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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., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: An estimated 20% of patients with oral and oropharyngeal squamous cell carcinoma (OOSCC) have micrometastases (Mi) or isolated tumor cells (ITC) in the cervical lymph nodes that evade detection by standard histological evaluation of lymph node sections. Lymph node Mi and ITC could be one reason for regional recurrence after neck dissection. The aim of this study was to review the existing data regarding the impact of Mi on the survival of patients with OOSCC., Methods: PubMed and the Cochrane Library were searched for articles reporting the impact of Mi and ITC on patient survival. Two authors independently assessed the methodological quality of retrieved studies using the Downs and Black index. Data were also extracted on study type, number of included patients, mode of histological analysis, statistical analysis, and prognostic impact., Results: Sixteen articles with a total of 2064 patients were included in the review. Among the 16 included studies, eight revealed a statistically significant impact of Mi on at least one endpoint in the Kaplan-Meier and/or multivariate analysis. Three studies regarded Mi as Ma, while five studies found no impact of Mi on survival. Only one study demonstrated an impact of ITC on patient's prognosis in the univariate but not in the multivariate analysis., Conclusion: The majority of cases included in the review were patients with oral cancer. The findings provide low-certainty evidence that Mi negatively impacts survival. Data on ITC were scarcer, so no conclusions can be drawn about their effect on survival. The lower threshold to discriminate between Mi and ITC should be defined for OOSCC since the existing thresholds are based on data from different tumors. The histological, immunohistological, and anatomical characteristics of Mi and ITC in OOSCC as well as the effect of radiotherapy on Mi should be further investigated separately for oral and oropharyngeal carcinomas., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To address the question of axillary lymph node staging in ductal carcinoma in situ with microinvasion (DCIS-MI), we retrospectively evaluated axillary lymph nodes metastasis (ALNM) rate in a cohort of postsurgical DCIS-MI patients. By analyzing these data, we aimed to generate clinically relevant insights to inform treatment decision-making for this patient population., Methods: A systematic search was conducted on PubMed, Web of Science, Embase, The Cochrane Library, CNKI, Wanfang Database, Wipe, and China Biomedical Literature Database to identify relevant publications in any language. All the analyses were performed using Stata 16.0 software., Results: Among the 28 studies involving 8279 patients, the pooled analysis revealed an ALNM rate of 8% (95% CI, 7% to 10%) in patients with DCIS-MI. Furthermore, the rates of axillary lymph node macrometastasis, micrometastasis, and ITC in patients with DCIS-MI were 2% (95% CI, 2% to 3%), 3% (95% CI, 2% to 4%), and 2% (95% CI, 1% to 3%), respectively. Moreover, 13 studies investigated the non-sentinel lymph node (Non-SLN) metastasis rate, encompassing a total of 1236 DCIS-MI cases. The pooled analysis identified a Non-SLN metastasis rate of 33% (95% CI, 14% to 55%) in patients with DCIS-MI., Conclusion: The SLNB for patients with DCIS-MI is justifiable and could provide a novel therapeutic basis for systemic treatment decisions., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

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., (© 2024 The Japanese Urological Association.)

Lymphadenectomy represents a fundamental step in the staging and treatment of non-small cell lung cancer (NSCLC). To date, the extension of lymphadenectomy in early-stage NSCLC is a debated topic due to its possible complications. The detection of sentinel lymph nodes (SLNs) is a strategy that can improve the selection of patients in which a more extended lymphadenectomy is necessary. This pilot study aimed to refine lymph nodal staging in early-stage NSCLC patients who underwent robotic lung resection through the application of innovative intraoperative sentinel lymph node (SLN) identification and the pathological evaluation using one-step nucleic acid amplification (OSNA). Clinical N0 NSCLC patients planning to undergo robotic lung resection were selected. The day before surgery, all patients underwent radionuclide computed tomography (CT)-guided marking of the primary lung lesion and subsequently Single Photon Emission Computed Tomography (SPECT) to identify tracer migration and, consequently, the area with higher radioactivity. On the day of surgery, the lymph nodal radioactivity was detected intraoperatively using a gamma camera. SLN was defined as the lymph node with the highest numerical value of radioactivity. The OSNA amplification, detecting the mRNA of CK19, was used for the detection of nodal metastases in the lymph nodes, including SLN. From March to July 2021, a total of 8 patients (3 female; 5 male), with a mean age of 66 years (range 48-77), were enrolled in the study. No complications relating to the CT-guided marking or preoperative SPECT were found. An average of 5.3 lymph nodal stations were examined (range 2-8). N2 positivity was found in 3 out of 8 patients (37.5%). Consequently, pathological examination of lymph nodes with OSNA resulted in three upstages from the clinical IB stage to pathological IIIA stage. Moreover, in 1 patient (18%) with nodal upstaging, a positive node was intraoperatively identified as SLN. Comparing this protocol to the usual practice, no difference was found in terms of the operating time, conversion rate, and complication rate. Our preliminary experience suggests that sentinel lymph node detection, in association with the accurate pathological staging of cN0 patients achieved using OSNA, is safe and effective in the identification of metastasis, which is usually undetected by standard diagnostic methods.

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., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The propensity to metastasize is the most important prognostic indicator for solid cancers. New insights into the mechanisms of early carcinogenesis have revealed micrometastases are generated far earlier than previously thought. Evidence supports a synergistic relationship between vascular and lymphatic seeding which can occur before there is clinical evidence of a primary tumour. Early vascular seeding prepares distal sites for colonisation while regional lymphatics are co-opted to promote facilitative cancer cell mutations. In response, the host mounts a global inflammatory and immunomodulatory response towards these cells supporting the concept that cancer is a systemic disease. Cancer staging systems should be refined to better reflect cancer cell loads in various tissue compartments while clinical perspectives should be broadened to encompass this view when approaching high-risk cancers. Measured adjunctive therapies implemented earlier for low-volume, in-transit cancer offers the prospect of preventing advanced disease and the need for heroic therapeutic interventions. This review seeks to re-appraise how we view the metastatic process for solid cancers. It will explore in-transit metastasis in the context of high-risk skin cancer and how it dictates disease progression. It will also discuss how these implications will influence our current staging systems and its consequences on management., (© 2023 Australasian College of Dermatologists.)

Objective: To investigate the clinicopathological factors and clinical significance of (micro)metastasis in No.12b lymph node in patients with gastric antrum cancer. Methods: This was a retrospective cohort study of data of 242 patients with gastric adenocarcinoma without distant metastasis, complete follow-up data, and no preoperative anti-tumor therapy or history of other malignancies. All study patients had undergone radical gastrectomy (at least D2 radical range) + No.12b lymph node dissection in the Department of Gastric Surgery of Liaoning Cancer Hospital from January 2007 to December 2012. Immunohistochemical staining with antibody CK8/18 was used to detect micrometastasis to lymph nodes. Patients with positive findings on hematoxylin and eosin stained specimens and/or CK8/18 positivity in No.12b lymph node were diagnosed as having No.12b (micro)metastasis and included in the No.12b positive group. All other patients were classified as 12b negative. We investigated the impact of No.12b (micro)metastasis by comparing the clinicopathological characteristics and recurrence free survival (RFS) of these two groups of patients and subjecting possible risk factors to statistical analysis. Results: Traditional hematoxylin-eosin staining showed that 15/242 patients were positive for No.12b lymph nodes and 227 were negative. A total of 241 negative No. 12b lymph nodes were detected. Immunohistochemical testing revealed that seven of these 241 No.12b lymph nodes (2.9%) were positive for micrometastasis. A further seven positive nodes were identified among the 227 nodes (3.1%) that had been evaluated as negative on hematoxylin-eosin-stained sections. Thus, 22 /242 patients' (9.1%) No.12b nodes were positive for micrometastases, the remaining 220 (90.9%) being negative. Factor analysis showed that No.12b lymph node (micro) metastasis is associated with more severe invasion of the gastric serosa (HR=3.873, 95%CI: 1.676-21.643, P =0.006), T3 stage (HR=1.615, 95%CI: 1.113-1.867, P =0.045), higher N stage (HR=1.768, 95%CI: 1.187-5.654, P =0.019), phase III of TNM stage (HR=2.129, 95%CI: 1.102-3.475, P =0.046), and lymph node metastasis in the No.1/No.8a/No.12a groups (HR=0.451, 95%CI: 0.121-0.552, P =0.035; HR=0.645, 95%CI:0.071-0.886, P =0.032; HR=1.512, 95%CI: 1.381-2.100, P =0.029, respectively). Survival analysis showed that the 5-year RFS of patients in the No.12b positive group was worse than that of those in the No.12b negative group (18.2% vs. 34.5%, P <0.001). Independent predictors of RFS were poorer differentiation of the primary tumor (HR=0.528, 95%CI:0.288-0.969, P =0.039), more severe serous invasion (HR=1.262, 95%CI:1.039-1.534, P =0.019), higher T/N/TNM stage (HR=4.880, 95%CI: 1.909-12.476, P <0.001; HR=2.332, 95%CI: 1.640-3.317, P <0.001; HR=0.139, 95%CI: 0.027-0.713, P =0.018, respectively), and lymph node metastasis in the No.12a/No.12b group(HR=0.698, 95%CI:0.518-0.941, P =0.018; HR=0.341, 95%CI:0.154-0.758, P =0.008, respectively). Conclusion: Detection of micrometastasis can improve the rate of positive lymph nodes. In patients with gastric antrum cancer, dissection of group No.12b lymph nodes may improve the prognosis of those with intraoperative evidence of tumor invasion into the serosa, more than two lymph node metastases, and suspicious lymph nodes in groups No.1 / No.8a / 12a.

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., (© The Author(s) 2023. Published by Oxford University Press.)

Competing Interests: Competing interests: None declared.

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., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Surgical resection is an effective treatment for colorectal cancer (CRC) patients, whereas occult metastases hinder the curative effect. Currently, there is no effective method to achieve intraoperatively diagnosis of tumor-positive lymph nodes (LNs). Herein, we adopt a near-infrared-II (NIR-II) organic donor-pi-acceptor-pi-donor probe FE-2PEG, which exhibits bright fluorescence over 1100 nm, excellent photostability, blood circulation time, and biocompatibility, to achieve high-performance bioimaging with improved temporal and spatial resolution. Importantly, the FE-2PEG shows efficient passive enrichment in orthotopic CRC, metastatic mesenteric LNs, and peritoneal metastases by enhanced permeability and retention effect. Under NIR-II fluorescence-guided surgery (FGS), the peritoneal micrometastases were resected with a sensitivity of 94.51%, specificity of 86.59%, positive predictive value (PPV) of 96.57%, and negative predictive value of 79.78%. The PPV still achieves 96.07% even for micrometastases less than 3 mm. Pathological staining and NIR-II microscopy imaging proved that FE-2PEG could successfully delineate the boundary between the tumor and normal tissues. Dual-color NIR-II imaging strategy with FE-2PEG (1100 ~ 1300 nm) and PbS@CdS quantum dots (> 1500 nm) successfully protects both blood supply and normal tissues during surgery. The NIR-II-based FGS provides a promising prospect for precise intraoperative diagnosis and minimally invasive surgery of CRC., (© 2023. The Author(s).)

Background: Sentinel lymph node (SLN) biopsy has recently been accepted to evaluate nodal status in endometrial cancer at early stage, which is key to tailoring adjuvant treatments. Our aim was to evaluate the national implementation of SLN biopsy in terms of accuracy to detect nodal disease in a clinical setting and oncologic outcomes according to the volume of nodal disease., Patients and Methods: A total of 29 Spanish centers participated in this retrospective, multicenter registry including patients with endometrial adenocarcinoma at preoperative early stage who had undergone SLN biopsy between 2015 and 2021. Each center collected data regarding demographic, clinical, histologic, therapeutic, and survival characteristics., Results: A total of 892 patients were enrolled. After the surgery, 12.9% were suprastaged to FIGO 2009 stages III-IV and 108 patients (12.1%) had nodal involvement: 54.6% macrometastasis, 22.2% micrometastases, and 23.1% isolated tumor cells (ITC). Sensitivity of SLN biopsy was 93.7% and false negative rate was 6.2%. After a median follow up of 1.81 years, overall surivial and disease-free survival were significantly lower in patients who had macrometastases when compared with patients with negative nodes, micrometastases or ITC., Conclusions: In our nationwide cohort we obtained high sensitivity of SLN biopsy to detect nodal disease. The oncologic outcomes of patients with negative nodes and low-volume disease were similar after tailoring adjuvant treatments. In total, 22% of patients with macrometastasis and 50% of patients with micrometastasis were at low risk of nodal metastasis according to their preoperative risk factors, revealing the importance of SLN biopsy in the surgical management of patients with early stage EC., (© 2023. The Author(s).)

Purpose: The outcome of the sentinel lymph node in breast cancer patients affects adjuvant treatment. Compared to conventional histopathology, analysis by one-step nucleic acid amplification (OSNA) harvests more micrometastasis, potentially inducing overtreatment. In this study we investigated the impact of OSNA analysis on adjuvant treatment, compared to histopathological analysis., Methods: Data from T1-3 breast cancer patients with sentinel nodes analysed between January 2016 and December 2019 by OSNA (OSNA group, n = 1086) from Zuyderland Medical Centre, the Netherlands, were compared to concurrent data from the Netherlands Cancer Registry (NKR) where sentinel nodes were examined by histology (histology group, n = 35,143). Primary outcomes were micro- or macrometastasis, axillary treatments (axillary lymph node dissection (ALND) or axillary radiotherapy (ART)), chemotherapy, and endocrine therapy. Statistics with Pearson Chi-square., Results: In the OSNA group more micrometastasis (14.9%) were detected compared to the histology group (7.9%, p < 0.001). No difference in axillary treatment between groups was detected (14.3 vs. 14.4%). In case of mastectomy and macrometastasis, ALND was preferred over ART in the OSNA group (14.9%) compared to the histology group (4.4%, p < 0.001). In cases of micrometastasis, no difference was seen. There was no difference in administration of adjuvant chemotherapy between groups. Endocrine treatment was administrated less often in the OSNA group compared to the histology group (45.8% vs. 50.8%, p < 0.002)., Conclusion: More micrometastasis were detected by OSNA compared to histopathology, but no subsequent increase in adjuvant axillary and systematic treatment was noticed. When performing mastectomy and OSNA, there was a preference for ALND compared to ART., (© 2023. The Author(s).)

Sentinel node biopsy (SNB) has become a critical part of standard surgical treatment for melanoma with no clinical metastatic evidence. However, for patients with a positive sentinel node, the MSLT-II and DeCOG-SLT trials have shown that immediate complete lymph node dissection (CLND) does not bring further survival benefits. There is still an argument among the Chinese population dominated by acral subtypes on whether CLND can be omitted. Thus, this study aims to investigate the impact of immediate CLND on relapse-free survival (RFS) in Chinese melanoma patients with a positive sentinel node. Patients with acral or cutaneous melanoma of clinical Stages I-II who received SNB procedure and were detected with nodal micrometastasis were retrospectively collected at Fudan University Cancer Center (FUSCC) from January 2017 to December 2021. The clinicopathologic features and prognostic factors for RFS were analyzed. Out of 381 patients who received SNB in the past 5 years, 130 (34%) cases with SN micrometastasis detected were included in this study. Ninety-nine patients underwent immediate CLND while the other 31 patients received observation alone. Among patients who received CLND, the non-SN(NSN)-positive rate was 22.2%. Most of the clinicopathologic factors were balanced well between the CLND and non-CLND groups. However, more patients in the CLND group were detected with BRAF and NRAS mutation (P = 0.006) and received adjuvant PD-1 monotherapy (P = 0.042) as well. There were slightly fewer N1 patients in the CLND group, although the difference did not reach statistical significance (P = 0.075). The study found no significant difference in RFS between the two groups (P = 0.184). Even for patients with the acral subtype (P = 0.925), primary T4 lesion (P = 0.769), or presence of ulceration (P = 0.249), immediate CLND did not bring more survival benefits. Immediate CLND did not bring further RFS benefit for Chinese melanoma patients with SN micrometastasis in real-world clinical practice, even for patients with acral subtype or more tumor burden such as thick Breslow invasion and ulceration., (© 2023. The Author(s).)

The present review intends to discuss the controversies and strengths in clinically node-positive patients with axillary nodal status ypN i+ / mi after neoadjuvant chemotherapy. Over the past 20 years, a de-escalation approach toward axillary surgery has been observed in patients with breast cancer. The worldwide use of sentinel node biopsy in the upfront setting and after primary systemic therapy substantially reduced surgical complications or late sequelae and eventually improving quality of life of patients. However, the role of axillary dissection is still unclear in patients with low residual disease post-chemotherapy, namely those with micrometastases in the sentinel node, and its prognostic role is still not very clear. The aim of the present narrative review is to report the available evidence on this topic, discussing the pros and cons of performing axillary lymph node dissection in the infrequent finding of micrometastases in the sentinel node after neoadjuvant chemotherapy. We will also describe the ongoing prospective studies which are expected to shed light and guide future decisions., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Sentinel lymph node (SLN) biopsy plays a critical role in axillary staging of breast cancer. However, traditional SLN mapping does not accurately discern the presence or absence of metastatic disease. Detection of SLN metastasis largely hinges on examination of frozen sections or paraffin-embedded tissues post-SLN biopsy. To improve detection of SLN metastasis, we developed a second near-infrared (NIR-II) in vivo fluorescence imaging system, pairing erbium-based rare-earth nanoparticles (ErNP) with bright down-conversion fluorescence at 1,556 nm. To visualize SLNs bearing breast cancer, ErNPs were modified by balixafortide (ErNPs@POL6326), a peptide antagonist of the chemokine receptor CXCR4. The ErNPs@POL6326 probes readily drained into SLNs when delivered subcutaneously, entering metastatic breast tumor cells specifically via CXCR4-mediated endocytosis. NIR fluorescence signals increased significantly in tumor-positive versus tumor-negative SLNs, enabling accurate determination of SLN breast cancer metastasis. In a syngeneic mouse mammary tumor model and a human breast cancer xenograft model, sensitivity for SLN metastasis detection was 92.86% and 93.33%, respectively, and specificity was 96.15% and 96.08%, respectively. Of note, the probes accurately detected both macrometastases and micrometastases in SLNs. These results overall underscore the potential of ErNPs@POL6326 for real-time visualization of SLNs and in vivo screening for SLN metastasis., Significance: NIR-IIb imaging of a rare-earth nanoprobe that is specifically taken up by breast cancer cells can accurately detect breast cancer macrometastases and micrometastases in sentinel lymph nodes., (©2023 The Authors; Published by the American Association for Cancer Research.)

Competing Interests: Competing interests: None declared.

Background: Adjuvant chemotherapy (AC) is an important, effective treatment for breast cancer. This study evaluates the effectiveness of post-mastectomy AC in treating patients with prognostic stage IB breast cancer., Method: We conducted a retrospective cohort-based study using Surveillance, Epidemiology, and End-Results database. Overall survival (OS) and breast cancer-specific survival (BCSS) were calculated using the Kaplan-Meier method. Multivariate Cox risk models were used to identify the impact of AC. Stratified analysis was performed according to molecular subtypes, anatomic stages, and other risk factors to evaluate the effect of AC on survival., Results: 28,825 women diagnosed with prognostic stage IB breast cancer were included. The 5-year OS was significantly higher in AC group than in non-adjuvant chemotherapy (NAC) group (P < 0.0001); however, the 5-year BCSS in AC group was significantly lower than in NAC group (P = 0.039). Multivariate analysis revealed that AC was a favorable prognostic factor for OS (P < 0.001), but not BCSS (P = 0.407). AC was not an independent prognostic factor for BCSS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR[+]/HER2[-]) subtype or pT1a-1b/N0-1 stage with HER2 overexpression (HER2[+]) subtype, regardless of whether HR was positive or negative (P > 0.05). Meanwhile, AC is not an independent prognostic factor for OS and BCSS in patients with lymph node micrometastases., Conclusion: Our study demonstrates that patients with prognostic stage IB do not fully benefit from AC. Individualized treatment management is required for patients with pT1a-1b/N0-1 tumors, lymph node micrometastases, or HR(+)/HER2(-) subtypes., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2023 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

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., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

The involvement of neutrophil extracellular traps (NETs) in cancer metastasis is being clarified, but the relationship between intrahepatic cholangiocarcinoma (iCCA) and NETs remains unclear. The presence of NETs was verified by multiple fluorescence staining in clinically resected specimens of iCCA. Human neutrophils were co-cultured with iCCA cells to observe NET induction and changes in cellular characteristics. Binding of platelets to iCCA cells and its mechanism were also examined, and their effects on NETs were analyzed in vitro and in in vivo mouse models. NETs were present in the tumor periphery of resected iCCAs. NETs promoted the motility and migration ability of iCCA cells in vitro. Although iCCA cells alone had a weak NET-inducing ability, the binding of platelets to iCCA cells via P-selectin promoted NET induction. Based on these results, antiplatelet drugs were applied to these cocultures in vitro and inhibited the binding of platelets to iCCA cells and the induction of NETs. Fluorescently labeled iCCA cells were injected into the spleen of mice, resulting in the formation of liver micrometastases coexisting with platelets and NETs. These mice were treated with dual antiplatelet therapy (DAPT) consisting of aspirin and ticagrelor, which dramatically reduced micrometastases. These results suggest that potent antiplatelet therapy prevents micrometastases of iCCA cells by inhibiting platelet activation and NET production, and it may contribute to a novel therapeutic strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To evaluate the diagnostic performance of the one-step nucleic acid amplification (OSNA) method for the detection of sentinel lymph node (SLN) metastases in women with apparent early-stage endometrial cancer compared with standard ultrastaging., Methods: Prospective, multicentric, interventional study. Patients with apparent early-stage endometrial cancer who underwent primary surgical staging with SLN mapping were included. SLNs were serially sectioned with 2 mm slices perpendicular to the longest axis of the node: the odd slices were submitted to ultrastaging, whereas the even slices were submitted to the OSNA analysis. Diagnostic performance was calculated taking ultrastaging as referral standard., Results: Three-hundred and sixteen patients with 668 SLNs were included. OSNA assay detected 22 (3.3%) positive SLNs, of which 17 (2.5%) were micrometastases and 5 (0.7%) macrometastases, whereas ultrastaging detected 24 (3.6%) positive SLNs, of which 15 (2.2%) were micrometastases and 9 (1.3%) macrometastases (p=0.48). Regarding negative SLNs, OSNA detected 646 (96.7%) negative nodes, including 8 (1.2%) isolated tumor cells, while ultrastaging detected 644 (96.4%) negative nodes with 26 (3.9%) isolated tumor cells. Specificity of OSNA was 98.4% (95% CI 97.5 to 99.4), accuracy was 96.7% (95% CI 95.4 to 98.1), sensitivity was 50% (95% CI 30.0 to 70.0), while negative predictive value was 98.1% (95% CI 97.1 to 99.2). Discordant results were found in 22 SLNs (3.3%) corresponding to 20 patients (6.3%). These were 10 (1.5%) false-positive SLNs (all micrometastases): one (0.1%) of these was a benign epithelial inclusion at ultrastaging. There were 12 (1.8%) false-negative SLNs of OSNA, of which 9 (1.3%) were micrometastases and 3 (0.5%) macrometastases. Overall, 17/668 (2.5%) benign epithelial inclusions were detected at ultrastaging., Conclusion: The OSNA method had high specificity and high accuracy in detecting SLN metastasis in apparent early-stage endometrial cancer. The advantage of the OSNA method could be represented as the possibility to analyze the entire lymph node thus eliminating sampling bias., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The landscape of early-stage endometrial cancer treatment has changed dramatically over the last decade. The aim of this study is to provide a real-world view of the impact sentinel lymph node (SLN) biopsy has had on both clinical practice and patient outcomes. We describe detection and recurrence rates, as well as our experience in managing low volume lymph node disease., Methods: We conducted an international, multicenter retrospective cohort study of 1012 patients with apparent early-stage endometrial cancer. Eligible patients underwent primary surgical staging and SLN biopsy in one of three large academic tertiary cancer centers in Canada or the Republic of Korea between 2015 and 2019. Demographic, surgical, clinicopathologic and recurrence data were collected through chart review., Results: A total of 1012 patients were included. Overall SLN detection rate for all tracer types was 94.1% and recurrence rate was 5.3%. Higher FIGO stage (III vs. I/II) was associated with failed bilateral mapping (OR 2.27, 95%CI 1.14-4.52). We identified seven patients with micrometastases and 12 with isolated tumor cells, of which only one patient with micrometastases recurred at 17 months. Recurrence rates based on risk groups were 2.1%, 5.3%, 8.1%, and 9.9% for low, intermediate, high-intermediate, and high risk, respectively., Conclusion: SLN biopsy is safe and feasible. Detection rates are high, regardless of which tracer type is used and recurrence rates are low, especially in low and intermediate risk disease. Patients with low volume metastases appear to have low risk of recurrence, but replication of our findings by large prospective studies are needed to elucidate their clinical importance., Competing Interests: Declaration of competing interest Dr. Lavecchia reports grants from Women & Children's Health Research Institute at the University of Alberta, during the conduct of the study. Dr. Jang reports no conflicts of interest. Dr. Lee reports no conflicts of interest. Dr. Pin reports no conflicts of interest. Dr. Steed reports no conflicts of interest. Dr. Ghosh reports no conflicts of interest. Dr. Kwon reports no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was to describe our final results using dual cervical and fundal indocyanine green injection for the detection of sentinel lymph nodes (SLNs) in endometrial cancer along parametrial and infundibular drainage pathways., Methods: We conducted a prospective observational study between 26 June 2014 and 31 December 2020 enrolling 332 patients that underwent laparoscopic surgery for endometrial cancer at our hospital. In all cases, we performed SLN biopsy with dual cervical and fundal indocyanine green injection identifying pelvic and aortic SLNs. All SLNs were processed with an ultrastaging technique. A total of 172 patients also underwent total pelvic and para-aortic lymphadenectomy., Results: The detection rates were as follows: 94.0% overall for SLNs; 91.3% overall for pelvic SLNs; 70.5% for bilateral SLNs; 68.1% for para-aortic SLNs, and 3.0% for isolated paraaortic SLNs. We found lymph node involvement in 56 (16.9%) cases, macrometastasis in 22, micrometastasis in 12 and isolated tumor cells in 22. Fourteen patients had isolated aortic nodal involvement, representing 25% of the positive cases. There was one false negative (SLN biopsy negative but lymphadenectomy positive). Applying the SLN algorithm, the sensitivity of the dual injection technique for SLN detection was 98.3% (95% CI 91-99.7), specificity 100% (95% CI 98.5-100), negative predictive value 99.6% (95% CI 97.8-99.9), and positive predictive value 100% (95% CI 93.8-100). Overall survival at 60 months was 91.35%, with no differences between patients with negative nodes, isolated tumor cells and treated nodal micrometastasis., Conclusions: Dual sentinel node injection is a feasible technique that achieves adequate detection rates. Additionally, this technique allows a high rate of aortic detection, identifying a non-negligible percentage of isolated aortic metastases. Aortic metastases in endometrial cancer account for as many as a quarter of the positive cases and should be considered, especially in high-risk patients., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

This sentinel node (SN) biopsy trial aimed to assess its effectiveness in identifying predictive factors of micrometastases and to determine whether elective neck dissection is necessary in oral squamous cell carcinoma. This retrospective study included 55 patients from three previous trials, with positive SNs. The relationship between the sizes of the metastatic focus and metastasis in non-sentinel node (NSN) was investigated. Four of the 55 largest metastatic focus were isolated tumor cells, and the remaining 51 were ranged from 0.2 to 15 mm, with a median of 2.6 mm. The difference of prevalence between 46 negative- and 9 positive-NSN was statistically significant with regard to age, long diameter of primary site and number of cases with regional recurrence. In comparing the size of largest metastatic focus dividing the number of positive SN, with metastaic focus range of < 3.0 mm in one-positive SN group, there were 18 (33%) negative-NSN and no positive-NSN. Regarding prognosis, 3-year overall survival rate of this group (n = 18) and other (n = 37) were 94% and 73% (p = 0.04), and 3-year recurrence free survival rate of this group and other were 94% and 51% (p = 0.03), respectively. Absolutely a further prospective clinical trial would be needed, micrometastases may be defined as solitary SN metastasis with < 3.0 mm of metastatic focus, and approximately 33% of neck dissections could be avoided using these criteria., (© 2023. The Author(s).)

Background: The randomized trials which include ACOSOG Z0011 and IBCSG 23-01 had found that the survival rates were not different in patients with cT1/2N0 and 1-2 sentinel lymph node (SLN)-positive, macro/micrometastases who underwent breast-conserving therapy, and micrometastases who underwent total mastectomy (TM), when axillary lymph node dissection (ALND) was omitted. However, for patients with cT1/2N0 and 1-2 SLN macrometastases who underwent TM; there was still insufficient evidence from clinical studies to support whether ALND can be exempted. This study aimed to investigate the risk factors of non-sentinel lymph node (nSLN) metastasis in breast cancer patients with 1-2 SLN macrometastases undergoing TM., Methods: The clinicopathological data of 1491 breast cancer patients who underwent TM and SLNB from January 2017 to February 2022 were retrospectively analyzed. Univariate and multivariate analyses were performed to analyze the risk factors for nSLN metastasis., Results: A total of 273 patients with 1-2 SLN macrometastases who underwent TM were enrolled. Postoperative pathological data showed that 35.2% patients had nSLN metastasis. The results of multivariate analysis indicated that tumor size (TS) (P = 0.002; OR: 1.051; 95% CI: 1.019-1.084) and ratio of SLN macrometastases (P = 0.0001; OR: 12.597: 95% CI: 4.302-36.890) were the independent risk factors for nSLN metastasis in breast cancer patients with 1-2 SLN macrometastases that underwent TM. The ROC curve analysis suggested that when TS ≤22 mm and ratio of SLN macrometastases ≤0.33, the incidence of nSLN metastasis could be reduced to 17.1%., Conclusions: The breast cancer patients with cT1/2N0 stage, undergoing TM and 1-2 SLN macrometastases, when the TS ≤22 mm and macrometastatic SLN does not exceed 1/3 of the total number of detected SLN, the incidence of nSLN metastasis is significantly reduced, but whether ALND can be exempted needs further exploration., (© 2023. The Author(s).)

Background: The predicament of achieving optimal surgical intervention faced by surgeons in treating ovarian cancer has driven research into improving intra-operative detection of cancer using fluorescent materials., Objective: To provide a literature overview on the clinical use of intra-operative fluorescence-guided surgery for ovarian cancer, either for cytoreductive surgery or sentinel lymph node (SLN) biopsy., Methods: The systematic review included studies from June 2002 until October 2021 from PubMed, Web of Science, and Scopus as well as those from a search of related literature. Studies were included if they investigated the use of fluorescence-guided surgery in patients with a diagnosis of ovarian cancer. Authors charted variables related to study characteristics, patient demographics, baseline clinical characteristics, fluorescence-guided surgery material, and treatment details, and surgical, oncological, and survival outcome variables. After screening 2817 potential studies, 24 studies were included., Results: Studies investigating the role of fluorescence-guided surgery to visualize tumor deposits or SLN biopsy included the data of 410 and 118 patients, respectively. Six studies used indocyanine green tracer with a mean SLN detection rate of 92.3% with a pelvic and para-aortic detection rate of 94.8% and 96.7%, respectively. The sensitivity, specificity, and positive predictive value for micrometastases detection of OTL38 and 5-aminolevulinc acid at time of cytoreduction were 92.2% vs 79.8%, 67.3% vs 94.8%, and 55.8% vs 95.8%, respectively., Conclusion: Fluorescence -guided surgery is a technique that may improve the detection rate of micrometastases and SLN identification in ovarian cancer. Further research is needed to establish whether this will lead to improved patient outcomes., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Standard treatment of early-stage vulvar cancer is a radical, wide, local excision of the primary tumor and a sentinel lymph node (SLN) procedure for the groins. An inguinofemoral lymphadenectomy is no longer necessary for patients who have a negative SLN or micrometastasis ( ≤ 2 mm). When there is macrometastasis (>2 mm) in the SLN, an inguinofemoral lymphadenectomy is indicated; however, this procedure is associated with major morbidity, such as wound healing, lymphoceles, and lymphedema., Primary Objective: To investigate the safety of replacing inguinofemoral lymphadenectomy by chemoradiation in patients with early-stage vulvar cancer with a macrometastasis (>2 mm) and/or extracapsular extension in the sentinel node., Study Hypothesis: Combination of 56 Gy of radiation to the inguinal site and concurrent cisplatin chemotherapy without completion inguinofemoral lymphadenectomy will be feasible and safe, with low groin recurrence rates., Trial Design: This is a single-arm, prospective phase II treatment trial with stopping rules for unacceptable groin recurrences. Eligible patients will receive 56 Gy of radiation to the involved inguinal site and chemotherapy with concurrent cisplatin., Major Inclusion/exclusion Criteria: Eligible patients undergoing sentinel node procedure will have stage I, unifocal, invasive (>1 mm depth of invasion) squamous cell carcinoma of the vulva with tumor size <4 cm, and no suspicious nodes on imaging. Those eligible for the trial are those with a metastasis >2 mm in the sentinel node and/or extracapsular extension, or more than one sentinel node with micrometastasis ≤2 mm., Primary Endpoint: Groin recurrence rate in the first 2 years after primary treatment., Sample Size: 157 patients with macrometastases in their SLN., Estimated Dates for Completing Accrual and Presenting Results: January 1, 2029., Trial Registration Number: NCT05076942., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Sentinel node procedure (SN) is a standard procedure that has shown its safety and effectiveness for T1/T2 cN0 oral squamous cell carcinoma (OSCC), with completion neck dissection (CND) for patients with positive SN. The aim of this study was to characterize the nodal involvement in a cohort of SN + OSCC., Materials and Methods: Patients with T1/T2 cN0 OSCC with positive SN with CND were included in this single-center, prospective cohort study between 2000 and 2013., Results: 54/301 patients had at least one positive SN. In 43/54 (80 %) cases, only the SN(s) were invaded; with only one SN involved (SN+=1) in 36/54 (67 %) cases. No predictive factors of nodal involvement in the CND were found considering the followings: SN micro/macrometastases, primary tumor's depth of invasion (DOI), perineural spread, lymphovascular involvement, primary tumor location, T stage and extranodal extension. The SN micrometastatic involvement (n = 22) was significantly associated with only one SN + CND- (p = 0.017). In the group of patients with unique micrometastatic involvement in the SN (n = 20/54), there was a higher isolated nodal recurrence free time (p = 0.017)., Conclusion: 80% of T1/T2 cN0 OSCC with positive SN had no other lymph node metastases in the CND, questioning the potential benefits of this procedure. Predictive factors such as the size of the SN metastasis need to be tested to stratify the risk of positive non-SN lymph nodes leading to a personalized treatment, lowering the therapeutic morbidity while maintaining the oncologic safety., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Lymph node micrometastases could be one of the reasons for the high recurrence rate after complete surgical resection in stage I-IIIA non-small cell lung cancer (NSCLC). The standard evaluation of a single haematoxylin and eosin (H&E) slide of a paraffin-embedded section of a lymph node is insufficient for the detection of micrometastases, and there is a need for additional histopathological evaluation. The association of lymph node micrometastases with survival remains as yet unresolved. The aim of this systematic review and meta-analysis is to investigate if lymph node micrometastases and isolated tumour cells in patients with stage I-IIIA NSCLC, detected with multiple sectioning and/or immunohistochemistry (IHC) and/or reverse transcriptase polymerase chain reaction (RT-PCR), are associated with overall survival (OS) and disease-free survival (DFS) after surgical resection. We performed a meta-analysis of time-to-event outcomes based on 15 articles using ancillary techniques to detect micrometastases. We extracted the OS and DFS every 3-6 months after surgery, for patients with and without occult lymph node micrometastasis, from the survival curves published in each article. These data were used to reconstruct OS and DFS for 'micrometastasis' and 'no micrometastasis' groups. Based on all included studies that used IHC, serial sectioning, or RT-PCR, we found a 5-year OS of 55% (micrometastasis) vs. 75% (no micrometastasis), and a 5-year DFS of 53% (micrometastasis) vs. 75% (no micrometastasis). Patients with stage I-IIIA NSCLC with lymph node micrometastases detected by ancillary histopathological and molecular techniques have a significantly poorer OS and DFS compared to patients without lymph node micrometastases., (© 2022 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Objectives: This study aimed to investigate the potential of complex glandular patterns (CGP) in lymph node micrometastasis (LNMM) and to determine the clinical beneficiaries in stage I lung adenocarcinoma (LUAD) with CGP. Meanwhile, the feasibility of detecting CGP on frozen section was also evaluated., Methods: We retrospectively analysed the clinicopathological characteristics of 848 pathologic-stage I LUADs. A logistic regression model and a Cox proportional-hazards model were conducted to define the risk factors for LNMM and survival respectively. Furthermore, 5 pathologists reviewed frozen sections of 100 LUADs independently., Results: The logistic regression model indicated that CGP [odds ratio 3.89, 95% confidence interval (CI) 2.46-6.15; P < 0.001] was an independent predictor of the presence of LNMM. Subgroup analysis revealed that CGP-present/LNMM-positive LUAD had the highest risk of both loco-regional and distant recurrence. Moreover, adequate lymphadenectomy [recurrence-free survival: hazard ratio (HR) 0.61, 95% CI 0.40-0.95; P = 0.028; overall survival: HR 0.64, 95% CI 0.41-0.99; P = 0.043] and adjuvant chemotherapy (recurrence-free survival: HR 0.30, 95% CI 0.18-0.52; P < 0.001; overall survival: HR 0.33, 95% CI 0.19-0.57; P < 0.001) brought survival benefits to CGP-present patients, especially to CGP-present/LNMM-positive subgroup. Across the 5 pathologists, sensitivity ranged from 59 to 68% and specificity ranged from 79 to 83%, with moderate diagnostic agreement and high interobserver agreement for detecting CGP on frozen section., Conclusions: LNMM was more frequently observed in stage I LUAD with CGP. Adequate lymphadenectomy and adjuvant chemotherapy were associated with improved survival in CGP-present patients, especially in CGP-present/LNMM-positive subgroup. Additionally, it is feasible to identify CGP on frozen section intraoperatively., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: In cervical cancer, presence of lymph-node macrometastases (MAC) is a major prognostic factor and an indication for adjuvant treatment. However, since clinical impact of micrometastases (MIC) and isolated tumor-cells (ITC) remains controversial, we sought to identify a cut-off value for the metastasis size not associated with negative prognosis., Methods: We analyzed data from 967 cervical cancer patients (T1a1L1-T2b) registered in the SCCAN (Surveillance in Cervical CANcer) database, who underwent primary surgical treatment, including sentinel lymph-node (SLN) biopsy with pathological ultrastaging. The size of SLN metastasis was considered a continuous variable and multiple testing was performed for cut-off values of 0.01-1.0 mm. Disease-free survival (DFS) was compared between N0 and subgroups of N1 patients defined by cut-off ranges., Results: LN metastases were found in 172 (18%) patients, classified as MAC, MIC, and ITC in 79, 54, and 39 patients, respectively. DFS was shorter in patients with MAC (HR 2.20, P = 0.003) and MIC (HR 2.87, P < 0.001), while not differing between MAC/MIC (P = 0.484). DFS in the ITC subgroup was neither different from N0 (P = 0.127) nor from MIC/MAC subgroups (P = 0.449). Cut-off analysis revealed significantly shorter DFS compared to N0 in all subgroups with metastases ≥0.4 mm (HR 2.311, P = 0.04). The significance of metastases <0.4 mm could not be assessed due to limited statistical power (<80%). We did not identify any cut-off for the size of metastasis with significantly better prognosis than the rest of N1 group., Conclusions: In cervical cancer patients, the presence of LN metastases ≥0.4 mm was associated with a significant negative impact on DFS and no cut-off value for the size of metastasis with better prognosis than N1 was found. Traditional metastasis stratification based on size has no clinical implication., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Indications for offering adjuvant systemic therapy for patients with early-stage melanomas with low disease burden sentinel node (SN) micrometastases, namely, American Joint Committee on Cancer (AJCC; eighth edition) stage IIIA disease, are presently controversial. The current study sought to identify high-risk SN-positive AJCC stage IIIA patients who are more likely to derive benefit from adjuvant systemic therapy., Methods: Patients were recruited from an intercontinental (Australia/Europe/North America) consortium of nine high-volume cancer centers. All were adult patients with pathologic stage pT1b/pT2a primary cutaneous melanomas who underwent SN biopsy between 2005 and 2020. Patient data, primary tumor and SN characteristics, and survival outcomes were analyzed., Results: Three thousand six hundred seven patients were included. The median follow-up was 34 months. Pairwise disease comparison demonstrated no significant survival difference between N1a and N2a subgroups. Survival analysis identified a SN tumor deposit maximum dimension of 0.3 mm as the optimal cut point for stratifying survival. Five-year disease-specific survival rates were 80.3% and 94.1% for patients with SN metastatic tumor deposits ≥ 0.3 mm and < 0.3 mm, respectively (hazard ratio, 1.26 [1.11 to 1.44]; P < .0001). Similar findings were seen for overall disease-free and distant metastasis-free survival. There were no survival differences between the AJCC IB patients and low-risk (< 0.3 mm) AJCC IIIA patients. The newly identified high-risk (≥ 0.3 mm) subgroup comprised 271 (66.4%) of the AJCC IIIA cohort, whereas only 142 (34.8%) patients had SN tumor deposits > 1 mm in maximum dimension., Conclusion: Patients with AJCC IIIA melanoma with SN tumor deposits ≥ 0.3 mm in maximum dimension are at higher risk of disease progression and may benefit from adjuvant systemic therapy or enrollment into a clinical trial. Patients with SN deposits < 0.3 mm in maximum dimension can be managed similar to their SN-negative, AJCC IB counterparts, thereby avoiding regular radiological surveillance and more intensive follow-up.

Aim: To investigate the diagnostic performance of dedicated axillary hybrid 18 F-2-[ 18 F]-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)/magnetic resonance imaging (MRI) in detecting axillary pathological complete response (pCR) following neoadjuvant systemic therapy (NST) in clinically node-positive breast cancer patients., Materials and Methods: Ten prospectively included clinically node-positive breast cancer patients underwent dedicated axillary hybrid 18 F-FDG PET/MRI after completing NST followed by axillary surgery. PET images were reviewed by a nuclear medicine physician and coronal T1-weighted and T2-weighted MRI images by a radiologist. All axillary lymph nodes visible on PET/MRI were matched with those removed during axillary surgery. Diagnostic performance parameters were calculated based on patient-by-patient and node-by-node validation with histopathology of the axillary surgical specimen as the reference standard., Results: Six patients achieved axillary pCR at final histopathology. A total of 84 surgically harvested axillary lymph nodes were matched with axillary lymph nodes depicted on PET/MRI. Histopathological examination of the matched axillary lymph nodes resulted in 10 lymph nodes with residual axillary disease of which eight contained macrometastases and two micrometastases. The patient-by-patient analysis yielded a sensitivity, specificity, positive predictive value, and negative predictive value of 25%, 100%, 100%, and 67%, respectively. The diagnostic performance parameters of the node-by-node analysis were 0%, 96%, 0%, and 88%, respectively. Excluding micrometastases from the node-by-node analysis increased the negative predictive value to 90%., Conclusion: This pilot study suggests that the negative predictive value and sensitivity of dedicated axillary 18 F-FDG PET/MRI are insufficiently accurate to detect axillary pCR or exclude residual axillary disease following NST in clinically node-positive breast cancer patients., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Molecular markers for the detection of lymph node micrometastases of malignant tumors have been extensively investigated. However, epigenetic signatures have rarely been reported for identification of metastatic lymph nodes and disease relapse. Septin 9 is the most frequently reported hypermethylated gene in colorectal cancer (CRC). This study aimed to assess the clinical relevance of Septin 9 methylation in regional lymph nodes in recurrence/metastases of CRC., Methods: We analyzed Septin 9 methylation of DNA from resected lymph nodes in 75 CRC patients with or without tumor recurrence using quantitative methylation-sensitive PCR (qMS-PCR)., Results: Of the 30 histologically negative lymph node CRC patients without recurrence (group 1), methylated Septin 9 was detected in 3 (10 %) cases. The positivity rate of methylated Septin 9 in group 2 containing 30 histologically node-negative CRC patients with recurrence was 30 % (9/30). For group 3, lymphatic invasion as well as tumor recurrence, 11 (73 %) out of 15 subjects had Septin 9 methylation-positive lymph nodes. Moreover, patients in group 3 had a higher level of methylated Septin 9 compared to subjects in group 1 and group 2 (p < 0.05). In addition, CRC patients with Septin 9 methylation in lymph nodes had significantly reduced survival (Log-rank P < 0.0001)., Conclusion: Our data support the predictive role of Septin 9 methylation analysis of lymph node micrometastases for tumor relapse after surgery., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Lymph node metastasis is a critical prognostic factor in cervical cancer. Considering the potential complications of lymphadenectomy and desirability of avoiding systemic lymphadenectomy, accurate intraoperative prediction of the existence of lymph node metastasis is important in patients undergoing surgery for cervical cancer. We evaluated the feasibility and value of indocyanine green (ICG) use for sentinel lymph node (SLN) mapping during laparoscopic surgery performed for cervical cancer., Methods: This single-center cohort study included 77 patients undergoing a new laparoscopic radical surgery method with pelvic lymphadenectomy for early-stage cervical cancer. The surgery, performed without using a uterine manipulator, included creation of a vaginal cuff. Bilateral ICG-guided SLN mapping and rapid histopathological examination were performed, and results were analyzed in relation to final histopathologic diagnoses., Results: The SLN pelvic side-specific detection rate was 93.5%, sensitivity (SLN-positive cases/SLN-detected pelvic lymph node-positive cases) was 100%, intraoperative negative predictive value (NPV) was 97.8%, and final pathological NPV was 100%. The detection rate was significantly lower for tumors ≥ 2 cm in diameter than for tumors < 2 cm in diameter. Micrometastases were missed by intraoperative examination in 3 cases., Conclusion: The high NPV suggests the feasibility and usefulness of ICG-based SLN mapping plus rapid intraoperative examination for identification of metastatic SLNs. Use of ICG-based mapping for intraoperative identification of SLNs in patients undergoing this new laparoscopic surgery method for early-stage cervical cancer was particularly effective for tumors < 2 cm in diameter. However, incorporating a search for micrometastases into rapid intraoperative histopathologic examination may be necessary., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Objective: Sentinel lymph node (SLN) biopsy is increasingly utilized at surgical staging for early endometrial cancer. This study examined the association between SLN biopsy and micrometastasis in endometrial cancer., Methods: This is a retrospective cohort study examining the National Cancer Institute's Surveillance, Epidemiology, and End Result Program. The study population was 6,414 women with T1-2 endometrial cancer who underwent primary hysterectomy and surgical nodal evaluation. Exclusion criteria included cases with isolated tumor cells. Exposure assignment was surgical nodal evaluation (SLN biopsy or lymphadenectomy). Main outcome measure was micrometastasis, assessed by inverse probability of treatment weighting propensity score in a stage-specific fashion., Results: In T1a disease (n = 4,608), SLN biopsy was performed in 1,164 (25.3%) cases. SLN biopsy was associated with a 90% increased likeliness of identifying micrometastasis compared to lymphadenectomy (1.3% versus 0.7%, odds ratio 1.90, 95% confidence interval 1.02-3.55, P = 0.040). In T1b disease (n = 1,369), 270 (19.7%) cases had SLN biopsy. The incidence of micrometastasis was significantly higher in the SLN biopsy group compared to the lymphadenectomy group (8.4% versus 5.0%, odds ratio 1.74, 95% confidence interval 1.06-2.86, P = 0.028). In T2 disease (SLN biopsy in 57 [13.0%] of 437 cases), the incidence of micrometastasis was similar between the two groups (7.9% versus 7.0%, odds ratio 0.88, 95% confidence interval 0.30-2.60, P = 0.818)., Conclusion: This study suggests that SLN biopsy protocol may identify more micrometastasis in the regional lymph nodes of T1 endometrial cancer. Whether national-level increase in the utilization of SLN biopsy for early endometrial cancer results in a stage-shifting to advanced disease on a population-basis warrants further investigation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: The localization pattern of metastatic sentinel lymph node (SN) and non-SNs and pathologic analysis of metastatic lymph nodes in SN lymphatic basin dissection (SLBD) were investigated in patients with cT2/T3cN0 oral squamous cell carcinoma (OSCC)., Methods: This prospective multicenter trial involved 10 institutions nationwide in Japan. A total of 57 patients were enrolled. The lateral neck was divided into 5 lymphatic basins. The lymphatic basin containing SNs was defined as the SN lymphatic basin. All patients underwent SLBD with backup selective neck dissection (I-III) combined with primary tumor removal. When SNs were found outside of levels I-III, including in the contralateral neck, SLBD was performed by removing the compartments containing SNs separately. SN metastasis was classified as isolated tumor cells (ITCs), micrometastasis, or macrometastasis. ITCs are defined as a lesion no larger than 0.2 mm in largest dimension and are classified as pN0., Results: SN metastasis was observed in 22 cases. All metastatic lymph nodes, including false-negative cases, were detected in the SN lymphatic basin. Isolated tumor cells in the SNs did not affect prognosis, whereas micrometastasis tended to have poor prognosis. After adjusting for other risk factors, a positive SN remained a significant predictor of poor 5-year overall survival in pT2-4 OSCC., Conclusion: SLBD for intraoperative SN biopsy is a sufficient therapeutic procedure and is valuable for determining pathologic nodal stage in OSCC. SN positivity was demonstrated to be an independent predictor of poor prognosis in patients with pT2-4 disease undergoing SLBD with backup selective neck dissection (I-III)., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: More than 25% of patients with node-negative colorectal cancer experience a recurrent disease even after curative surgery. This suggests the existence and oncologic influence of micrometastasis in regional lymph nodes or in distant organs. The objective of this study was to identify mesorectal lymph node micrometastases using an immunohistochemical analysis and to determine its prognostic value in node-negative rectal cancer after neoadjuvant chemoradiation., Materials and Methods: A total of 91 patients who received preoperative chemoradiation and radical resection for rectal cancer were included. Based on conventional hematoxylin and eosin staining, all patients had a node-negative disease. Mesorectal lymph nodes from resected specimens were re-evaluated to detect micrometastases by immunohistochemistry using anticytokeratin antibody AE1/AE3. The clinicopathologic data were collected from a prospectively maintained database of colorectal cancer patients and analyzed retrospectively., Results: Micrometastases of mesorectal lymph nodes were detected in nine patients (9.9%). The three-year overall survival was similar regardless of micrometastasis (88.9% in the positive group versus 90.7% in the negative group, P = 0.681); however, the three-year disease-free survival was significantly poorer in the patients with micrometastases (40.0% versus 84.2%, P = 0.001). In the multivariate analysis, the advanced pT category (ypT3/T4 versus ypT0: hazard ratio [HR] 10.477, 95% confidence interval [CI] 1.102-99.594, P = 0.041) and micrometastases in mesorectal lymph nodes (HR 5.655, 95% CI 1.837-17.409, P = 0.003) were independent prognostic factors for disease-free survival., Conclusions: In node-negative rectal cancer after preoperative chemoradiation, immunohistochemically detected micrometastases of mesorectal lymph nodes were significantly correlated with poor disease-free survival., (Copyright © 2022. Published by Elsevier Inc.)

Molecular analysis of disseminated tumour cells (DTC) may aid in predicting the course of the disease and response to therapies in individual patients. It has been shown in bladder cancer and many other cancer types that the presence of disseminated tumour cells or occult micrometastases in bone marrow or lymph nodes is associated with shorter survival. This type of analysis is particularly important for patients who have been declared disease-free after postsurgery histopathological and clinical imaging analysis. However, comprehensive molecular analysis of disseminated tumour cells is challenging due to the low amount of material and great heterogeneity of the disease. Therefore, currently the routine molecular analysis of these cells is hardly possible in daily clinical practice. Nevertheless, we see daily advances in clinical utility of analysis of cellular or cell-free liquid biopsy analytes taken before, during or after surgery. These advances will enable an integration of translational research workflows into clinical decision-making., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Lymph node mapping for tumor micrometastasis is of great significance for the prevention, prognosis, and treatment of cancer. Currently, the traditional clinical detection methods (computed tomography, magnetic resonance imaging, or positron emission tomography/computed tomography) in clinical lymph node mapping still have some inherent disadvantages, which have prompted the development of various fluorescent probes for lymph node mapping. However, the conventional fluorescent probes such as indocyanine green or methylene blue in lymph node mapping are still accompanied by several problems such as impaired surgical field vision due to dye staining or less accumulation and shorter retention time in the lymph node. In a recent achievement, newly designed nanoparticles are prepared with novel properties that could be attractive for lymph node mapping. In this review, we will provide details on the progress of various nanoparticles for lymph node mapping and emphasize other multivariant properties in different nanoparticles, including strong tumor-targeting affinity and specificity, self-luminescence, and even with the function to kill metastatic cancer cells.

Micrometastases of colorectal cancer can remain dormant for years prior to the formation of actively growing, clinically detectable lesions (i.e., colonization). A better understanding of this step in the metastatic cascade could help improve metastasis prevention and treatment. Here we analyzed liver specimens of patients with colorectal cancer and monitored real-time metastasis formation in mouse livers using intravital microscopy to reveal that micrometastatic lesions are devoid of cancer stem cells (CSC). However, lesions that grow into overt metastases demonstrated appearance of de novo CSCs through cellular plasticity at a multicellular stage. Clonal outgrowth of patient-derived colorectal cancer organoids phenocopied the cellular and transcriptomic changes observed during in vivo metastasis formation. First, formation of mature CSCs occurred at a multicellular stage and promoted growth. Conversely, failure of immature CSCs to generate more differentiated cells arrested growth, implying that cellular heterogeneity is required for continuous growth. Second, early-stage YAP activity was required for the survival of organoid-forming cells. However, subsequent attenuation of early-stage YAP activity was essential to allow for the formation of cell type heterogeneity, while persistent YAP signaling locked micro-organoids in a cellularly homogenous and growth-stalled state. Analysis of metastasis formation in mouse livers using single-cell RNA sequencing confirmed the transient presence of early-stage YAP activity, followed by emergence of CSC and non-CSC phenotypes, irrespective of the initial phenotype of the metastatic cell of origin. Thus, establishment of cellular heterogeneity after an initial YAP-controlled outgrowth phase marks the transition to continuously growing macrometastases., Significance: Characterization of the cell type dynamics, composition, and transcriptome of early colorectal cancer liver metastases reveals that failure to establish cellular heterogeneity through YAP-controlled epithelial self-organization prohibits the outgrowth of micrometastases. See related commentary by LeBleu, p. 1870., (©2022 The Authors; Published by the American Association for Cancer Research.)

Lung cancer has some of the highest morbidity and mortality rates of all cancers, and an important risk factor for mortality in patients with lung cancer is tumor metastasis. Even if a tumor is completely removed at an early stage of the disease, quite a number of patients still have the risk of recurrence. With the advent of molecular diagnostic and therapeutics, more and more studies have found that a poor prognosis may be related to lymph node micrometastasis. However, clinicians still find that predicting the prognosis and choosing the type of surgery and postoperative adjuvant chemotherapy are still challenging. Thus, this article reviews the current research status of lymph node micrometastasis in non-small cell lung cancer, envision to provide some updates and insights in this area., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Investigation of lymph node micrometastasis (mN) of gastric cancer has been focused on either T1 disease or T1-4N0 disease. Yet, it is unclear whether standard management algorithm toward poorly differentiated gastric cancer (PDGC) is more vulnerable to existence of mN, given its inherently biological aggressiveness, as compared with other histological types., Patients and Methods: A surgical series (n = 3456) of gastric cancer categorized by histological differentiation was enrolled to analyze survival stratification. Of them, a cohort of T1-T4 N0 PDGC (n = 100) were subjected to cytokeratin immunohistochemistry, a surrogate of mN., Results: Cancer-specific survival by AJCC8 staging system could be nicely differentiated in both well-/moderately differentiated and signet ring cell types, while those between stage IA versus IB (p = 0.105), and stage IB versus IIA (p = 0.141) in PDGC could not. Thirteen (13%) out of 100 node-negative PDGC cases exhibited mN, with 5, 2, 5 and 1 cases occurring in T1, T2, T3, and T4 stage, respectively, without identifiable contributing factors. Prognostic performance of AJCC8 working upon PDGC became more discriminative by incorporating mN, as hazard ratio of stage IIIC referenced to stage IA increased from 43 to 78., Conclusion: Defective discriminative survival of PDGC by standard staging algorithm prompted us to survey mN occurring in T1-T4N0 PDGC. The prognostic performance of AJCC8 working upon PDGC was enhanced by incorporating mN. As so, we recommend documentation of mN exclusively on node-negative PDGC that helps unveil stage migration phenomenon and switch to appropriate adjuvant therapy in need., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)