Functional Hallmarks of Healthy Macrophage Responses: Their Regulatory Basis and Disease Relevance.

Macrophages are first responders for the immune system. In this role, they have both effector functions for neutralizing pathogens and sentinel functions for alerting other immune cells of diverse pathologic threats, thereby initiating and coordinating a multipronged immune response. Macrophages are distributed throughout the body-they circulate in the blood, line the mucosal membranes, reside within organs, and survey the connective tissue. Several reviews have summarized their diverse roles in different physiological scenarios and in the initiation or amplification of different pathologies. In this review, we propose that both the effector and the sentinel functions of healthy macrophages rely on three hallmark properties: response specificity, context dependence, and stimulus memory. When these hallmark properties are diminished, the macrophage's biological functions are impaired, which in turn results in increased risk for immune dysregulation, manifested by immune deficiency or autoimmunity. We review the evidence and the molecular mechanisms supporting these functional hallmarks.

Immune Responses in the Liver.

The liver is a key, frontline immune tissue. Ideally positioned to detect pathogens entering the body via the gut, the liver appears designed to detect, capture, and clear bacteria, viruses, and macromolecules. Containing the largest collection of phagocytic cells in the body, this organ is an important barrier between us and the outside world. Importantly, as portal blood also transports a large number of foreign but harmless molecules (e.g., food antigens), the liver's default immune status is anti-inflammatory or immunotolerant; however, under appropriate conditions, the liver is able to mount a rapid and robust immune response. This balance between immunity and tolerance is essential to liver function. Excessive inflammation in the absence of infection leads to sterile liver injury, tissue damage, and remodeling; insufficient immunity allows for chronic infection and cancer. Dynamic interactions between the numerous populations of immune cells in the liver are key to maintaining this balance and overall tissue health.

Six distinct NFκB signaling codons convey discrete information to distinguish stimuli and enable appropriate macrophage responses.

Macrophages initiate inflammatory responses via the transcription factor NFκB. The temporal pattern of NFκB activity determines which genes are expressed and thus, the type of response that ensues. Here, we examined how information about the stimulus is encoded in the dynamics of NFκB activity. We generated an mVenus-RelA reporter mouse line to enable high-throughput live-cell analysis of primary macrophages responding to host- and pathogen-derived stimuli. An information-theoretic workflow identified six dynamical features-termed signaling codons-that convey stimulus information to the nucleus. In particular, oscillatory trajectories were a hallmark of responses to cytokine but not pathogen-derived stimuli. Single-cell imaging and RNA sequencing of macrophages from a mouse model of Sjögren's syndrome revealed inappropriate responses to stimuli, suggestive of confusion of two NFκB signaling codons. Thus, the dynamics of NFκB signaling classify immune threats through six signaling codons, and signal confusion based on defective codon deployment may underlie the etiology of some inflammatory diseases.

Melanoma-derived mediators can foster the premetastatic niche: crossroad to lymphatic metastasis.

The natural history of advanced malignant melanoma demonstrates that, in most cases, widespread tumor dissemination is preceded by regional metastases involving tumor-draining lymph nodes [sentinel lymph nodes (SLNs)]. Under physiological conditions, LNs play a central role in immunosurveillance to non-self-antigens to which they are exposed via afferent lymph. The dysfunctional immunity in SLNs is mediated by tumor secretory factors that allow the survival of metastatic melanoma cells within the LN by creating a premetastatic niche (PMN). Recent studies outline the altered microenvironment of LNs shaped by melanoma mediators. Here, we discuss tumor secretory factors involved in subverting tumor immunity and remodeling LNs and highlight emerging therapeutic strategies to reinvigorate antitumoral immunity in SLNs.

Both long-term grasslands and crop diversity are needed to limit pest and weed infestations in agricultural landscapes.

Increasing landscape heterogeneity has been suggested to be an important strategy to strengthen natural pest control in crops, especially through enhancing the amount of seminatural habitats. Increasing crop diversity is also a promising strategy to complement or replace seminatural habitat when seminatural habitat is scarce. However, their relative or possibly interactive effects on pest and weed infestation remain poorly investigated, and the role of different types of seminatural habitats has been understudied. Using an extensive sampling effort in 974 arable fields across 7 y, we evaluated the separate and interactive effects of crop diversity (seven arable crop types) and the amount of four types of seminatural habitats (meadows, hay, forests, and hedgerows) in the landscape on pest and weed control. Meadows and crop diversity, respectively, supported insect pest and weed control services in agricultural landscapes through a complementarity effect. Crop diversity increased weed seed predation rate (by 16%) and reduced weed infestation (by 6%), whereas long-term grasslands (to a much higher degree than hay or woody habitats) increased insect pest predation rates (by 23%) and reduced pest infestation (by 19%) in most arable crops. Our results demonstrate that diversification of the agricultural landscape requires long-term grasslands as well as improved crop diversity to ensure the delivery of efficient pest and weed control services.

Tonic TNF conditioning of macrophages safeguards stimulus-specific inflammatory responses.

Tumor necrosis factor (TNF) is a key inflammatory cytokine that warns recipient cells of a nearby infection or tissue damage. Acute exposure to TNF activates characteristic oscillatory dynamics of the transcription factor NFκB and induces a characteristic gene expression program; these are distinct from the responses of cells directly exposed to pathogen-associated molecular patterns (PAMPs). Here, we report that tonic TNF exposure is critical for safeguarding TNF's specific functions. In the absence of tonic TNF conditioning, acute exposure to TNF causes (i) NFκB signaling dynamics that are less oscillatory and more like PAMP-responsive NFκB dynamics, (ii) immune gene expression that is more similar to the Pam3CSK4 response program, and (iii) broader epigenomic reprogramming that is characteristic of PAMP-responsive changes. We show that the absence of tonic TNF signaling effects subtle changes to TNF receptor availability and dynamics such that enhanced pathway activity results in non-oscillatory NFκB. Our results reveal tonic TNF as a key tissue determinant of the specific cellular responses to acute paracrine TNF exposure, and their distinction from responses to direct exposure to PAMPs.

Bitter taste receptors in the reproductive system: Function and therapeutic implications.

Type 2 taste receptors (TAS2Rs), traditionally known for their role in bitter taste perception, are present in diverse reproductive tissues of both sexes. This review explores our current understanding of TAS2R functions with a particular focus on reproductive health. In males, TAS2Rs are believed to play potential roles in processes such as sperm chemotaxis and male fertility. Genetic insights from mouse models and human polymorphism studies provide some evidence for their contribution to male infertility. In female reproduction, it is speculated that TAS2Rs influence the ovarian milieu, shaping the functions of granulosa and cumulus cells and their interactions with oocytes. In the uterus, TAS2Rs contribute to uterine relaxation and hold potential as therapeutic targets for preventing preterm birth. In the placenta, they are proposed to function as vigilant sentinels, responding to infection and potentially modulating mechanisms of fetal protection. In the cervix and vagina, their analogous functions to those in other extraoral tissues suggest a potential role in infection defense. In addition, TAS2Rs exhibit altered expression patterns that profoundly affect cancer cell proliferation and apoptosis in reproductive cancers. Notably, TAS2R agonists show promise in inducing apoptosis and overcoming chemoresistance in these malignancies. Despite these advances, challenges remain, including a lack of genetic and functional studies. The application of techniques such as single-cell RNA sequencing and clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated endonuclease 9 gene editing could provide deeper insights into TAS2Rs in reproduction, paving the way for novel therapeutic strategies for reproductive disorders.

Outcomes of sentinel node biopsy according to MRI response in an association with the subtypes in cN1-3 breast cancer after neoadjuvant systemic therapy, multicenter cohort study.

BACKGROUND: This study investigated the feasibility of sentinel lymph node biopsy (SLNB) after neoadjuvant systemic therapy (NAST) in patients with initially high nodal burden. METHODS: In the multicenter retrospective cohort, 388 individuals with cN1-3 breast cancer who underwent NAST and had SLNB followed by completion axillary lymph node dissection were included. In an external validation cohort, 267 patients with HER2+ or triple-negative breast cancer (TNBC) meeting similar inclusion criteria were included. Primary outcome was the false-negative rates (FNRs) of SLNB according to the MRI response and subtypes. We defined complete MRI responders as patients who experienced disappearance of suspicious features in the breast and axilla after NAST. RESULTS: In the multicenter retrospective cohort, 130 (33.5%) of 388 patients were of cN2-3, and 55 (14.2%) of 388 patients showed complete MRI responses. In hormone receptor-positive HER2- (n = 207), complete and non-complete responders had a high FNRs (31.3% [95% CI 8.6-54.0] and 20.9% [95% CI 14.1-27.6], respectively). However, in HER2+ or TNBC (n = 181), the FNR of complete MRI responders was 0% (95% CI 0-0), whereas that of non-complete responders was 33.3% (95% CI 20.8-45.9). When we validated our findings in the external cohort with HER2+ or TNBC (n = 267), of which 34.2% were cN2-3, the FNRs of complete were 7.1% (95% CI 0-16.7). CONCLUSIONS: Our findings suggest that SLNB can be a reliable option for nodal status evaluation in selected patients who have responded well to NAST, especially in HER2+ and TNBC patients who show a complete MRI response.

Should patients with hormone receptor-positive, HER2-negative breast cancer and one or two positive sentinel nodes undergo axillary dissection to determine candidacy for adjuvant abemaciclib?

BACKGROUND: The monarchE trial demonstrated improved outcomes with the use of adjuvant abemaciclib in patients with high-risk hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer defined as ≥4 positive lymph nodes (+LNs) or one to three +LNs with one or more additional high-risk features (HRFs). The proportion of patients with one or two positive sentinel lymph nodes (+SLNs) without HRFs who had ≥4 +LNs at the time of completion axillary lymph node dissection (cALND), and who therefore qualified for receipt of abemaciclib, was investigated. METHODS: Females with pathologically node-positive nonmetastatic HR+/HER2- breast cancer stratified by the number of +SLNs and +LNs and the presence of one or more HRFs were identified from the National Cancer Database (2018-2019). The proportion of patients meeting the criteria for abemaciclib both before and after ALND was assessed. RESULTS: Of the 22,048 patients identified, 1578 patients underwent upfront surgery, had one or two +SLNs without HRFs, and went on to cALND. Only 213 (13%) of these patients had ≥4 +LNs; thus, cALND performed solely to determine abemaciclib candidacy would have constituted surgical overtreatment in 1365 patients (87%). When stratified by the number of +SLNs, only 10% of those with one +SLN and 24% of those with two +SLNs had ≥4 +LNs after cALND, which meets the criteria for abemaciclib. CONCLUSIONS: Patients with one +SLN without HRFs are unlikely to have ≥4 +LNs and should not be subjected to the morbidity of ALND in order to inform candidacy for abemaciclib. An individualized multidisciplinary discussion should be undertaken about the risk:benefit ratio of ALND and abemaciclib for those with two +SLNs.

Investigating the role of tumour-to-skin proximity in predicting nodal metastasis in breast cancer.

BACKGROUND: Understanding the factors influencing nodal status in breast cancer is vital for axillary staging, therapy, and patient survival. The nodal stage remains a crucial factor in prognostication indices. This study investigates the relationship between tumour-to-skin distance (in T1-T3 tumours where the skin is not clinically involved) and the risk of nodal metastasis. METHODS: We retrospectively reviewed data from 100 patients who underwent neoadjuvant chemotherapy (NACT). Besides patient demographics and tumour variables, a radiologist retrospectively reviewed pre-operative MRI to measure tumour-to-skin distance. R core packages were used for univariate (χ2 and T-Wilcoxon tests) and bivariate logistic regression statistical analysis. RESULTS: Of 95 analysable datasets, patients' median age was 51 years (IQR: 42-61), 97% were symptomatic (rest screen detected), and the median tumour size was 43 mm (IQR, 26-52). On multivariate analysis, increasing invasive tumour size (p = 0.02), ER positivity (p = 0.007) and shorter tumour-to-skin distance (p = 0.05) correlated with nodal metastasis.  HER2 was not included in multivariate analysis as there was no association with nodal status on univariate analysis. In node-positive tumours, as tumour size increased, the tumour-to-skin distance decreased (r = - 0.34, p = 0.026). In node-negative tumours, there was no correlation (r = + 0.18, p = 0.23). CONCLUSION: This study shows that non-locally advanced cancers closer to the skin (and consequent proximity to subdermal lymphatics) are associated with a greater risk of nodal metastasis. Pre-operative identification of those more likely to be node positive may suggest the need for a second-look USS since a higher nodal stage may lead to a change in therapeutic strategies, such as upfront systemic therapy, node marking, and axillary clearance without the need to return to theatre following sentinel node biopsy.

Superparamagnetic iron oxide (SPIO) for axillary mapping in patients with ductal carcinoma in situ undergoing mastectomy: single-institution experience.

PURPOSE: Unnecessary axillary surgery can potentially be avoided in patients with DCIS undergoing mastectomy. Current guidelines recommend upfront sentinel lymph node biopsy during the index operation due to the potential of upstaging to invasive cancer. This study reviews a single institution's experience with de-escalating axillary surgery using superparamagnetic iron oxide dye for axillary mapping in patients undergoing mastectomy for DCIS. METHODS: This is a retrospective single-institution cross-sectional study. All medical records of patients who underwent mastectomy for a diagnosis of DCIS from August 2021 to January 2023 were reviewed and patients who had SPIO injected at the time of the index mastectomy were included in the study. Descriptive statistics of demographics, clinical information, pathology results, and interval sentinel lymph node biopsy were performed. RESULTS: A total of 41 participants underwent 45 mastectomies for DCIS. The median age of the participants was 58 years (IQR = 17; range 25 to 76 years), and the majority of participants were female (97.8%). The most common indication for mastectomy was diffuse extent of disease (31.7%). On final pathology, 75.6% (34/45) of mastectomy specimens had DCIS without any type of invasion and 15.6% (7/45) had invasive cancer. Of the 7 cases with upgrade to invasive disease, 2 (28.6%) of them underwent interval sentinel lymph node biopsy. All sentinel lymph nodes biopsied were negative for cancer. CONCLUSION: The use of superparamagnetic iron oxide dye can prevent unnecessary axillary surgery in patients with DCIS undergoing mastectomy.

Gene expression profiles in clinically T1-2N0 ER+HER2- breast cancer patients treated with breast-conserving therapy: their added value in case sentinel lymph node biopsy is not performed.

PURPOSE: Omitting sentinel lymph node biopsy (SLNB) in breast cancer treatment results in patients with unknown positive nodal status and potential risk for systemic undertreatment. This study aimed to investigate whether gene expression profiles (GEPs) can lower this risk in cT1-2N0 ER+ HER2- breast cancer patients treated with BCT. METHODS: Patients were included if diagnosed between 2011 and 2017 with cT1-2N0 ER+ HER2- breast cancer, treated with BCT and SLNB, and in whom GEP was applied. Adjuvant chemotherapy recommendations based on clinical risk status (Dutch breast cancer guideline of 2020 versus PREDICT v2.1) with and without knowledge on SLNB outcome were compared to GEP outcome. We examined missing adjuvant chemotherapy indications, and the number of GEPs needed to identify one patient at risk for systemic undertreatment. RESULTS: Of 3585 patients, 2863 (79.9%) had pN0 and 722 (20.1%) pN + disease. Chemotherapy was recommended in 1354 (37.8% guideline-2020) and 1888 patients (52.7% PREDICT). Eliminating SLNB outcome (n = 722) resulted in omission of chemotherapy recommendation in 475 (35.1% guideline-2020) and 412 patients (21.8% PREDICT). GEP revealed genomic high risk in 126 (26.5% guideline-2020) and 82 patients (19.9% PREDICT) in case of omitted chemotherapy recommendation in the absence of SLNB. Extrapolated to the whole group, this concerns 3.5% and 2.3%, respectively, resulting in the need for 28-44 GEPs to identify one patient at risk for systemic undertreatment. CONCLUSION: If no SLNB is performed, clinical risk status according to the guideline of 2020 and PREDICT predicts a very low risk for systemic undertreatment. The number of GEPs needed to identify one patient at risk for undertreatment does not justify its standard use.

Long-term outcome in patients with nodal-positive breast cancer treated with sentinel lymph node biopsy alone after neoadjuvant chemotherapy.

PURPOSE: Sentinel lymph node biopsy (SLNB) has yet to be accepted as the standard staging procedure in node positive (cN1) breast cancer patients who had clinical complete response in the axilla (cN0) following neoadjuvant chemotherapy (NAC), due to the presumed high false negative rate associated with SLNB in such scenario. This study aimed to determine whether there is a significant difference in the axillary recurrence rate (ARR) and long-term survival in this group of patients, receiving SLNB alone versus axillary lymph node dissection (ALND). METHODS: A retrospective cohort of cN1 patients who were rendered cN0 by NAC from January 2014 to December 2018 were identified from the Asan Medical Center database. Patients' characteristics and outcomes were collected and analyzed. RESULTS: 902 cN1 patients treated with NAC and turned cN0 were identified. 477 (52.9%) patients achieved complete pathological response in the axilla (ypN0). At a median follow up of 65 months, ARR was 3.2% in the SLNB only group and 1.8% in the ALND group (p = 0.398). DFS and OS were significantly worse in patients with ALND as compared to patients with SLNB only (p = 0.011 and 0.047, respectively). We noted more patients in the ALND group had T3-4 tumor. In the subgroup analysis, we showed that in the T1-2 subgroup (n = 377), there was no statistically significant difference in DFS and OS (p = 0.242 and 0.671, respectively) between SLNB only and ALND group. CONCLUSION: Our findings suggest that cN1 patients who were converted to ypN0 following NAC may be safely treated with SLNB only.

Sentinel lymph node biopsy before and after neoadjuvant chemotherapy in cN0 breast cancer patients: impact on axillary morbidity and survival-a propensity score cohort study.

PURPOSE: In patients with clinically lymph node-negative (cN0) breast cancer, performing sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NACT) has been preferentially embraced in comparison to before NACT. However, survival outcomes associated with both strategies remain understudied. We aimed to compare the axillary lymphadenectomy (ALND) rate, disease-free survival (DFS), and overall survival (OS), between two strategies. METHODS: We included 310 patients in a retrospective observational study. SNLB was performed before NACT from December 2006 to April 2014 (107 cases) and after NACT from May 2014 to May 2020 (203 patients). An inverse probability of treatment weighting (IPTW) method was applied to homogenize both groups. Hazard ratios (HR) and odd ratios (OR) are reported with 95% confidence intervals (95%CI). RESULTS: The lymphadenectomy rate was 29.9% before NACT and 7.4% after NACT (p < 0.001), with an OR of 5.35 95%CI (2.7-10.4); p = .002. After 4 years of follow-up, SLNB after NACT was associated with lower risk for DFS, HR 0.42 95%CI (0.17-1.06); p = 0.066 and better OS, HR 0.21 CI 95% (0.07-0.67); p = 0.009 than SLNB before NACT. After multivariate analysis, independent adverse prognostic factors for OS included SLNB before NACT, HR 3.095 95%CI (2.323-4.123), clinical nonresponse to NACT, HR 1.702 95% CI (1.012-2.861), and small tumors (cT1) with high proliferation index, HR 1.889 95% (1.195-2.985). CONCLUSION: Performing SLNB before NACT results in more ALND and has no benefit for patient survival. These findings support discontinuing the practice of SLNB before NACT in patients with cN0 breast cancer.

Use of ultrasound and MRI to stage the axilla for breast cancer before and after neoadjuvant chemotherapy prior to targeted sentinel lymphadenectomy.

PURPOSE: Prior data from this Center demonstrated that for patients who had biopsy-proven axillary metastases, were ycN0 after neoadjuvant chemotherapy (NAC), and had a wire-directed (targeted) sentinel lymphadenectomy (WD-SLND), 60% were node negative. The hypothesis of this study was that results of axillary imaging either before or after NAC would be predictive of final pathologic status after WD-SLND. METHODS: For patients treated with NAC between 2015 and 2023, ultrasound and MRI images of the axilla were retrospectively reviewed by radiologists specializing in breast imaging, who were blinded to the surgical and pathology results. RESULTS: Of 113 patients who fit the clinical criteria, 66 (58%) were ypN0 at WD-SLND and 34 (30%) had a pathologic complete response to NAC. There was no correlation between the number of abnormal lymph nodes on pre-NAC ultrasound or MRI imaging and the final pathologic status of the lymph nodes. The positive predictive value (PPV) of abnormal post-NAC axillary imaging was 48% for ultrasound and 53% for MRI. The negative predictive value (NPV) for normal post-NAC axillary imaging was 67% for ultrasound and 68% for MRI. CONCLUSION: The results of axillary imaging were not adequate to identify lymph nodes after NAC that were persistently pathologically node positive or those which had become pathologically node negative.

A systematic review and meta-analysis of diagnostic performance of fluorescein-guided sentinel lymph node biopsy in early breast cancer.

BACKGROUND: Evaluation of axillary lymph nodes status in cN0 axilla is performed by sentinel lymph node biopsy (SLNB) utilizing a combination of radioactive isotope and blue dye or alternative to isotope like Indocyanine green (ICG). Both are very resource-intensive; which has prompted development of low-cost technique of Fluorescein Sodium (FS)-guided SLNB. This systematic review and meta-analysis evaluate the diagnostic performance of FS-guided SLNB in early breast cancer. OBJECTIVES: The objective was to evaluate the diagnostic performance of FS for sentinel lymph node biopsy. METHODS: Eligibility criteria: Studies where SLNB was performed using FS. INFORMATION SOURCES: PubMed, EMBASE, Cochrane library and online clinical trial registers. Risk of bias: Articles were assessed for risk of bias using the QUADAS-2 tool. SYNTHESIS OF RESULTS: The main summary measures were pooled Sentinel Lymph Node Identification Rate (SLN-IR) and pooled False Negative Rate (FNR) using random-effects model. RESULTS: A total of 45 articles were retrieved by the initial systematic search. 7 out of the 45 studies comprising a total of 332 patients were included in the meta-analysis. The pooled SLN-IR was 93.2% (95% confidence interval [CI], 0.87-0.97; 87% to 97%). Five validation studies were included for pooling the false negative rate and included a total of 211 patients. The pooled FNR was 5.6% (95% confidence interval [CI], 2.9-9.07). CONCLUSION: Fluorescein-guided SLNB is a viable option for detection of lymph node metastases in clinically node negative patients with early breast cancer. It achieves a high pooled Sentinel Lymph Node Identification Rate (SLN-IR) of 93% with a false negative rate of 5.6% for the detection of axillary lymph node metastasis.

Characteristics and risk factors of axillary lymph node metastasis of microinvasive breast cancer.

PURPOSE: To select patients who would benefit most from sentinel lymph node biopsy (SLNB) by investigating the characteristics and risk factors of axillary lymph node metastasis (ALNM) in microinvasive breast cancer (MIBC). METHODS: This retrospective study included 1688 patients with MIBC who underwent breast surgery with axillary staging at the Asan Medical Center from 1995 to 2020. RESULTS: Most patients underwent SLNB alone (83.5%). Seventy (4.1%) patients were node-positive, and the majority had positive lymph nodes < 10 mm, with micro-metastases occurring frequently (n = 37; 55%). Node-positive patients underwent total mastectomy and axillary lymph node dissection (ALND) more than breast-conserving surgery (BCS) and SLNB compared with node-negative patients (p < 0.001). In the multivariate analysis, independent predictors of ALNM included young age [odds ratio (OR) 0.959; 95% confidence interval (CI) 0.927-0.993; p = 0.019], ALND (OR 11.486; 95% CI 5.767-22.877; p < 0.001), number of lymph nodes harvested (≥ 5) (OR 3.184; 95% CI 1.555-6.522; p < 0.001), lymphovascular invasion (OR 6.831; 95% CI 2.386-19.557; p < 0.001), presence of multiple microinvasion foci (OR 2.771; 95% CI 1.329-5.779; p = 0.007), prominent lymph nodes in preoperative imaging (OR 2.675; 95% CI 1.362-5.253; p = 0.004), and hormone receptor positivity (OR 2.491; 95% CI 1.230-5.046; p = 0.011). CONCLUSION: Low ALNM rate (4.1%) suggests that routine SLNB for patients with MIBC is unnecessary but can be valuable for patients with specific risk factors. Ongoing trials for omitting SLNB in early breast cancer, and further subanalyses focusing on rare populations with MIBC are necessary.

Targeted axillary dissection: worldwide variations in clinical practice.

PURPOSE: Targeted axillary dissection (TAD) for the axillary staging of clinically node-positive (cN +) breast cancer patients converting to clinically node negative post neoadjuvant chemotherapy (NAC), has gained popularity due to its minimal false negative rate and low arm morbidity. The aim of this study is to shed more light on the variation in the clinical practice globally in terms of indications and perceived limitations of TAD. METHODS: A panel of expert breast surgeons constructed a structured questionnaire comprising of 18 questions and asked surgeons worldwide for their opinions and routine practice on TAD. The questionnaire was electronically distributed and answers were collected between May 1st and August 1st 2022. RESULTS: Responses included 137 entries from 36 countries. Of them, 73.7% consider TAD for cN + patients planned to receive NAC. Among them, the greatest number of respondents (45%) perform the procedure for tumours up to T3, whereas 27% regardless of T-stage. The majority (42%) perform TAD on patients with 1-3 positive nodes and only 30% consider TAD when matted nodes are present. HER2 positive and Triple Negative subtypes are more likely to undergo TAD than Luminal A and B (86%, 79.1%, 39.5%, and 62.8%, respectively). Maximum acceptable lymph node burden is median 3 nodes for any subtype with a tendency to accept more positive nodes for Triple Negative. CONCLUSION: This study demonstrates the differences in current practice regarding TAD as well as the fact that the biology of the tumour heavily affects the method of axillary staging.

Omission of axillary lymph node dissection for breast cancer patients with three or more positive sentinel lymph nodes.

PURPOSE: The ACOSOG Z0011 (Z11) trial assessed the benefit of axillary dissection (ALND) for breast cancer patients with sentinel lymph node (SLN) metastases; however, Z11 excluded patients with ≥ 3 positive SLNs. We analyzed trends in ALND omission in patients with ≥ 3 positive SLNs. METHODS: Women with ≥ 3 positive SLNs who underwent breast-conserving surgery (BCS) or mastectomy between 2018 and 2020 in the National Cancer Database were included using SLN codes initiated in 2018. Patients with stage IV disease, recurrent breast cancer, and who underwent neoadjuvant chemotherapy were excluded. A multivariable logistic regression model was utilized to determine the proportion who received ALND and factors associated with ALND omission. A subgroup analysis was performed among patients who met the remainder of the Z11 inclusion criteria (BCS, T1/T2 breast cancer). RESULTS: We identified 3654 patients with ≥ 3 positive SLNs. ALND was omitted in 37% of patients, and omission significantly increased from 2018 to 2020 (29% vs. 41%, p < 0.0001). Older age, lower grade tumors, no radiation, non-academic facility, BCS, more SLNs examined and fewer positive SLNs were significantly associated with ALND omission. 942 patients with ≥ 3 positive SLNs met the remainder of the Z11 inclusion criteria. ALND was omitted in 49% of these patients, and omission increased from 2018 to 2020 (44% vs. 49%, p = 0.22). CONCLUSION: Approximately one-third of patients with ≥ 3 positive SLNs do not undergo ALND; omission of ALND increased from 2018 to 2020. Studies assessing oncologic outcomes of patients with ≥ 3 positive SLNs who do and do not receive ALND are required.

Location-Based Oncological Outcomes of Sentinel Node Dissection in Radical Prostatectomy.

PURPOSE: To assess the oncological outcomes of sentinel-node dissection during radical prostatectomy according to nodal location in comparison to extended pelvic lymph node dissection. MATERIALS AND METHODS: Prospectively collected data of clinically node negative patients that underwent prostatectomy and extended lymph node dissection with or without sentinel-node from 2013 to January 2023 was retrospectively analyzed. The primary endpoint was to assess oncological outcomes on the whole population. Kaplan-Meier curves were used to depict biochemical and clinical recurrence free survival. Multivariable Cox regression models assessed the impact of nodal location on SPECT on oncological outcomes. Adjustment for case mix included: pathological T stage, ISUP grade group, initial PSA, nodal burden, age at surgery and surgical margin status. Secondarily, a propensity score match was performed according to age at surgery, PSA, biopsy ISUP, clinical T stage and Briganti risk of nodal invasion. Survival and regression analyses were than performed also in the matched population. RESULTS: 55.8% patients had at least one sentinel node outside of lymph node dissection template at SPECT/CT. Log-rank test showed comparable 36-months biochemical (P = .3) and clinical recurrence-free survival (P = .6) among patients with sentinel-node inside template, outside template or ePLND alone. At Cox regression, sentinel-node location outside template was associated with lower hazard of metastases (HR 0.62; P = .04) in the overall cohort, while in the matched cohort benefits were observed only for biochemical recurrence (HR 0.57; P = .001). CONCLUSIONS: Wider nodal resection boundaries outside "classic" template, driven by sentinel node procedure, have a positive impact on oncological outcomes in selected patient.