In this review, we discuss our current understanding of the underlying cellular and molecular mechanisms, which include tumor-specific as well as normal, developmental and immunological processes "hijacked" by tumor cells to gain access to the lymphatic system. Furthermore, we summarize the prognostic value of lymphatic invasion, discuss its relationship with local recurrence, lymph node and distant metastasis, and highlight potential therapeutic options and challenges.

Background: To analyze the characteristics, related risk factors, and prognosis of lymph node metastasis (Number [No.] 5 and No.6) in the group of adenocarcinoma of esophagogastric junction (AEG)., Methods: The patients with Siewert II AEG who underwent total gastrectomy and D2 lymph node dissection from September 2015 to December 2018 in Lanzhou University Second Hospital were enrolled in this study. The pathological features of the postoperative specimens were analyzed (sex, age, maximum diameter, location, depth of invasion, degree of differentiation, neurological and vascular invasion, etc), and the lymph node metastasis rate of No.5, No.6 groups were calculated. The analysis was performed by IBM SPSS statistical software. The risk factors associated with lymph node metastasis in No.5 and No.6 groups were analyzed. Survival analysis was performed by Kaplan-M method, and survival rate was estimated, Log-rank test was used for comparison, and the difference was statistically significant at P < .05., Results: There were 142 cases of Siewert type II AEG with the positive rate of No.5 lymph nodes being 10.81% (8/74), and the positive rate of No.6 lymph nodes was 8.33% (11/132). No.5 and No.6 lymph nodes metastasis were not associated with gender, age, tumor maximum diameter, location (cardiac left/cardiac right) (P > .05), and were associated with invasion depth, differentiation degree, nerve and vascular invasion (P < .05). In the No.5 lymph node-positive group, the 3-year Overall Survival (OS) was 25.0%, and the No.5 lymph node-negative group had a 5-year OS of 57.8%, which was statistically different (P < .05). The 3-year OS was 18.2% in No.6 node-positive group and 53.8% in No.6 node-negative group, and the difference was statistically significant (P < .05)., Conclusion: For Siewert type II AEG, the lymph node metastasis rate was higher in No.5 and No.6 groups when the tumor invaded all layers of gastric wall and was poorly differentiated complicated with vascular nerve invasion, and the lymph node metastasis rate was lower at 3 years, which may be more appropriate for total gastrectomy +D2 lymph node dissection., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Accurate methods for identifying pelvic lymph node metastasis (LNM) of prostate cancer (PCa) prior to surgery are still lacking. We aimed to investigate the predictive value of peripheral monocyte count (PMC) for LNM of PCa in this study. Two hundred and ninety-eight patients from three centers were divided into a training set (n = 125) and a validation set (n = 173). In the training set, the independent predictors of LNM were analyzed using univariate and multivariate logistic regression analyses, and the optimal cutoff value was calculated by the receiver operating characteristic (ROC) curve. The sensitivity and specificity of the optimal cutoff were authenticated in the validation cohort. Finally, a nomogram based on the PMC was constructed for predicting LNM. Multivariate analyses of the training cohort demonstrated that clinical T stage, preoperative Gleason score, and PMC were independent risk factors for LNM. The subsequent ROC analysis showed that the optimal cutoff value of PMC for diagnosing LNM was 0.405 × 109 l -1 with a sensitivity of 60.0% and a specificity of 67.8%. In the validation set, the optimal cutoff value showed significantly higher sensitivity than that of conventional magnetic resonance imaging (MRI) (0.619 vs 0.238, P < 0.001). The nomogram involving PMC, free prostate-specific antigen (fPSA), clinical T stage, preoperative Gleason score, and monocyte-to-lymphocyte ratio (MLR) was generated, which showed a robust predictive capacity for predicting LNM before the operation. Our results indicated that PMC as a single agent, or combined with other clinical parameters, showed a robust predictive capacity for LNM in PCa. It can be employed as a complementary factor for the decision of whether to conduct pelvic lymph node dissection., Competing Interests: None

Competing Interests: Competing interests: None declared.

Meningiomas are common intracranial neoplasms with benign features, and extracranial metastases are very rare. There have been no previous reports of solitary mediastinal lymph node metastasis from benign meningiomas without pulmonary lesions. Here, we present a case of an 82-year-old female who visited our department for mediastinal lymphadenopathy with a history of meningioma treated with total surgical resection six years prior. Endobronchial ultrasound-guided transbronchial needle aspiration of the left lower paratracheal lymph node revealed a benign meningothelial meningioma. In patients with a history of meningioma, extracranial metastasis should be considered in the differential diagnosis of mediastinal lymphadenopathy., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

The aim of this study was to determine the clinicopathological features of papillary thyroid carcinomas (PTC) without extrathyroidal extension (ETE) and with lymph node metastasis (LNM). PTC > 1 cm increased the risk of LNM by 2.161 times compared to papillary thyroid microcarcinoma. The risk increased by 3.774 times in males and 1.553 times in the presence of multifocality. Presence of vascular invasion (VI) increased the risk of LNM by 3.093 times in patients without capsular invasion (CI). Clinicians should be careful about possible LNM in patients with large primary tumor diameter, multifocal tumors, CI and VI.

Background: Although perineural invasion is a well known prognostic factor used in several cancers, its prognostic role in esophageal squamous cell carcinoma remains controversial. Here, we investigated the prognostic role of perineural invasion in surgically treated esophageal squamous cell carcinoma., Methods: We retrospectively reviewed the medical records of 316 patients who underwent esophagectomy and lymph node dissection for esophageal squamous cell carcinoma between 2007 and 2016., Results: Overall, 287 men (mean age: 62.73 ± 7.97 years) were included in the study. The median follow-up period was 35.97 ± 30.99 months, perineural invasion was confirmed in 25 patients, and three-year overall and disease-free survival were significantly lower in the perineural invasion group than in the no-perineural invasion group (75.9% vs. 40.0%, p < 0.001; 70.3% vs. 21.6%, p < 0.001). Cumulative incidences of locoregional recurrence and distant metastasis over three years were higher in the perineural invasion group (13.8% vs. 9.6%, p = 0.009 and 52.8% vs. 14.6%, p < 0.001). On performing multivariable analysis, perineural invasion, pathological stage, incomplete resection, and neoadjuvant therapy were adverse risk factors for disease-free survival. The concordance index increased when perineural invasion was included in the model (0.712 vs. 0.723). On subgroup analysis, perineural invasion demonstrated a prognostic value in node-negative patients (79.4% vs. 35.7%, p = 0.012)., Conclusions: Perineural invasion was found to be an adverse risk factor for disease-free survival in surgically treated patients with esophageal squamous cell carcinoma. Close observation and individualized adjuvant therapy may be helpful for patients with perineural invasion., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Objectives: The importance of treating the bilateral neck in lateralized small oral cavity squamous cell carcinoma (OCC) is unclear. We sought to define the incidence and predictors of contralateral neck failure (CLF) in patients who underwent unilateral treatment., Materials and Methods: We performed a multi-institutional retrospective study of patients with pathologic T1-T2 (AJCC 7th edition) OCC with clinically node negative contralateral neck who underwent unilateral treatment with primary surgical resection ± adjuvant radiotherapy between 2005 and 2015. Incidence of CLF was estimated using the cumulative incidence method. Clinicopathological factors were analyzed by univariate (UVA) and multivariate analysis (MVA) for possible association with CLF. Kaplan-Meier analysis was used to estimate overall survival (OS)., Results: 176 patients were evaluated with a median of 65.9 months of follow-up. Predominant pathologic T-stage was T1 (68%), 8.5% of patients were N1, 2.8% were N2b. Adjuvant radiotherapy was delivered to 17% of patients. 5-year incidence of CLF was 4.3% (95% CI 1.2-7.4%). Depth of invasion (DOI) > 10 mm and positive ipsilateral neck node were significant predictors for CLF on UVA. DOI > 10 mm remained significant on MVA (HR = 6.7, 95% CI 1.4-32.3, p = 0.02). The 2- and 5-year OS was 90.6% (95% CI 86.2-95.0%) and 80.6% (95% CI 74.5-86.8%), respectively., Conclusion: Observation of the clinically node negative contralateral neck in small lateralized OCC can be a suitable management approach in well selected patients, however caution should be applied when DOI upstages small but deeply invasive tumors to T3 on 8th edition AJCC staging., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The optimal number of examined lymph nodes (ELNs) and the prognostic value of different nodal staging systems remain unclear in the context of N3b gastric cancer., Aim: To evaluate the optimal number of ELNs and compare the predictive ability of the ELN number, LN ratio (LNR), and log odds of metastatic LNs (LODDS) for overall survival (OS) in patients with resected stage N3b gastric adenocarcinoma in an international database., Methods: A total of 868 patients diagnosed between 2004 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database (training cohort) and 144 patients diagnosed between 2011 and 2016 at the Liaoning Cancer Hospital (validation cohort) were identified. Cutoff values were established with X-tile. The 5-year OS rates were compared using Kaplan-Meier curves. Multivariate analysis was conducted with a Cox regression model. The Harrell's concordance index and Akaike's information criterion were used to compare the predictive accuracy of different nodal staging systems., Results: The ELN number, LNR, and LODDS were independent prognostic factors for both the training and validation cohorts in the multivariate analysis. Patient with ≤26 ELNs, LNR of more than 0.9, and LODDS of more than 1.0 were associated with decrease OS. The LNR and LODDS had similar discriminatory ability for OS and performed better than the ELN number in the Eastern and Western populations., Conclusion: The optimal number of ELN may be 27 or more because LNs retrieved ≤26 was an independent risk factor for the prognosis. The prognostic prediction efficacy of LNR and LODDS was similar and better than that of ELN. Thus, LNR and LODDS could both serve as valid tools to predict OS for stage N3b patients., (© 2020 John Wiley & Sons Australia, Ltd.)

Competing Interests: Competing interests: None declared.

Background: Although lobectomy is considered the standard surgery for any non-small cell lung cancer (NSCLC), recent evidence indicates that for early NSCLCs segmentectomy may be equally effective. For segmentectomy to be oncologically safe, however, adequate intraoperative lymph node staging is essential. The aim of this study was to compare the results of a new rapid-IHC system to the HE analysis for intraoperative nodal diagnosis in lung cancer patients considered for segmentectomy., Methods: This retrospective study analyzed the pathological reports from NSCLC resections over a six-year period between 2014 and 2020. Using a new device for rapid-IHC, we applied a high-voltage, low-frequency alternating current (AC) field, which mixes the antipancytokeratin antibody as the voltage is switched on/off. Rapid-IHC can provide a nodal diagnosis within 20 minutes., Results: Frozen sections from 106 resected lymph nodes from 70 patients were intraoperatively evaluated for metastasis. Of those, five nodes were deemed positive based on both HE staining and rapid-IHC. In addition, rapid-IHC alone detected isolated tumor cells in one hilar lymph node. Three cStage IA patients with nodal metastasis detected with HE staining and rapid-IHC received complete lobectomies. Five-year relapse-free survival and overall survival among patients receiving segmentectomy with rapid-IHC were 88.77% and 88.79%, respectively., Conclusions: Rapid-IHC driven by AC mixing is simple, highly accurate, and preserves nodal tissue for subsequent tests. This system can be used effectively for intraoperative nodal diagnosis. Rapid immunohistochemistry based on alternating-current field mixing (completed within 20 minutes) is simple and highly accurate. This system will assist clinicians when making intraoperative diagnoses of lymph node metastasis and deciding upon the appropriate surgical procedure in segmentectomy for lung cancer., Key Points: SIGNIFICANT FINDINGS OF THE STUDY: Rapid immunohistochemistry driven by alternating-current field mixing (completed within 20 minutes intraoperatively) is simple, highly accurate, and preserves lymph node tissue for subsequent pathological examination, including molecular assessments., What This Study Adds: Segmentectomy for lung cancer is oncologically safe, but only when there is adequate intraoperative node staging. Rapid immunohistochemistry will assist clinicians when making intraoperative nodal diagnoses., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Metastasis and recurrence are the main causes of lung adenocarcinoma patients' death. Lymphatic metastasis is the main way of non-small cell lung cancer (NSCLC) metastasis. C-C chemokine receptor type 7 (CCR7) overexpression has been demonstrated to mediate occurrence and progression of NSCLC. Moreover, Chemokine ligand 21 (CCL21) was used to activate CCR7. The CCR7-CCL21 axis is one of the most common "chemokine-receptor" modes of action in the development and metastasis of multiple tumors. However, the role of the CCR7-CCL21 axis in lymphatic metastasis of NSCLC is poorly understood. The study was conducted to investigate the molecular mechanism underlying CCR7-CCL21 axis-mediated lymphatic metastasis of NSCLC A549 cells. Tumor necrosis factor α (TNF-α) could regulate the tumor microenvironment balance by promoting chemokine secretion. Our study demonstrated that TNF-α promoted CCL21 production in human lymphatic endothelial cells (HLEC). Results further showed that TNF-α significantly activated the NF-κB pathway in HLEC. NF-κB pathway inhibition with ammonium pyrrolidinedithiocarbamate (PDTC) caused a significant decrease in CCL21 secretion, suggesting that TNF-α-induced CCL21 secretion in HLEC was through NF-κB pathway. Co-culture of A549 cells and TNF-α-treated HLEC confirmed that the metastasis of A549 cells was enhanced, meanwhile, apoptosis-related proteins were hardly affected. The data proved that a co-culture system prevented cell apoptosis while inducing the lymphatic metastasis of A549 cells. However, the situation was reversed after neutralizing CCL21 expression, suggesting that TNF-α-induced CCL21 secretion in HLEC is involved in A549 cells metastasis. Collectively, our finding demonstrated that NF-κB pathway-controlled CCL21 secretion of HLEC contributing to the lymphatic metastasis of A549 cells via the CCR7-CCL21 axis, validating the CCR7-CCL21 axis as a potential target to inhibit metastasis of NSCLC., Competing Interests: The authors declare no conflict of interest.

Importance: Regional nodal irradiation (RNI) for node-positive breast cancer reduces distant metastases and improves survival, albeit with limited reduction in regional nodal recurrences. The mechanism by which RNI robustly reduces distant metastases while modestly influencing nodal recurrences (ie, the presumed target of RNI) remains unclear., Objective: To determine whether some distant metastases putatively arise from occult regional nodal disease and whether regional recurrences otherwise remain largely undetected until an advanced cancer presentation., Design, Setting, and Participants: This cohort study examined patients presenting with de novo stage IV breast cancer to the Memorial Sloan Kettering Cancer Center in New York, New York, from 2006 to 2018. Medical records were reviewed to ascertain clinicopathological parameters, including estrogen receptor status and survival. Pretreatment positron emission tomography-computed tomography (PET-CT) imaging was reviewed to ascertain the extent of regional nodal involvement at metastatic diagnosis using standard nodal assessment criteria. A subset underwent regional lymph node biopsy for diagnostic confirmation and served to validate the radiographic nodal assessment. Data analysis was performed from October 2019 to February 2020., Exposures: Untreated metastatic breast cancer., Main Outcome and Measures: The primary outcome was the likelihood of regional nodal involvement at the time of metastatic breast cancer presentation and was determined by reviewing pretreatment PET-CT imaging and lymph node biopsy findings., Results: Among 597 women (median [interquartile range] age, 53 [44-65] years) with untreated metastatic breast cancer, 512 (85.8%) exhibited regional lymph node involvement by PET-CT or nodal biopsy, 509 (85%) had involvement of axillary level I, 328 (55%) had involvement in axillary level II, 136 (23%) had involvement in axillary level III, 101 (17%) had involvement in the supraclavicular fossa, and 96 (16%) had involvement in the internal mammary chain. Lymph node involvement was more prevalent among estrogen receptor-negative tumors (92.4%) than estrogen receptor-positive tumors (83.6%). Nodal involvement at the time of metastatic diagnosis was not associated with overall survival., Conclusions and Relevance: These findings suggest that a majority of patients with de novo metastatic breast cancer harbor regional lymph node disease at presentation, consistent with the hypothesis that regional involvement may precede metastatic dissemination. This is in alignment with the findings of landmark trials suggesting that RNI reduces distant recurrences. It is possible that this distant effect of RNI may act via eradication of occult regional disease prior to systemic seeding. The challenges inherent in detecting isolated nodal disease (which is typically asymptomatic) may account for the more modest observed benefit of RNI on regional recurrences. Alternative explanations of nodal involvement that arises concurrently or after metastatic dissemination remain possible, but do not otherwise explain the association of RNI with distant recurrence.

There are several clinicopathological factors associated with the prognosis of cutaneous squamous cell carcinomas (cSCC), but there remains a lack of molecular markers associated with cSCC tumor progression. This study aimed to determine the association between histopathological prognostic parameters and tumoral podoplanin expression in cSCC. This study included 63 paraffin embedded cSCC samples that were evaluated for tumoral podoplanin expression using immunohistochemistry. Among the 63 tumor samples, 27% lacked podoplanin expression, 22% exhibited diffuse podoplanin expression, and 51% exhibited focal podoplanin expression. Tumoral podoplanin expression was correlated with lymphovascular invasion and lymph node metastasis ( p value < 0.05, for both). Additional research is needed to further delineate how the tumoral podoplanin expression can be used as a prognostic marker in patients with cSCC.

Background: Dormant avascular micrometastases and single, or small groups of, non-proliferating cells are currently assumed to explain the multipeak dynamics of distant metastases (DM) following primary breast cancer surgical removal., Methods: The hazard rate pattern for DM was analysed in 1518 premenopausal node-positive patients, enrolled in a series of randomized clinical trials on early breast cancer, which were carried out in Italy and Belgium. Patients underwent surgery alone (n = 397) or surgery plus adjuvant chemotherapy (n = 1121) and the minimal follow up was 15 years., Results: The DM hazard rate for patients undergoing surgery alone displayed two early sharp peaks at 9 and 33 months, a wide intermediate one spanning from about 50 to 90 months and a late peak at 115-120 months. Adjuvant chemotherapy was associated with a prominent reduction of the two early peaks leaving a residual one at about 18 months and a reduction of the intermediate peak leaving two small peaks at about 50 and 80 months. The late peak remained unchanged., Conclusions: Present results reveal the ability of adjuvant chemotherapy to reduce not only the rate of early relapses, but also the rate of intermediate relapses at about the sixth year of follow up. Adjuvant chemotherapy is not impacting on the development of metastases underlying the late peak detected at the tenth year. These findings suggest the existence of a previously unknown dormancy state that, at the primary tumour surgical removal, results in evolving chemo-sensitive metastatic processes, and, moreover, of a later chemo-refractory dormancy state., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

BACKGROUND Merkel cell carcinoma (MCC) occurs primarily among elderly patients over 70 years old, but the ability to predict the prognosis of these elderly patients is poor. This population-based study aimed to identify prognostic risk factors for elderly patients with MCC. MATERIAL AND METHODS The survival and disease information of MCC patients age 65 years or older was downloaded from the SEER database, and all data were split into 2 groups based on age 80 years, with overall survival and MCC-specific survival as the main outcome indicators. RESULTS Application of the inclusion criteria yielded 1973 patients with MCC, of whom 55.6% were age 65-80 years. Among them, 1258 were males, accounting for 63.8%. In survival analysis, factors that were significantly correlated with overall survival and MCC-specific survival were N stage, M stage, liver metastasis, and lymph node surgery. CONCLUSIONS We provide epidemiological insights into Merkel cell carcinoma in elderly patients and confirmed that patients receiving lymph node surgery have better outcomes. To the best of our knowledge, this is the first study to show that the occurrence of liver metastasis is associated with poor prognosis. Our results will help strengthen monitoring of the liver condition of elderly patients and to perform necessary lymph node surgery within the patient's tolerance.

Background: The heterogeneity of receptor profiles in breast cancer is well known. The differing receptor profiles of primary breast cancer and nodal metastases have been investigated and found to range between 10-50% depending on the hormone receptor tested. A study comparing the hormone status of primary breast cancers and the synchronous ipsilateral involved sentinel lymph node has not been performed in a South African population., Method: This is a prospective study where two specialist radiologists performed the simultaneous core needle biopsies of the primary breast cancer and the clinically positive axillary nodes. All receptor status analysis was conducted by one specialist histopathologist., Results: Of 141 patients who gave written informed consent for this study, 29 were excluded; 112 patients met the inclusion criteria. Anonymised demographics of age, clinical stage, HIV status and metastatic screening were recorded. The simultaneous biopsies and receptor measurements identified 10 patients with discordant receptor status in the positive axillary lymph nodes. In each case, the receptor profile of the axillary lymphatic metastases was more aggressive than that of the primary tumour. The luminal A subtype had a significantly greater risk of discordance than other subtypes ( p = 0.02)., Conclusion: Core needle biopsy and receptor analysis should be considered on the positive axillary nodes in breast cancer patients. Adjuvant treatment should be targeted to the receptor profile of the lymph node metastases., (Copyright© Authors.)

The lymph node metastasis of colorectal cancer (LMN-CRC) seriously threatens the prognosis of patients. Chemotherapy, as the most common treatment, results in severe bone marrow suppression. 20(S)-ginsenoside Rh2 (SGRh2), a major effective constituent of ginseng, has demonstrated therapeutic effects on a variety of diseases, including some tumours. SGRh2 treatment had no effect on other organs. Therefore, ginsenosides are considered a safe and effective antineoplastic drug. However, the effects of SGRh2 on LMN-CRC remain unknown. The present study investigated the potential effect of SGRh2 on LMN-CRC in vitro and in vivo. SW480 and CoLo205 cell lines were treated with SGRh2. SGRh2 dose-dependently decreased CRC cell proliferation by CCK-8, colony formation and Edu assays. The Transwell and scratch assays revealed that SGRh2 inhibits the migratory and invasive abilities of CRC cells in a dose-dependent manner. Furthermore, the results of Western blotting revealed that SGRh2 decreased the expression of matrix metalloproteinase (MMP)-2 and MMP9. In terms of the underlying mechanisms, SGRh2 regulates CRC metastasis by affecting epithelial-mesenchymal transition (EMT), which significantly up-regulated epithelial biomarkers (E-cadherin) and down-regulated mesenchymal biomarkers (N-cadherin and vimentin) and EMT transcriptional factors (Smad-3, Snail-1, and Twist-1). In vivo, SGRh2 significantly inhibited LMN-CRC without affecting other normal organs. Immunohistochemical results showed that SGRh2 treats LMN-CRC by regulating EMT. These results demonstrate that SGRh2 has therapeutic potential for LMN-CRC., (© 2020 The Author(s).)

Background: Although endoscopic resection is increasingly performed to treat submucosal invasive colorectal cancer (T1CRC), approximately 10% are at risk of lymph node metastasis. The Japanese Society for Cancer of the Colon and Rectum guideline indicates that the following risk factors should be considered when deciding whether to perform additional surgical resection with lymph node dissection: depth of T1 invasion, lymphovascular invasion, poor histological grade, and budding grade 2/3. However, there is little information about the prognosis of T1CRC patients, or factors to consider when deciding subsequent treatment of high-risk T1CRC., Methods: This retrospective mixed method study was conducted using electronic medical records at Kyoto University Hospital between February 2005 and February 2015. Participants were T1CRC patients at risk of lymph node metastasis with at least one of the above four risk factors. They were assigned either careful follow-up (FU) or additional surgery (AS) through shared decision-making. To identify factors affecting decision-making in the FU group, we performed qualitative content analysis of electronic medical records. The prognosis of the groups was compared using the Kaplan-Meier method and the log-rank test., Results: Of 161 T1CRC patients, 18 were included in the FU group and 19 in the AS group. The median follow-up time was 39.5 (range 23-126) months for the FU group and 62 (range 22-141) months for the AS group. Factors considered in selecting FU were advanced age, comorbidities, the sole presence of the "depth" risk factor, and lower rectal cancer. For AS, the risk factors cited in the guideline were considered. There was one recurrent case in each group during the research period. There were no significant differences in overall survival, cause-specific survival, or recurrence-free survival between the groups., Conclusions: Age, comorbidities, and lower-rectal cancer location were considered in deciding posttreatment strategy among high-risk T1CRC patients, alongside with positive vertical margin, depth, lymphovascular invasion, poor histologic grade, and budding. During the research period, there was no prognostic difference between the FU and AS groups.

Background: In endometrioid endometrial cancer (EEC), current clinical algorithms do not accurately predict patients with lymph node metastasis (LNM), leading to both under- and over-treatment. We aimed to develop models that integrate protein data with clinical information to identify patients requiring more aggressive surgery, including lymphadenectomy., Methods: Protein expression profiles were generated for 399 patients using reverse-phase protein array. Three generalised linear models were built on proteins and clinical information (model 1), also with magnetic resonance imaging included (model 2), and on proteins only (model 3), using a training set, and tested in independent sets. Gene expression data from the tumours were used for confirmatory testing., Results: LNM was predicted with area under the curve 0.72-0.89 and cyclin D1; fibronectin and grade were identified as important markers. High levels of fibronectin and cyclin D1 were associated with poor survival (p = 0.018), and with markers of tumour aggressiveness. Upregulation of both FN1 and CCND1 messenger RNA was related to cancer invasion and mesenchymal phenotype., Conclusions: We demonstrate that data-driven prediction models, adding protein markers to clinical information, have potential to significantly improve preoperative identification of patients with LNM in EEC.

The functions of immune cells in lymph node metastasis (LNM) have attracted considerable attention. This study aimed to screen the key immune-related and LNM-related genes in PTC. In the discovery phase, the immune-related genes in LNM were screened by using bioinformatics methods. In the validation phases, the association of the genes with LNM was first confirmed in a cohort from The Cancer Genome Atlas and a cohort based on a tissue chip. Then, the relationship of the genes with immune cell infiltration was further explored. Consequently, CLDN10 was identified, and its high expression was correlated with the presence of LNM in PTC but predicted a favorable prognosis. High CLDN10 expression was positively correlated with the infiltration of several immune cells, such as B cells, CD8+T cells, and macrophages. High CLDN10 expression may improve the outcomes of patients with PTC by increasing immune cell infiltration, although it might be associated with LNM. In conclusion, although CLDN1 might be correlated with LNM, it may also increase the infiltration of immune cells, including CD8+T cells and macrophages, and improve the clinical outcomes of patients with PTC. The effects of tumor purity and immune cell infiltration need to be considered in prognosis evaluation.

Objective: To develop a method for analysis of lymphatic drainage pathways from the lobe of the lung affected by non-small cell lung cancer (NSCLC) using infrared fluorescence., Material and Methods: A study enrolled patients with NSCLC who underwent anatomic resection of the lung with systematic lymph node dissection and preliminary intraoperative peritumoral injection of indocyanine green conjugate with human albumin. Registration of fluorescence in regional lymph nodes (LN) was carried out immediately after excision of specimen using the FLUM-808 instrumental system., Results: Infrared fluorescence was observed in 117 hilar and mediastinal lymph nodes from 43 patients (2.7 nodes per a patient). Comparison of localization of fluorescent LN with localization of tumor in various lobes established significant variability of lymphatic drainage pathways., Conclusion: The developed method of infrared fluorescent evaluation of lymphatic drainage in patients with NSCLC confirms the necessity of systematic lymph node dissection for adequate staging.

Background and objectives: The presenting study aimed to elucidate the prognostic role of the metastatic lymph node ratio (mLNR) in patients with colorectal cancer (CRC), using a meta-analysis. Materials and Methods: Using data from 90,274 patients from 14 eligible studies, we performed a meta-analysis for the correlation between mLNR and survival rate. Besides, subgroup analyses were performed, based on tumor stage, tumor location, and mLNR. Results: A high mLNR showed significant correlation with worse overall survival and disease-free survival rates in CRC patients (hazard ratio (HR), 1.617, 95% confidence interval (CI) 1.393-1.877, and HR 2.345, 95% CI 1.879-2.926, respectively). In patients with stage III, who had regional LN metastasis, the HRs were 1.730 (95% CI 1.266-2.362) and 2.451 (95% CI 1.719-3.494) for overall and disease-free survival, respectively. According to tumor location, rectal cancer showed a worse survival rate when compared to colon cancer. In the analysis for overall survival, when mLNR was 0.2, HR was the highest across the different subgroups (HR 5.040, 95% CI 1.780-14.270). However, in the analysis for disease-free survival, the subgroup with an mLNR < 0.2 had a higher HR than the other subgroups (HR 2.878, 95% CI 1.401-5.912). Conclusions: The mLNR may be a useful prognostic factor for patients with CRC, regardless of the tumor stage or tumor location. Further studies are necessary for the detailed criteria of mLNR before its application in daily practice., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the result.

Purpose: Pseudopodia are actin-rich ventral protrusions associated with cell motility and cancer cell invasion. We previously applied our established method of using excimer laser cell etching to isolate pseudopodial proteins from MDA-MB-231 breast cancer cells. We later identified 14-3-3γ as an oncogenic molecule among 46 candidate proteins that are specific to pseudopodia. The present study aimed to determine the function of 14-3-3γ in the motility of breast cancer cells., Methods: MDA-MB-231 cells were cultured on 3-µm porous membranes and double stained to localize 14-3-3γ and phalloidin in pseudopodia using confocal imaging. We assessed pseudopodia numbers and length, as well as migration and wound healing in MDA-MB-231 cells with knockdown and forced expression of 14-3-3γ to determine 14-3-3γ involvement in cell motility. We also immunohistochemically analyzed 14-3-3γ in human breast cancer tissues with high-grade lymphatic invasion., Results: We specifically located 14-3-3γ in pseudopodia of MDA-MB-231 cells. Knockdown and forced expression of 14-3-3γ, respectively, decreased and increased pseudopodial formation and elongation. Migration and wound healing assays also showed that 14-3-3γ knockdown and forced expression, respectively, decreased and increased the number of underside cells and acellular areas in MDA-MB-231 breast cancer cells. More 14-3-3γ was expressed in sites of lymphatic invasion, than in the center and periphery of human breast cancer tissues., Conclusion: The role of 14-3-3γ in breast cancer invasiveness might be to promote cell motility. Inhibition of 14-3-3γ could, therefore, become a novel target of therapy to prevent invasion and metastasis in patients with breast cancers expressing 14-3-3γ.

Hyaluronan controls cell migration, differentiation, and proliferation, and it is involved in tumor invasion. The extracellular matrix containing hyaluronan regulates cell behavior via cell surface receptors such as CD44 and receptor for hyaluronan-mediated motility (RHAMM, CD168). We investigated the expression of CD44 and RHAMM in tissue samples of endometrial cancer and the relation of their expression with clinicopathologic parameters of patients. In order to evaluate the value of CD44 and RHAMM as prognostic factors, we investigated the relation of their expression with patients' survival. Our results demonstrated a statistically significant correlation with the depth of myometrial invasion, lymphovascular invasion (LVSI), The International Federation of Gynecology and Obstetrics stage of disease, and, in the case of RHAMM expression, a significant correlation with histologic tumor grade as well. CD44 expression was present in the cell membrane in all cases, but in a proportion of tumors in the cytoplasm as well. In this group of patients, we noticed a significantly greater number of cases with deeper myometrial invasion and LVSI. Finally, we sorted out the group of tumors with simultaneous strong CD44 and strong RHAMM expression, and found a statistically significant correlation with the depth of myometrial invasion and LVSI. Using an univariate analysis, we demonstrated that, in our sample of patients, CD44 expression showed a statistically significant influence on patients' 5-year survival. However, using a multivariate Cox regression analysis, neither CD44 nor RHAMM confirmed themselves as independent prognostic factors.

Objective: To investigate the relationship between body mass index (BMI) and clinicopathological characteristics and prognosis of gastric cancer patients. Methods: The clinical data of 788 patients with advanced gastric cancer were retrospectively analyzed. According to WHO weight standard, BMI<18.5 kg/m(2) was the low weight group, BMI 18.5~< 25.0 kg/m(2) was the normal weight group, BMI ≥ 25.0 kg/m(2) was the overweight group. The low weight group included 127 cases, the normal weight group included 540 cases and the overweight group included 121 cases. The relationship between different BMI groups and clinicopathological characteristics of patients was analyzed. Cox multivariate regression model was used to analyze the independent factor of the prognosis of patients. Results: The average BMI of 788 patients was 21.70 kg/m(2). The patients' BMI was significantly correlated with depth of invasion, maximum diameter of tumors, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) (all P <0.05). BMI was marginally correlated with gender, age, smoking, alcohol consumption, TNM stage, lymph node metastasis and histological type (all P >0.05). Furthermore, BMI was significantly correlated with prealbumin, prognostic nutritional index, total protein, albumin and hemoglobin levels (all P <0.05). BMI was also significantly correlated with intraoperative bleeding volume, operation time, number of lymph node resection, number of lymph node metastasis and lymph node metastatic ratio (all P <0.05). The median survival time of the entire group was 35.3 months. The median survival time of patients in low weight group, normal weight group, and overweight group was 21.0 months, 26.3 months, and 31.2 months, respectively, the differences were statistically significant ( P <0.001). Cox multivariate analysis showed that TNM stage, depth of tumor invasion, lymph node metastasis, PLR and BMI were independent risk factors of the prognosis of patients with gastric cancer (all P <0.05). Conclusions: BMI is associated with the nutritional status, intraoperative blood loss, operative time, and lymph node metastatic ratio of patients with gastric cancer. BMI is an independent risk factor of the prognosis of patients with gastric cancer. The overall survival time of patients with low body weight is shorter than those of normal weight and overweight patients.

Objective: To investigate the diagnostic value of serum miRNAlet-7a in laryngeal carcinoma and the effect of let-7a on proliferation and apoptosis of laryngeal carcinoma cells. Methods: Real-time quantitative PCR was used to determine the expression level of serum miRNAlet-7a. The miRNA let-7a mimetic was synthesized and transiently transfected into the laryngeal carcinoma Hep-2 cell line by cationic liposome method. The effects of up-regulation of let-7a expression on laryngeal cancer Hep-2 cells were detected by FCM and MTT assays,respectively. The association of let-7a levels with laryngeal cancer and the diagnostic value for laryngeal cancer were analyzed. Measurement data were taken by t test or analysis of variance; Counting data were analyzed by χ(2) test and Fisher exact probability method. The receiver operating characteristic curve was used to analyze the diagnostic value of let-7a for laryngeal cancer. Results: The relative expression of serum let-7a in healthy subjects was significantly higher than that in patients with laryngeal cancer (0.931±0.094) vs (0.380±0.113) ( t= 26.507, P< 0.01). The relative expressions of serum let-7a in patients with laryngeal cancer before and after surgery were (0.380±0.113) vs (0.493±0.164),with significant difference ( t= 3.848, P< 0.01).The relative expression of serum let-7a was related to lymph node metastasis ( t =2.946, P< 0.01). There was a positive correlation between the relative expression of let-7a in laryngeal carcinoma and that in serum ( r= 0.466, P= 0.003). After transfection of let-7a mimics, Hep-2 cells showed an increased significant increase in the expression of let-7a ( P< 0.01), proliferation ( P< 0.01) and apoptosis ( P< 0.01). ROC curve analysis showed that the best critical value for relative expression of let-7a in the diagnosis of laryngeal carcinoma was 0.557 with a sensitivity of 0.794,a specificity of 0.727,an area under curve(AUC) of 0.859,and a 95 %CI of 0.773-0.926. Conclusions: miRNA let-7a can inhibit the proliferation of laryngeal carcinoma Hep-2 cells and promote apoptosis. Serum let-7a is down-regulated in patients with laryngeal cancer and the level of let-7a is related to lymph node metastasis,which would help early diagnosis and postoperative disease monitoring of laryngeal cancer,but further research is needed.

This study aimed to investigate the sentinel lymph node (SLN) tumour burden to predict the non-SLN positivity rate and the survival of melanoma patients to evaluate whether SLN microstaging could predict the prognosis, similar to what is currently performed by examining the lymph nodes excised by complete lymph node dissection. Of 1130 consecutive melanoma patients who underwent SLN biopsy, 226 were tumour-positive and 204 were included in this study. SLN metastases were classified on the basis of dimensional (Rotterdam) and topographic (Dewar) criteria either separately or combined. SLN metastases more than 1 mm in diameter had the highest non-SLN positivity rate (31%) compared with metastases 0.1-1 mm (10%) and less than 0.1 mm (4%). The non-SLN positivity rate was 45% for extensive metastases, 5% for subcapsular metastases and 23-29% for parenchymal, combined and multifocal classes, therefore suggesting a simplification of the parenchymal SLN metastases into only two classes: extensive and 'not extensive'. The dimension of the metastasis was correlated with a different non-SLN positivity rate only when the metastasis was in the parenchyma (20-36%) and not when it was in the subcapsular location (4-7%). Interestingly, the 5-year melanoma-specific survival (MSS) was 89% for patients with subcapsular less than 0.1 mm metastases and 45% for patients with nonsubcapsular more than 1 mm metastases (P=0.017). In the parenchyma, larger metastases (>1 mm) were related to a lower 5-year MSS (46%) than smaller (<1 mm) metastases (MSS 77%). SLN tumour burden characterization can be simplified and it can provide prognostic information on non-SLN positivity and survival, which is especially useful in patients who do not undergo complete lymph node dissection.

BACKGROUND The aim of this study was to assess the presence of HPV DNA in cervical tissues and lymph nodes in patients who have uterine cervical neoplasms with lymphatic metastases and who underwent surgery for invasive cervical cancer and pelvic lymphadenectomy, to establish the utility of HPV type and viral load in predicting disease progression. MATERIAL AND METHODS We retrospectively assessed 88 patients with uterine cervical neoplasms with lymph node metastases. All 88 patients were in FIGO stage IA-IIB. A total of 316 paraffin-embedded archival tissues (88 cervical samples and 228 pelvic lymph node specimens) were acquired. All the samples were analyzed using real-time PCR to determine HPV DNA presence/type and to quantify viral load. RESULTS In total, 17 HPV genotypes were detected in the cervical lesions and pelvic lymph nodes of the patients. The most common HPV type in all samples was HPV16, followed by HPV18. The existence of HPV16 DNA and low HPV16 viral load in cervical lesions were also significantly associated with disease recurrence. Furthermore, lymphovascular space involvement was also correlated with worse disease outcome. CONCLUSIONS HPV16 DNA presence and low viral load in primary lesions can be used to predict disease recurrence. HPV DNA is a favorable prognostic indicator in patients with uterine cervical neoplasms who have lymphatic metastases.

Prostate cancer (PCa) is one of the primary causes of cancer-related mortality in men worldwide. Patients with locally advanced PCa with metastases in regional lymph nodes are usually marked as a high-risk group. One of the chief concerns for this group is to make an informed decision about the necessity of conducting adjuvant androgen deprivation therapy after radical surgical treatment. During the oncogenic transformation and progression of the disease, the expression of many genes is altered. Some of these genes can serve as markers for diagnosis, predicting the prognosis or effectiveness of drug therapy, as well as possible therapeutic targets. We undertook bioinformatic analysis of the RNA-seq data deposited in The Cancer Genome Atlas consortium database to identify possible prognostic markers. We compared the groups with favorable and unfavorable prognosis for the cohort of patients with PCa showing lymph node metastasis (pT2N1M0, pT3N1M0, and pT4N1M0) and for the most common molecular type carrying the fusion transcript TMPRSS2-ERG. For the entire cohort, we revealed at least six potential markers (IDO1, UGT2B15, IFNG, MUC6, CXCL11, and GBP1). Most of these genes are involved in the positive regulation of immune response. For the TMPRSS2-ERG subtype, we also identified six genes, the expression of which may be associated with prognosis: TOB1, GALNT7, INAFM1, APELA, RAC3, and NNMT. The identified genes, after additional studies and validation in the extended cohort, could serve as a prognostic marker of locally advanced lymph node-positive PCa.

Objective: To evaluate association between histopathological factors and cervical lymph node metastasis in postoperative gingiva-buccal complex squamous cell carcinoma., Methods: We retrospectively analyzed 98 postoperative gingiva buccal complex squamous cell carcinoma patients' clinical and histopathological findings. The variables assessed were age, sex, tumour site, tumour size, degree of differentiation (grade), depth of invasion (DOI), lymphovascular invasion (LVI), perineural invasion (PNI) and extracapsular extension (ECE) and their relation with nodal metastasis., Result: Out of 98 patients, 76 patients were pathologically node positive (pN+), including 39 of the 53 patients who were classified as cN0 (clinically node negative). The prevalence of occult neck metastasis was 73.5 %. Various parameters like tumour size, LVI, PNI, ECE and Grade showed statistically significant association with lymph node metastasis (p value: 0.029, 0.007, 0.003, 0.001 and 0.001 respectively) on bivariate analysis. Depth of invasion increases incidence of nodal metastasis but was not statistically significant (p value: 0.166). On multivariate logistic regression analysis male gender and presence of PNI were found as independent predicting factors for nodal metastasis (Odds Ratio 7.0826 to 8.65 respectively) while poorly differentiated carcinoma grade appeared non-inferior factor paradoxically (Odds Ratio 0.1033, overall 82.65 % cases were correctly classified by this model and area under ROC curve (AUC) was 0.794 of the model., Conclusion: Male gender, poorly differentiated carcinoma and presence of PNI were found as independent predicting factors for nodal metastasis. Male gender and PNI were found risk factors while poorly differentiated carcinoma grade appeared non-inferior factor (protective) paradoxical.

Advanced colorectal cancer (CRC) is one of the deadliest cancers, and the 5-year survival rate of patients with metastasis is extremely low. The epithelial-mesenchymal transition (EMT) is considered essential for metastatic CRC, but the fundamental molecular basis underlying this effect remains unknown. Here, we identified that O-GlcNAcylation, a unique posttranslational modification (PTM) involved in cancer metabolic reprogramming, increased the metastatic capability of CRC. The levels of O-GlcNAcylation were increased in the metastatic CRC tissues and cell lines, which likely promoted the EMT by enhancing EZH2 protein stability and function. The CRC patients with higher levels of O-GlcNAcylation exhibited greater lymph node metastasis potential and lower overall survival. Bioinformatic analysis and luciferase reporter assays revealed that both O-GlcNAcylation transferase (OGT) and EZH2 are posttranscriptionally inhibited by microRNA-101. In addition, O-GlcNAcylation and H3K27me3 modification in the miR-101 promoter region further inhibited the transcription of miR-101, resulting in the upregulation of OGT and EZH2 in metastatic CRC, thus forming a vicious cycle. In this study, we demonstrated that O-GlcNAcylation, which is negatively regulated by microRNA-101, likely promotes CRC metastasis by enhancing EZH2 protein stability and function. Reducing O-GlcNAcylation may be a potential therapeutic strategy for metastatic CRC.

Background: In melanoma, like in other cancers, both genetic alterations and epigenetic underlie the metastatic process. These effects are usually measured by changes in both methylome and transcriptome profiles, whose cross-correlation remains uncertain. We aimed to assess at systems scale the significance of epigenetic treatment in melanoma cells with different metastatic potential., Methods and Findings: Treatment by DAC demethylation with 5-Aza-2'-deoxycytidine of two melanoma cell lines endowed with different metastatic potential, SKMEL-2 and HS294T, was performed and high-throughput coupled RNA-Seq and RRBS-Seq experiments delivered differential profiles (DiP) of both transcriptomes and methylomes. Methylation levels measured at both TSS and gene body were studied to inspect correlated patterns with wide-spectrum transcript abundance levels quantified in both protein coding and non-coding RNA (ncRNA) regions. The DiP were then mapped onto standard bio-annotation sources (pathways, biological processes) and network configurations were obtained. The prioritized associations for target identification purposes were expected to elucidate the reprogramming dynamics induced by the epigenetic therapy. The interactomic connectivity maps of each cell line were formed to support the analysis of epigenetically re-activated genes. i.e. those supposedly silenced by melanoma. In particular, modular protein interaction networks (PIN) were used, evidencing a limited number of shared annotations, with an example being MAPK13 (cascade of cellular responses evoked by extracellular stimuli). This gene is also a target associated to the PANDAR ncRNA, therapeutically relevant because of its aberrant expression observed in various cancers. Overall, the non-metastatic SKMEL-2 map reveals post-treatment re-activation of a richer pathway landscape, involving cadherins and integrins as signatures of cell adhesion and proliferation. Relatively more lncRNAs were also annotated, indicating more complex regulation patterns in view of target identification. Finally, the antigen maps matched to DiP display other differential signatures with respect to the metastatic potential of the cell lines. In particular, as demethylated melanomas show connected targets that grow with the increased metastatic potential, also the potential target actionability seems to depend to some degree on the metastatic state. However, caution is required when assessing the direct influence of re-activated genes over the identified targets. In light of the stronger treatment effects observed in non-metastatic conditions, some limitations likely refer to in silico data integration tools and resources available for the analysis of tumor antigens., Conclusion: Demethylation treatment strongly affects early melanoma progression by re-activating many genes. This evidence suggests that the efficacy of this type of therapeutic intervention is potentially high at the pre-metastatic stages. The biomarkers that can be assessed through antigens seem informative depending on the metastatic conditions, and networks help to elucidate the assessment of possible targets actionability., Competing Interests: The authors have declared that no competing interests exist.

Carcinoma breast presenting with paraneoplastic cerebellar degeneration is a rare scenario. We report a case of a 52-year-old woman, which is a follow-up case of completely treated carcinoma breast presenting with paraneoplastic cerebellar degeneration which, on investigation, revealed metastatic disease with recurrence at previous scar site and metastasis to contralateral axilla. The patient was given pulse methyl prednisolone therapy and underwent wide local excision of nodule and right axillary lymph node dissection with 14 cycles of trastuzumab and paclitaxel as adjuvant therapy. However, there was no detectable change in neurological symptoms at 6-month follow-up postoperatively. This case report highlights the need for clinicians to be aware of all possible presentations of carcinoma breast and its recurrence, including rare manifestations as in this case., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Difficulty in precise decision making on necessity of surgery is a major problem when managing oral squamous cell carcinomas (OSCCs) with clinically negative neck. Therefore, use of clinical and histopathological parameters in combination would be important to improve patient management. The main objective is to develop a model that predicts the presence of nodal metastasis in patients with OSCC.623 patients faced neck dissections with buccal mucosal or tongue squamous cell carcinoma (SCC) were selected from patients' records. Demographic data, clinical information, nodal status, Depth of invasion (DOI) and pattern of invasion (POI) were recorded. The parameters which showed a significant association with nodal metastasis were used to develop a multivariable predictive model (PM). Univariate logistic regression was used to estimate the strengths of those associations in terms of odds ratios (OR). This showed statistically significant associations between status of the nodal metastasis and each of the following 4 histopathological parameters individually: size of the tumour (T), site, POI, and DOI. Specifically, OR of nodal metastasis for tongue cancers relative to buccal mucosal cancers was 1.89, P-value < 0.001. Similarly, ORs for POI type 3 and 4 relative to type 2 were 1.99 and 5.83 respectively. A similar relationship was found with tumour size; ORs for T2, T3, and T4 compared to T1 were 2.79, 8.27 and 8.75 respectively. These four histopathological parameters were then used to develop a predictive model for nodal metastasis. This model showed that probability of nodal metastasis is higher among tongue cancers with increasing POI, with increasing T, and with larger depths while other characteristics remained unchanged. The proposed model provides a way of using combinations of histopathological parameters to identify patients with higher risks of nodal metastasis for surgical management., Competing Interests: The authors have declared that no competing interests exist.

Introduction and Aim: Papillary thyroid cancer (PTC) constitutes more than 90% of newly emerging differentiated thyroid cancers. Lymph node metastasis is often seen in PTC. There is a high risk of central metastasis in the presence of clinicopathological factors such as extrathyroidal extension, multifocality and lymphovascular invasion. The aim of this study is to evaluate the clinicopathological features that are effective in the development of lymph node metastasis., Material and Method: A retrospective examination was made of the records of patients diagnosed with papillary thyroid cancer and followed up in our clinic. Patients with and without lymph node metastasis were compared in respect of demographic features such as age, gender, pathology, histopathology, tumor size, lymph node metastasis, lymphovascular invasion, multifocality, capsule invasion, extrathyroidal extension and bilaterality., Results: Lymph node metastasis was determined in 52 of 419 papillary thyroid cancers. In the logistic regression analysis, a statistically significant relationship was determined between cervical lymph node metastasis and age <45 years (p < 0.001, OR:4.193), lymphovascular invasion (p < 0.001, OR:7.762), capsule invasion (p < 0.002, OR:3.054), extrathyroidal extension (p < 0.001, OR:6.450) and bilaterality (p < 0.001, OR: 0.217)., Conclusion: The risk of cervical lymph node metastasis was determined to be high in the presence of clinicopathological factors such as extrathyroidal extension, multifocality and lymphovascular invasion. Although lymph node metastasis does not clinically develop in all patients, knowing the risk factors related to lymph node metastasis can contribute to the evaluation of prophylactic central neck dissection in high-risk patients and follow-up of the patient in respect of recurrence., (Copyright © 2017 National Medical Association. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the impact of primary gross tumor volume (pGTV) and nodal gross tumor volume (nGTV) in oropharyngeal squamous cell carcinoma (OPSCC) and the difference in their role between human papillomavirus (HPV)-positive and HPV-negative patients., Methods: The patient cohort consists of 91 OPSCC patients treated with definitive radiochemotherapy or radiotherapy using intensity-modulated radiotherapy (IMRT). All patients had a minimum follow-up of 31 months. Volume measurements were made from computer tomography (CT) scans and HPV status was assessed by p16 immunohistochemistry. The end points were as follows: overall survival (OS), disease-free survival (DFS) and locoregional control (LRC)., Results: pGTV was a significant independent prognostic factor for overall survival (OS; p = 0.020) in p16-negative patients. nGTV of p16-negative tumors had significant prognostic value in all end points in multivariate analyses. High-stage (III-IVc) p16-negative tumors were only associated with significantly poorer OS (p = 0.046) but not with poorer LRC or DFS when compared with the low-stage (I-II) tumors. nGTV of p16-positive tumors was an independent prognostic factor for DFS (p = 0.005) and LRC (p = 0.007) in multivariate analyses., Conclusion: pGTV may serve as an independent prognostic factor in p16-negative patients and nGTV may serve as an independent prognostic factor both in p16-positive and p16-negative patients treated with radiochemotherapy or radiotherapy using IMRT. Tumor volume may have an impact on selecting patients for de-escalation protocols in the future, both in p16-positive and p16-negative patients.

Objective: To investigate the expression characteristics of long non-coding RNA (lncRNA) ZFAS1 in nasopharyngeal carcinoma (NPC) and to further investigate the role and mechanism of ZFAS1 in the occurrence and development of NPC., Patients and Methods: 76 surgical excision samples from newly diagnosed NPC patients and 76 cases of paracancerous tissues were selected. The expression of ZFAS1 was detected by qRT-PCR (quantitative real-time polymerase chain reaction), and the relationship between the expression of ZFAS1 and the clinical prognosis of patients with NPC was analyzed. After the knockdown, the expression of ZFAS1 in nasopharyngeal carcinoma cell line CNE-1 by small interfering RNA, the effect of ZFAS1 on the biological function of NPC cells was analyzed by cell counting kit-8 (CCK8), colony formation assay, flow cytometry and apoptosis assay. The effect of ZFAS1 on the Wnt/β-catenin pathway was analyzed by Western blot., Results: After analyzing the clinical data of enrolled patients, we found that ZFAS1 was overexpressed in NPC patients, which was closely correlated with tumor size and lymph node metastasis of NPC. Moreover, ZFAS1 was negatively correlated to the survival of NPC patients. After interfering with the expression of ZFAS1, the proliferation of NPC cells was significantly decreased, the cell cycle was inhibited and the apoptosis rate was increased. Western Blot showed that ZFAS1 promoted the occurrence of NPC by activating the Wnt/β-catenin pathway., Conclusions: ZFAS1 was overexpressed in NPC and was significantly related to tumor size, lymph node metastasis and poor prognosis of NPC. ZFAS1 could promote NPC by activating Wnt/β-catenin pathway.

Background: The purpose of this study is to establish whether the lymph node metastases of the papillary thyroid carcinoma are a significant factor in recurrence of the disease by analyzing the time until recurrence of the disease and frequency of recurrence of the disease., Methods: From 1 January 1995 until 30 June 2017, 102 patients were treated at the Public Health Institute Hospital "Sveti Vracevi" in Bijeljina for PTC. In all patients, surgery of the thyroid gland and/or lymph nodes of the neck was performed. Total thyroidectomy (TT) was performed in 20 patients and near-total thyroidectomy leaving <1 g thyroid tissue adjacent to the recurrent laryngeal nerve in 7 patients. TT and lymph nodes dissection were performed in 71 patients. Palliative surgery and biopsy due to locally advanced disease were performed in 3 patients., Results: In our study, 102 patients with PTC were analyzed. 82 patients experienced pure PTC (80.4%), the other 20 patients (19.6%) experienced other variants of PTC. 24 patients (23.5%) experienced multi centric or bilateral tumors. 71 patients (69.6%) experienced histologically verified metastases in the lymph nodes of the neck. 7 patients (6.8%) experienced distant metastases. 20 patients underwent total thyroidectomy (TT), and 7 near-total thyroidectomy. Total thyroidectomy + dissection of central and lower jugular lymph nodes with frozen section histopathology verification was performed in 71 patients (69.6%). Out of these 71 patients, in 50 patients (70.4%) metastases were verified in the lower jugular lymph nodes. A modified lymph node dissection (MRND) was also performed in these patients., Conclusion: Lymph node metastases of the papillary thyroid carcinoma are a plausible prognostic factor. They are important for recurrence of the disease, but not for survival.

Competing Interests: None

Background: Although the numeric-based lymph node (LN) staging was widely used in the worldwide, it did not represent the anatomical location of metastatic lymph nodes (MLNs) and not reflect extent of LN dissection. Therefore, in the present study, we investigated whether the anatomical location of MLNs was still necessary to evaluate the prognosis of node-positive gastric cancer (GC) patients., Methods: We reviewed 1451 GC patients who underwent radical gastrectomy in our institution between January 1986 and January 2008. All patients were reclassified into several groups according to the anatomical location of MLNs and the number of MLNs. The prognostic differences between different patient groups were compared and clinicopathologic features were analyzed., Results: In the present study, both anatomical location of MLNs and the number of MLNs were identified as the independent prognostic factors (p < .01). The patients with extraperigastric LN involvement showed a poorer prognosis compared with the perigastric-only group (p < .001). For the N1-N2 stage patients, the prognostic discrepancy was still observed among them when the anatomical location of MLNs was considered (p < .05). For the N3-stage patients, although the anatomical location of MLNs had no significant effect on the prognosis of these patients, the higher number of MLNs in the extraperigastric area was correlated with the unfavorable prognosis (p < .05)., Conclusion: The anatomical location of MLNs was an important factor influencing the prognostic outcome of GC patients. To provide more accurate prognostic information for GC patients, the anatomical location of MLNs should not be ignored.

Introduction: CD73 is an enzyme crucial in the metabolism of immunosuppressive adenosine. In cancer, it has various functions including tumor growth and metastases. Squamous cell carcinoma of the head and neck has an overall poor prognosis, also due to early spread of metastatic cells., Materials and Methods: Tumor and lymph node specimens of 65 patients with HNSCC were subjected to immunohistochemical and H-score analysis of CD73 expression. Demographics, diagnoses, histopathology and subsequent outcome were analyzed., Results: The primary cancer was squamous cell carcinoma in all patients (male/female 55:10) with the following locations: oral cavity n:16, oropharynx n:28, hypopharynx n:11 and larynx n:10. H-score for CD73 expression in the primary lesion and metastatic lymph nodes was significantly higher in advanced compared to early stages with no significant differences among tumor locations. High CD73 expression was associated with reduced overall survival rates at a mean follow-up of 83.4 months (6-204 months)., Conclusions: CD73 expression in HNSCC correlated positively with tumor stage and was associated with poor prognosis. Therefore, CD73 expression in primary lesions and regional metastases appears to predict HNSCC patients at high risk of all tumor sites. Therapeutic approaches targeting CD73 might seem promising for this patient population.