Circ-HMGCS1, an Indicator of Survival and Prognosis in Cervical Cancer Patients.

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.

C/EBP-Family Redundancy Determines Patient Survival and Lymph Node Involvement in PDAC.

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/EBPß 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/EBPß and C/EBPγ can partially compensate for low C/EBPδ and improve patient survival. Further, we uncovered C/EBPß as a novel predictor of a decreased likelihood of lymph node involvement in PDAC, and found that C/EBPß 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/EPBß and C/EBPγ should be taken into account when dichotomizing patients according to C/EBPδ expression.

A novel DNA methylation signature associated with lymph node metastasis status in early gastric cancer.

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.

Genomic landscape of secretory carcinoma of the breast with axillary lymph node metastasis.

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.

Upregulated WTAP expression appears to both promote breast cancer growth and inhibit lymph node metastasis.

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.

Epstein-Barr Virus Induces Lymphangiogenesis and Lympth Node Metastasis via Upregulation of VEGF-C in Nasopharyngeal Carcinoma.

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.

Expression of VEGF-A, HER2/neu, and KRAS in gall bladder carcinoma and their correlation with clinico-pathological parameters.

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.

Mechanisms and Clinical Significance of Tumor Lymphatic Invasion.

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.

Characteristics of lymph node (No.5 and No.6) metastasis and significance of lymph node dissection in Siewert type II esophagogastric junction adenocarcinoma (AEG): No.5 and No.6 lymph node metastases of AEG and clearance.

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.

Delayed solitary mediastinal lymph node metastasis from a benign meningothelial meningioma six years after surgical resection of an intracranial tumor.

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.

Prognostic effect of perineural invasion in surgically treated esophageal squamous cell carcinoma.

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.

Enemy Beyond the Wall: Clinicopathological Features of Intrathyroidal Papillary Thyroid Carcinoma (T1-T3a) That Metastasize to Lymph Nodes Without Extrathyroidal Extension.

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.

A novel robust nomogram based on peripheral monocyte counts for predicting lymph node metastasis of prostate cancer.

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.

Failure rate in the untreated contralateral node negative neck of small lateralized oral cavity cancers: A multi-institutional collaborative study.

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.

The assessment of the optimal number of examined lymph nodes and prognostic models based on lymph nodes for predicting survival outcome in patients with stage N3b gastric cancer.

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.

Lymphatic Metastasis of NSCLC Involves Chemotaxis Effects of Lymphatic Endothelial Cells through the CCR7-CCL21 Axis Modulated by TNF-α.

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.

Regional Lymph Node Involvement Among Patients With De Novo Metastatic Breast Cancer.

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.

Intraoperative diagnosis of lymph node metastasis during segmentectomy for non-small cell lung cancer by rapid immunohistochemistry using noncontact alternating current electric field mixing.

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.