Low-Volume Metastases in Apparent Early-Stage Endometrial Cancer: Prevalence, Clinical Significance, and Future Perspectives.

Endometrial cancer (EC) is the most diagnosed gynecologic malignancy, and its incidence and mortality are increasing. The prognosis is highly dependent on the disease spread. Surgical staging includes retroperitoneal evaluation to detect potential lymph node metastases. In recent years, systematic lymphadenectomy has been replaced by sentinel lymph node (SLN) biopsy and ultrastaging, allowing for the detection of macrometastases, micrometastases, and isolated tumor cells (ITCs). Micrometastases and ITCs have been grouped as low-volume metastases (LVM). The reported prevalence of LVM in studies enrolling more than one thousand patients with apparent early-stage EC ranges from 1.9% to 10.2%. Different rates of LVM are observed when patients are stratified according to disease characteristics and their risk of recurrence. Patients with EC at low risk for recurrence have low rates of LVM, while intermediate- and high-risk patients have a higher likelihood of being diagnosed with nodal metastases, including LVM. Macro- and micrometastases increase the risk of recurrence and cause upstaging, while the clinical significance of ITCs is still uncertain. A recent meta-analysis found that patients with LVM have a higher relative risk of recurrence [1.34 (95% CI: 1.07-1.67)], regardless of adjuvant treatment. In a retrospective study on patients with low-risk EC and no adjuvant treatment, those with ITCs had worse recurrence-free survival compared to node-negative patients (85.1%; CI 95% 73.8-98.2 versus 90.2%; CI 95% 84.9-95.8). However, a difference was no longer observed after the exclusion of cases with lymphovascular space invasion. There is no consensus on adjuvant treatment in ITC patients at otherwise low risk, and their recurrence rate is low. Multi-institutional, prospective studies are warranted to evaluate the clinical significance of ITCs in low-risk patients. Further stratification of patients, considering histopathological and molecular features of the disease, may clarify the role of LVM and especially ITCs in specific contexts.

Endometrial cancer with positive sentinel lymph nodes: pathologic characteristics of metastases as predictors of extent of lymphatic dissemination and prognosis.

OBJECTIVES: To assess predictors of extensive lymph node dissemination and non-vaginal recurrence in patients with endometrial cancer with positive sentinel lymph nodes (SLNs). METHODS: Patients with endometrial cancer who underwent primary surgery with SLN mapping and had at least one positive node between October 2013 and May 2019 were included. Positive SLNs were reviewed, and cases were classified according to the location of the metastasis (extracapsular vs intracapsular), and the size of the largest SLN metastasis (isolated tumor cells, micrometastasis, macrometastasis). Associations were assessed based on fitting logistic regression models and Cox proportional hazards models. RESULTS: A total of 103 patients met the inclusion criteria: including 36 (34.9%) with isolated tumor cells, 27 (26.2%) with micrometastasis, and 40 (38.8%) with macrometastasis. Notably, 71.4% of patients exhibiting extracapsular SLN metastases had multiple positive SLNs (p=0.008). Extracapsular invasion (adjusted odds ratio (aOR) 5.81, 95% CI 1.4 to 23.6) and age (aOR=1.8, 95% CI 1.1 to 3.0) emerged as independent predictors of multiple positive SLNs. Among the 38 patients who underwent a backup pelvic lymphadenectomy, 18 (47.4%) presented with positive pelvic non-SLNs, a phenomenon more prevalent in patients with macrometastasis (p=0.004).Independent predictors of non-vaginal recurrence included SLN macrometastasis (adjusted hazard ratio (aHR) 3.3, 95% CI 1.3 to 8.3), non-endometrioid histology (aHR=3.7, 95% CI 1.5 to 9.3), and cervical stromal invasion (aHR=5.5, 95% CI 2.0 to 14.9). Among the 34 patients with isolated tumor cells and endometrioid histology, 3 (9%) experienced a recurrence, all of whom had not received any adjuvant chemotherapy or external beam radiotherapy. CONCLUSION: Patients with positive SLN macrometastasis are independently associated with extensive lymphatic dissemination and distant recurrences. The risk of multiple positive SLNs increases with the extracapsular location of the SLN metastasis and with age. Independent uterine pathologic predictors of non-vaginal recurrence are non-endometrioid histology and cervical stromal invasion.

Postmastectomy radiation therapy in breast cancer patients with micrometastatic disease in sentinel node dissection: A cohort study and meta-analysis.

Aim: The potential role of postmastectomy radiation therapy (PMRT) on prognosis in patients with T1-2 breast cancer and micrometastatic disease in sentinel lymph node dissection (SLND) has not yet been established. The aim of this study was to investigate the impact of PMRT on prognosis in patients with T1-2 breast cancer and micrometastatic in SLND. Method: A register- and population-based cohort was utilized by identifying eligible patients on the research database BcBase 3.0. Multivariate Cox regression models were applied for survival outcomes. In addition, a systematic literature review and meta-analysis including all relevant studies on this topic was performed. Results: In total, 956 patients fulfilling the inclusion criteria were found through the BcBaSe 3.0 with 237 (25.0 %) receiving PMRT and 719 (75.0 %) not receiving PMRT. No statistically significant differences between the two patient groups in terms of neither breast cancer-specific (adjusted Hazard Ratio (HR): 0.49; 95 % Confidence Interval (CI): 0.14 - 1.73) nor overall survival (adjusted HR: 0.63; 95 % CI: 0.29 - 1.35) was found. In the pooled analyses after literature review, PMRT did not result in better breast cancer-specific (5 studies; pooled HR: 1.06; 95 % CI: 0.88-1.27; I2 = 1 %; low certainty of evidence) or overall survival (6 studies; pooled HR: 1.01; 95 % CI: 0.91-1.13; I2 = 10 %; low certainty of evidence). Conclusion: PMRT does not seem to impact survival in patients with T1 or T2 breast cancer with micrometastatic disease in SLND. Considering the low level of evidence and the relatively short follow-up of included studies, caution in interpreting the results into clinical practice is suggested.

Biomarkers of minimal residual disease and treatment.

Minimal residual disease (MRD) has been defined as a very small numbers of cancer cells that remain in the body after curative treatment. Its presence or absence will ultimately determine prognosis. With the introduction of new technologies the presence of MRD in patients with solid tumours can be detected and characterized. As MRD predicts future relapse, be it early or late treatment failure, in an otherwise asymptomatic patient its treatment and when to start treatment remains to be determined. Thus the concepts of personalized medicine using different biomarkers to classify the biological properties of MRD maybe come possible. Based on this determinations it may be possible to use targeted therapies rather than all patients with the same type of cancer receiving a standard treatment. However, it is important to understand the limitations of the different technologies, what these techniques are detecting and how they may help in the treatment of patients with cancer. The majority of published studies are in patients with metastatic cancer and there are few reports in patients with MRD. In this chapter the concept of MRD, the methods used to detect it and what treatments may be effective based on the biological characteristics of the tumour cells as determined by different biomarkers is reviewed. MRD depends on the phenotypic properties of the tumour cells to survive in their new environment and the anti-tumour immune response. This is a dynamic process and changes with time in the wake of immunosuppression caused by the tumour cells and/or the effects of treatment to select resistant tumour cells. With the use of biomarkers to typify the characteristics of MRD and the development of new drugs a personalized treatment can be designed rather than all patients given the same treatment. Patients who are initially negative for MRD may not require further treatment with liquid biopsies used to monitor the patients during follow-up in order to detect those patients who may become MRD positive. The liquid biopsy used during the follow up of MRD positive patients can be used to detect changes in the biological properties of the tumour cells and thus may need treatment changes to overcome tumour cell resistance.

Frequency and predictive factors of nodal micro-metastasis (NMM) in resectable non-small cell lung cancer.

Background: The frequency of lymph nodal micrometastasis (NMM) in resectable non-small cell lung cancer (NSCLC) is frequently underestimated when relying solely on standard hematoxylin and eosin staining during pathological examination. Methods: This is a retrospective cross-sectional diagnostic research. Medical records of resectable pN0 NSCLC patients who underwent curative resection in Maharaj Nakorn Chiang Mai Hospital between January 2006 to December 2017 were retrospectively reviewed. Immunohistochemistry (IHC) staining using cytokeratin AE1/AE3, p53 and BerEP4 markers was employed to detect NMM. Primary objective of this study was to determine frequency of NMM in pN0 resectable NSCLC. Results: This study included 98 patients with pN0 NSCLC, of which 47 were male and 51 were female. NMM was detected in 21 of 98 patients (21.43%). Lymph node station 10 and 7 were the most common site of micrometastasis among patients with N1 and N2 micrometastasis, respectively. Cytokeratin AE1/AE3 was the most sensitive antibody in detecting micrometastasis in lymph nodes, identifying 25 out of 27 positive lymph nodes. Tumor size greater than 4 cm was a statistically significant predictive factor for NMM with risk ratio 6.69 [95% confidence interval (CI): 2.38-18.85, P<0.001]. Conclusions: NMM was identified in 21.43% of pN0 resectable NSCLC patients and tumor size greater than 4 cm is predictive factor for NMM.

Validation study on the 2 mm diameter cutoff in lymph node-positive cases following radical prostatectomy in accordance with the AJCC/UICC TNM 8th edition: Real-world data analysis from a Japanese cohort.

OBJECTIVES: The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) 8th edition has proposed micrometastasis as a lymph node metastasis (LN+) of diameter ≤2 mm in prostate cancer. However, supporting evidence has not described. We evaluated LN+ patients' survival after radical prostatectomy (RP) based on the LN maximum tumor diameter (MTD). METHODS: Data from 561 LN+ patients after RP and pelvic LN dissection (PLND) treated between 2006 and 2019 at 33 institutions were retrospectively investigated. Patients were stratified by a LN+ MTD cutoff of 2 mm. Outcomes included castration resistance-free survival (CRFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: In total, 282 patients were divided into two groups (LN+ MTD >2 mm [n = 206] and ≤2 mm [n = 76]). Patients of LN+ status >2 mm exhibited significantly decreased CRFS and MFS, and poorer CSS and OS. No patients developed CRPC in the LN+ status ≤2 mm group when the PLND number was ≥14. Multivariate analysis showed the number of LN removed, RP Gleason pattern 5, and MTD in LN+ significantly predicted CRFS. CONCLUSIONS: Patients of LN+ status ≤2 mm showed better prognoses after RP. In all the patients in the ≤2-mm group, the progression to CRPC could be prevented with appropriate interventions, particularly when PLND is performed accurately. Our findings support the utility of the pN substaging proposed by the AJCC/UICC 8th edition; this will facilitate precision medicine for patients with advanced prostate cancer.

Incidence of sentinel lymph node metastases in apparent early-stage endometrial cancer: a multicenter observational study.

OBJECTIVE: Ultrastaging is accurate in detecting nodal metastases, but increases costs and may not be necessary in certain low-risk subgroups. In this study we examined the risk of nodal involvement detected by sentinel lymph node (SLN) biopsy in a large population of apparent early-stage endometrial cancer and stratified by histopathologic characteristics. Furthermore, we aimed to identify a subgroup in which ultrastaging may be omitted. METHODS: We retrospectively included patients who underwent SLN (with bilateral mapping and no empty nodal packets on final pathology) ± systematic lymphadenectomy for apparent early-stage endometrial cancer at two referral cancer centers. Lymph node status was determined by SLN only, regardless of non-SLN findings. The incidence of macrometastasis, micrometastasis, and isolated tumor cells (ITC) was measured in the overall population and after stratification by histotype (endometrioid vs serous), myometrial invasion (none, <50%, ≥50%), and grade (G1, G2, G3). RESULTS: Bilateral SLN mapping was accomplished in 1570 patients: 1359 endometrioid and 211 non-endometrioid, of which 117 were serous. The incidence of macrometastasis, micrometastasis, and ITC was 3.8%, 3.4%, and 4.8%, respectively. In patients with endometrioid histology (n=1359) there were 2.9% macrometastases, 3.2% micrometastases, and 5.3% ITC. No macro/micrometastases and only one ITC were found in a subset of 274 patients with low-grade (G1-G2) endometrioid endometrial cancer without myometrial invasion (all <1%). The incidence of micro/macrometastasis was higher, 2.8%, in 708 patients with low-grade endometrioid endometrial cancer invading <50% of the myometrium. In patients with serous histology (n=117), the incidence of macrometastases, micrometastasis, and ITC was 11.1%, 6.0%, and 1.7%, respectively. For serous carcinoma without myometrial invasion (n=36), two patients had micrometastases for an incidence of 5.6%. CONCLUSIONS: Ultrastaging may be safely omitted in patients with low-grade endometrioid endometrial cancer without myometrial invasion. No other subgroups with a risk of nodal metastasis of less than 1% have been identified.

Tertiary prevention strategies for micrometastatic lymph node cervical cancer: A systematic review and a prototype of an adapted model of care.

PURPOSE: We found a need for balancing the application of clinical guidelines and tailored approaches to follow-up of cervical cancer (CC) patients in the lymph node micrometastatic (MICs) setting. This review aimed to determine the current knowledge of management of MIC-positive CC cases. METHODOLOGY: We addressed prognostic and risk of recurrence monitoring impacts associated with MIC+ cases. The electronic databases for literature and relevant articles were analysed. RESULTS: Fifteen studies, (4882 patients), were included in our systematic review. While the results show that MICs significantly worsen prognosis in early CC. A tertiary prevention algorithm for low volume lymph node disease may stratify follow-up according to the burden of nodal disease and provide data that helps improve follow-up performance. CONCLUSION: MICs worsen prognosis and should be managed as suggested by the algorithm. However, this algorithm must be externally validated. The clinical impact of isolated tumor cells (ITC) remains unclear.

Omission of axillary lymph node dissection in breast cancer patients with micrometastasis or isolated tumor cells in sentinel lymph nodes: a 12-year experience in a tertiary breast unit.

INTRODUCTION: After the IBCSG 23-01 trial, our breast center no longer performed axillary lymph node dissection (ALND) after detection of isolated tumor cells (ITC) or micrometastasis in the sentinel lymph nodes (SLN). A recent study suggested that up to half of the patients with micrometastasis in the SLN could benefit from ALND in terms of disease-free survival (DFS) and overall survival (OS). METHODS: This retrospective, unicentric, study analyzed 261 consecutive cT1-3 cN0 breast cancer patients with ITC or micrometastasis in their SLN. Primary objective was comparison of ALND vs. SLN biopsy (SLNB) with regard to DFS and OS. Secondary objectives included analysis of factors associated with an increased rate of locoregional recurrence (LRR), distant metastasis (DM) and metachronous contralateral breast cancer (MCBC). RESULTS: DFS events occurred in 19 patients (7.3%) and 14 patients died (5.4%). Median follow-up time was 78 months. 251 patients (96.2%) had micrometastasis in their SLN. There was no difference in the OS or DFS of ALND vs. SLNB patients. History of previous contralateral breast cancer and WBI were associated with an increased and decreased rate of LRR, respectively. Larger tumor size was associated with an increased rate of DM. Non-ductal histological types were associated with an increased rate of MCBC. DISCUSSION: Avoiding ALND may be safe in pN1mi/pN0(i+) patients. Besides, we strongly encourage clinicians to develop their own follow-up protocols based on the best available evidence, to rapidly identify and treat breast cancer recurrence.

The Possible Role of Matrix Metalloprotienase-2 in the Relapse in Patients with Stage II Colon Cancer Treated by Curative Surgery.

AIMS: To determine the association of micro-metastatic matrix metalloproteinase-2 (MMP-2) expression,  the absolute lymphocyte count (ALC)) and outcome in stage II colon cancer. MATERIALS AND METHODS: A single centre, prospective observational study, one month post-surgery blood for ALC, circulating tumour cell (CTC) detection and a bone marrow biopsy for micro-metastasis detection were obtained.  CTCs were detected using differential gel centrifugation and immunocytochemistry with anti-CEA and anti-MMP-2, the bone marrow biopsy for the detection of micro-metastasis was processed as for CTCs . At each follow-up  ALC and CTC counts were determined. Bone marrow sampling was repeated if the ALC decreased by >10%, at relapse or at the end of the study period. Three MRD subgroups were defined, Group I MRD negative, Group II only positive for micro-metastasis and   Group III in which CTCs were detected. RESULTS: One hundred and eighty one patients  participated; 105 (58%) patients formed Group 1, 36 (20%) formed Group II  and 40 (22%)  formed Group III for a median follow-up of 4 years .  Of Group I 3/105 (3%), Group II 16/36 (44%) and Group III 34/40 (84%) patients relapsed. The ALC was significantly higher in Groups I and II, the expression of MMP-2 and MMP-2 score in Group II was significantly lower than in Group III patients. A low ALC was associated with a higher expression of MMP-2 in the micro-metastasis and presence of CTCs. CONCLUSIONS: Patients with stable ALCs did not relapse; decreasing ALCs were associated with increasing MMP-2 scores, the appearance of CTCs and relapse.

Outcomes in Premenopausal Patients with HR+/HER2- Breast Cancer and Lymph Node Micrometastasis Based on the 21-Gene Recurrence Score.

BACKGROUND: Postmenopausal patients with hormone receptor positive, HER2-negative (HR+/HER2-) early breast cancer (EBC) and 21-gene OncotypeDX (ODX) recurrence scores (RS) <26 do not benefit from chemoendocrine therapy ("CET") compared to endocrine monotherapy ("E"), regardless of nodal status. In premenopausal patients, nodal status is significant in interpretation of RS. However, guidelines are not explicit in recommendations for patients with micrometastasis ("pN1mi" staging). METHODS: A cohort of patients aged <50 years with HR+/HER2- EBC who underwent ODX testing was identified within the National Cancer Database 2004-2019 dataset. We confirmed the prognostic value of ODX in pN1mi disease with multivariate Cox regression for overall survival (OS). We explored how patterns of practice differed by nodal status in cases of low RS (<26) with chi-squared testing. Finally, we performed Kaplan-Meier models comparing OS for those with RS <26 receiving E versus CET, controlling for nodal status. RESULTS: Of 72 068 patients aged <50 years with HR+/HER2- EBC, 6.1% (n = 4402) had micrometastasis. Multivariate Cox regression confirmed prognostic value of ODX in this pN1mi cohort (P < .001). In the context of RS <26, CET was used most commonly in patients with 1-3 involved lymph nodes ("pN1a-c" disease), less frequently in pN1mi disease, and least in node-negative ("pN0") disease. A benefit in OS was observed in cases with RS <26 and pN1a-c receiving CET vs. E (P = .017), but not in pN1mi (P = .49) or pN0 (P = .57) disease. CONCLUSION: Our large registry analysis found CET was associated with improved OS in pN1a-c, but not in pN1mi or pN0 disease.

MILACC study: could undetected lymph node micrometastases have impacted recurrence rate in the LACC trial?

OBJECTIVE: The etiology of inferior oncologic outcomes associated with minimally invasive surgery for early-stage cervical cancer remains unknown. Manipulation of lymph nodes with previously unrecognized low-volume disease might explain this finding. We re-analyzed lymph nodes by pathologic ultrastaging in node-negative patients who recurred in the LACC (Laparoscopic Approach to Cervical Cancer) trial. METHODS: Included patients were drawn from the LACC trial database, had negative lymph nodes on routine pathologic evaluation, and recurred to the abdomen and/or pelvis. Patients without recurrence or without available lymph node tissue were excluded. Paraffin tissue blocks and slides from all lymph nodes removed by lymphadenectomy were re-analyzed per standard ultrastaging protocol aimed at the detection of micrometastases (>0.2 mm and ≤2 mm) and isolated tumor cells (clusters up to 0.2 mm or <200 cells). RESULTS: The study included 20 patients with median age of 42 (range 30-68) years. Most patients were randomized to minimally invasive surgery (90%), had squamous cell carcinoma (65%), FIGO 2009 stage 1B1 (95%), grade 2 (60%) disease, had no adjuvant treatment (75%), and had a single site of recurrence (55%), most commonly at the vaginal cuff (45%). Only one patient had pelvic sidewall recurrence in the absence of other disease sites. The median number of lymph nodes analyzed per patient was 18.5 (range 4-32) for a total of 412 lymph nodes. A total of 621 series and 1242 slides were reviewed centrally by the ultrastaging protocol. No metastatic disease of any size was found in any lymph node. CONCLUSIONS: There were no lymph node low-volume metastases among patients with initially negative lymph nodes who recurred in the LACC trial. Therefore, it is unlikely that manipulation of lymph nodes containing clinically undetected metastases is the underlying cause of the higher local recurrence risk in the minimally invasive arm of the LACC trial.

Detection of micro-metastasis using cytokeratins (AE1/AE3) in haematoxylin & eosin-stained N0 lymph nodes of oral squamous cell carcinoma.

Background & objectives: Oral squamous cell carcinoma (OSCC) is one of the most common malignancies affecting the head-and-neck region, regional lymph nodes being an important prognostication factor dictating the survival rate. Despite an array of modalities used, clinically, radiographically and routine histopathologically, the detection of micro-metastasis (2-3 mm tumour cell deposits) in the lymph nodes often escapes identification. The presence of few of these tumour epithelial cells in the lymph nodes drastically increases mortality and alters treatment plan. Hence, the identification of these cells is of major prognostic significance for a patient. Thus, the present study was aimed to evaluate and detect the efficacy of the immunohistochemical (IHC) marker [cytokeratin (CK) AE1/AE3] over routine Hematoxylin & eosin (H & E) staining in detecting micro-metastasis in the lymph nodes of OSCC cases. Methods: Hundred H & E-stained N0 lymph nodes of OSCC cases treated with radical neck dissection were subjected to IHC with marker AE1/AE3 antibody cocktail for detecting micro-metastasis. Results: The IHC marker CK cocktail (AE1/AE3) did not demonstrate any positive reactivity for the target antigen in all the 100 H & E stained lymph node sections evaluated in the present study. Interpretation & conclusions: This study was undertaken to check the efficacy of IHC (CK cocktail AE1/AE3) in the detection of micro-metastasis in lymph nodes that are found to be negative in routine H&E stained sections. The findings of this study suggest that the IHC marker AE1/AE3 did not prove to be useful to detect micro-metastasis in this study population.

Prognostic impact of micrometastasis in patients with esophageal cancer.

Squamous cell carcinoma (SCC) of the esophagus and adenocarcinoma of the esophago-gastric junction (AEG) are diseases with poor prognosis. Despite radical surgery having been carried out, many patients are at risk of cancer recurrence, especially with the presence of metastases in the lymph nodes. The study involved 60 patients suffering from SCC and AEG who had lymph nodes surgically removed between 2012 and 2018. Only lymph nodes with N0 status were subjected to immunohistochemistry examination. Histopathological criteria were used for the diagnosis of micrometastases (MM), defined as tumor cells or cell clusters of 0.2-2 mm diameter in the lymph node and tumor cell microinvolvement defined as free-floating neoplastic cells or cell clusters within the sub-capsular sinus or intramedullary sinuses of the lymph node. A total of 1130 lymph nodes were removed during surgery, with an average of 22 lymph nodes per patient (range 8-58). Micrometastases were found in 7 (11.66%) patients: 6 (10.0%) with AEG and 1 (1.66%) with SCC, representing a statistically significant difference p = 0.017. Multivariate analysis of the study group did not confirm the dependence of the MM on the T features ( p = 0.7) or G ( p = 0.5). In a Cox regression analysis, MM were not a risk factor for death, HR: 2.57 (0.95; 7.00), p = 0.064. There was no difference in overall survival for patients with MM (N (+)) and those without (N0), p = 0.055, but there was a statistically significant difference in time of relapse between patients with and without MM ( p = 0.049). Patients with the N (+) status are at high risk of cancer recurrence, and therefore we believe that complementary treatment should be considered in this group.

Combination of CEACAM5, EpCAM and CK19 gene expressions in mediastinal lymph node micrometastasis is a prognostic factor for non-small cell lung cancer.

BACKGROUND: Lung cancer is known as the most common and highly metastatic form of cancer worldwide. Tumour node metastasis (TNM) staging is the gold standard classification system for the decision-making process for appropriate treatment. Particularly N status has the most important prognostic value in the absence of distant metastasis. Traditional diagnostic methods are capable of detecting metastasis; however, they may fail to detect micrometastasis, which plays a role in disease recurrence and patients' long-term survival. Occult micrometastasis can change the tumour's TNM staging and, consequently, the patient's treatment regimen. METHODS: The median number of three lymph node tissues were collected from 30 patients who underwent surgery for non-small cell lung cancer. Lymph node tissues were collected from different lymph node stations according to the location of the patient's tumour. CK19, EpCAM and CEACAM5 gene expressions were analysed in tissues using quantitative real-time polymerase chain reaction to detect micrometastasis in distant lymph nodes. RESULTS: Triple positivity was seen in 26 out of 30 patients which 19 patients were upstaged from N0 to N2. While survival was not significantly affected between upstaged and non-upstaged patients, patients upstaged with multiple-station N2 had a significantly higher recurrence and lower survival compared to single-station N2. CONCLUSION: A combination of CK19, EpCAM and CEACAM5 gene expressions in lymph nodes can be used to identify micrometastasis which postoperatively may be used as a tool to predict patients' recurrence and survival.

Mucin 1 expression correlation with lymph node metastasis and micrometastasis and poor prognosis in patients with esophageal squamous cell carcinomas.

Introduction: Lymph node metastasis (LNM) and lymph node micrometastasis (LNMM) are prognostic factors in esophageal squamous cell carcinoma (ESCC) patients. The purpose of this research is to investigate whether mucin 1 expression detected by immunohistochemistry in lymph nodes correlates with LNM, LNMM and prognosis in ESCC patients. Material and methods: There were 92 ESCC patients enrolled in the research, and 1382 lymph nodes were obtained from these 92 patients. All lymph nodes were immunohistochemically analyzed using an anticytokeratin and mucin 1 antibody cocktail. Results: In the pN1-2 patients' group, 68 lymph nodes from 15 patients had tumor metastasis. All these 68 tumor metastatic lymph nodes were positive for mucin 1. Mucin 1 was detected in another 231 lymph nodes and among them, 3 (3/231 1.3%) lymph nodes from 2 (2/15 13.3%) patients were positive for mucin 1. In 77 pN0 patients, mucin 1 was detected in 1083 lymph nodes from the 77 patients; 17 (17/1083 1.6%) lymph nodes from 15 (15/77 19.5%) patients were positive for mucin 1. The 5-year survival rate was 39.1%, and it was significantly related to tumor invasion (pT, p < 0.05), lymph node metastasis (pN, p < 0.01), pTNM stage (p < 0.01) and mucin 1 expression (p < 0.01). Cox regression of multivariate analysis demonstrated that mucin 1 expression and pT were independent prognostic factors. Conclusions: Mucin 1 expression was related to LNM and LNMM and poor prognosis in ESCC patients. Immunohistochemistry for mucin 1 can be applied for the detection of LNM and LNMM.

Protocol for a prospective study evaluating circulating tumour cells status to predict radical prostatectomy treatment failure in localised prostate cancer patients (C-ProMeta-1).

BACKGROUND: Treatment decisions in prostate cancer (PCa) rely on disease stratification between localised and metastatic stages, but current imaging staging technologies are not sensitive to micro-metastatic disease. Circulating tumour cells (CTCs) status is a promising tool in this regard. The Parsortix® CTC isolation system employs an epitope-independent approach based on cell size and deformability to increase the capture rate of CTCs. Here, we present a protocol for prospective evaluation of this method to predict post radical prostatectomy (RP) PCa cancer recurrence. METHODS: We plan to recruit 294 patients diagnosed with unfavourable intermediate, to high and very high-risk localised PCa. Exclusion criteria include synchronous cancer diagnosis or prior PCa treatment, including hormone therapy. RP is performed according to the standard of care. Two blood samples (20 ml) are collected before and again 3-months after RP. The clinical team are blinded to CTC results and the laboratory researchers are blinded to clinical information. Treatment failure is defined as a PSA ≥ 0.2 mg/ml, start of salvage treatment or imaging-proven metastatic lesions. The CTC analysis entails enumeration and RNA analysis of gene expression in captured CTCs. The primary outcome is the accuracy of CTC status to predict post-RP treatment failure at 4.5 years. Observed sensitivity, positive and negative predictive values will be reported. Specificity will be presented over time. DISCUSSION: CTC status may reflect the true potential for PCa metastasis and may predict clinical outcomes better than the current PCa progression risk grading systems. Therefore establishing a robust biomarker for predicting treatment failure in localized high-risk PCa would significantly enhance guidance in treatment decision-making, optimizing cure rates while minimizing unnecessary harm from overtreatment. TRIAL REGISTRATION: ISRCTN17332543.

Clinical utility of artificial intelligence assistance in histopathologic review of lymph node metastasis for gastric adenocarcinoma.

BACKGROUND: Advances in whole-slide image capture and computer image analyses using deep learning technologies have enabled the development of computer-assisted diagnostics in pathology. Herein, we built a deep learning algorithm to detect lymph node (LN) metastasis on whole-slide images of LNs retrieved from patients with gastric adenocarcinoma and evaluated its performance in clinical settings. METHODS: We randomly selected 18 patients with gastric adenocarcinoma who underwent surgery with curative intent and were positive for LN metastasis at Chiba University Hospital. A ResNet-152-based assistance system was established to detect LN metastases and to outline regions that are highly probable for metastasis in LN images. Reference standards comprising 70 LN images from two different institutions were reviewed by six pathologists with or without algorithm assistance, and their diagnostic performances were compared between the two settings. RESULTS: No statistically significant differences were observed between these two settings regarding sensitivity, review time, or confidence levels in classifying macrometastases, isolated tumor cells, and metastasis-negative. Meanwhile, the sensitivity for detecting micrometastases significantly improved with algorithm assistance, although the review time was significantly longer than that without assistance. Analysis of the algorithm's sensitivity in detecting metastasis in the reference standard indicated an area under the curve of 0.869, whereas that for the detection of micrometastases was 0.785. CONCLUSIONS: A wide variety of histological types in gastric adenocarcinoma could account for these relatively low performances; however, this level of algorithm performance could suffice to help pathologists improve diagnostic accuracy.