Tumor-positive Sentinel Lymph Node Research Articles

Implications of tumor-positive sentinel lymph nodes in single vs multiple nodal basins in melanoma.

Melanoma patients' prognosis is based on the primary tumor characteristics and the tumor status of the regional lymph nodes. The advent of lymphoscintigraphy with SLN biopsy (SLNB) has shown that melanoma can drain to multiple nodal basins but the significance of multiple basins (vs. one basin) with tumor-positive sentinel lymph node(s) (+SLN) of similar tumor burden has not been shown. We examined the impact of the number of nodal basins with +SLN (+basin) in melanoma patients and its significance for patients' prognosis and survival. We identified 1,915 patients with +SLN from two randomized surgical clinical trials: Multicenter Selective Lymphadenectomy Trials I and II. Patient groups were divided based on number of +SLNs and number of +basins. Disease-free survival (DFS), distant disease-free survival (DDFS) and melanoma-specific survival (MSS) were compared with the Kaplan-Meier method and log-rank tests. Univariable and multivariable analyses were performed using Cox proportional hazard regressions. Among the 1,915 patients, 1,501 had only one +SLN (78%) in one basin and 414 (22%) had multiple +SLNs: 340 located in one basin and 74 in multiple basins. Among patients with multiple +SLNs, those with multiple +basins have a worse DFS, DDFS and MSS than those with a single basin (p ≤ 0.0001 for all comparisons). MSS was significantly different based on AJCC stages: AJCC IIIA and IIIB (p ≤ 0.001 and 0.0287, respectively). Our results suggest that the number of tumor-positive basins may be important for staging and in understanding the biology of lymph node metastases.

An ultra-small organic dye nanocluster for enhancing NIR-II imaging-guided surgery outcomes.

The accuracy of surgery for patients with solid tumors can be greatly improved through fluorescence-guided surgery (FGS). However, existing FGS technologies have limitations due to their low penetration depth and sensitivity/selectivity, which are particularly prevalent in the relatively short imaging window (< 900nm). A solution to these issues is near-infrared-II (NIR-II) FGS, which benefits from low autofluorescence and scattering under the long imaging window (> 900nm). However, the inherent self-assembly of organic dyes has led to high accumulation in main organs, resulting in significant background signals and potential long-term toxicity. We rationalize the donor structure of donor-acceptor-donor-based dyes to control the self-assembly process to form an ultra-small dye nanocluster, thus facilitating renal excretion and minimizing background signals. Our dye nanocluster can not only show clear vessel imaging, tumor and tumor sentinel lymph nodes definition, but also achieve high-performance NIR-II imaging-guided surgery of tumor-positive sentinel lymph nodes. In summary, our study demonstrates that the dye nanocluster-based NIR-II FGS has substantially improved outcomes for radical lymphadenectomy.

The rational of Cloquet lymph node as a sentinel lymph node in iliac dissection in lower limb melanoma

Background and aims Intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) is a growingly popular operating procedure for staging regional lymph nodes in early-stage melanoma. The groin is a promising area for this method since superficial groin dissection and iliac dissection have a significant risk of morbidity. There is currently no consensus on how best to treat cases with tumor-positive sentinel lymph nodes (SNs) during surgery involving these basins. Methods A total of 182 cases were treated using the LM/SL method. There was consistent detection of sentinel lymph nodes. SN dissection was performed on patients who had tumor in their SN. A hematoxylin and eosin stain was used to analyze the sentinel lymph nodes. Patient selection for SN dissection was based only on the presence of tumor in that node. Computerized database containing log-rank tests and Cox regression models for statistical analysis. Results 61% of the 182 cases were female, with an average age of 50 (range, 15–89). Tumor-positive SNs were detected in 21% of cases. 67% of cases were identified to have sentinel full lymph node dissection and a single tumor-positive lymph node after LM/SL, whereas 27% had 2 tumor-positive lymph nodes and 6% had 3 or more tumor-positive lymph nodes. Recurrence in the dissected basin occurs in just 4% of individuals with tumor-negative SNs. Cases whose lymph nodes tested negative for tumors had a significantly greater 5-year overall survival (mean±SD, 94% 5%) compared with those whose lymph nodes tested positive for tumors (meanSD, 75% 4%; P 0.01). Primary tumor thickness (P = 0.03), Tumor-positive SN (P 0.001) and ulceration (P = 0.001) were revealed to be important indicators of survival in multivariate studies using a Cox regression model. Conclusions This surgical treatment ought to become common for cases with early-stage melanoma of the lower extremities and trunk because the accuracy of LM/SL as judged by the infrequent recurrences implies that it should. When a tumor-positive SN is found in the groin, it is important to take a sample from the Cloquet node so that one may decide whether or not an iliac dissection is necessary.

Could axillary lymph node dissection be omitted in the mastectomy patient with tumor positive sentinel node?

Recent data from the ACOSOG Z0011 trial suggest that axillary lymph node dissection (ALND) may not be necessary for patients with positive sentinel lymph node biopsy (SLNB) receiving breast-conserving surgery (BCS) with irradiation. However, consensus statements and guidelines have recommended that patients undergoing mastectomy with tumor-positive sentinel node undergo completion ALND. In this study, we compared the locoregional recurrence rate of patients with tumor-positive sentinel nodes among three groups: mastectomy with SLNB, mastectomy with ALND and BCS with SLNB. We identified 6,163 women with invasive breast cancer who underwent surgical resection at our institution between January 2000 and December 2011. Clinicopathologic data obtained from the prospectively collected medical database were analyzed retrospectively. Among the patients with sentinel node positive, mastectomy with SLNB was performed in 39 cases, mastectomy with ALND in 181 cases, and BCS with SLNB in 165 cases. The primary end point was the loco-regional recurrence rate. Clinicopathologic characteristics were similar among the groups. There were no cases of loco-regional recurrence in the sentinel groups. At a median follow-up of 61.0 months (last follow-up May 2013), the loco-regional recurrence rate of each group was 0% for BCS with SLNB and mastectomy with SLNB only, and 1.7% for mastectomy with ALND (p=0.182). In our study, there was no significant difference in loco-regional recurrence rates between groups. This result lends weight to the argument that SLNB without ALND may be a reasonable management for selected patients with appropriate surgery and adjuvant systemic therapy.

ASO Visual Abstract: Predicting Regional Lymph Node Recurrence in the Modern Age of Tumor-Positive Sentinel Node Melanoma: The Role of the First Postoperative Ultrasound.

ASO Visual Abstract: Predicting Regional Lymph Node Recurrence in the Modern Age of Tumor-Positive Sentinel Node Melanoma: The Role of the First Postoperative Ultrasound.

Computer-aided clinical image analysis as a predictor of sentinel lymph node positivity in cutaneous melanoma.

BACKGROUNDDelays in sentinel lymph node (SLN) biopsy may affect the positivity of non-SLNs. For these reasons, effort is being directed at obtaining reliable information regarding SLN positivity prior to surgical excision. However, the existing tools, e.g., dermoscopy, do not recognize statistically significant predictive criteria for SLN positivity in melanomas.AIMTo investigate the possible association of computer-assisted objectively obtained color, color texture, sharpness and geometry variables with SLN positivity.METHODSWe retrospectively reviewed and analyzed the computerized medical records of all patients diagnosed with cutaneous melanoma in a tertiary hospital in Germany during a 3-year period. The study included patients with histologically confirmed melanomas with Breslow > 0.75 mm who underwent lesion excision and SLN biopsy during the study period and who had clinical images shot with a digital camera and a handheld ruler aligned beside the lesion.RESULTSNinety-nine patients with an equal number of lesions met the inclusion criteria and were included in the analysis. Overall mean (± standard deviation) age was 66 (15) years. The study group consisted of 20 patients with tumor-positive SLN (SLN+) biopsy, who were compared to 79 patients with tumor-negative SLN biopsy specimen (control group). The two groups differed significantly in terms of age (61 years vs 68 years) and histological subtype, with the SLN+ patients being younger and presenting more often with nodular or secondary nodular tumors (P < 0.05). The study group patients showed significantly higher eccentricity (i.e. distance between color and geometrical midpoint) as well as higher sharpness (i.e. these lesions were more discrete from the surrounding normal skin, P < 0.05). Regarding color variables, SLN+ patients demonstrated higher range in all four color intensities (gray, red, green, blue) and significantly higher skewness in three color intensities (gray, red, blue), P < 0.05. Color texture variables, i.e. lacunarity, were comparable in both groups.CONCLUSIONSLN+ patients demonstrated significantly higher eccentricity, higher sharpness, higher range in all four color intensities (gray, red, green, blue) and significantly higher skewness in three color intensities (gray, red, blue). Further prospective studies are needed to better understand the effectiveness of clinical image processing in SLN+ melanoma patients.

Near-infrared-II ratiometric fluorescence probes for non-invasive detection and precise navigation surgery of metastatic sentinel lymph nodes.

Sentinel lymph node (SLN) biopsy is the key diagnostic procedure to determine tumor metastasis and treatment plan. Current SLN biopsy has considerable drawbacks in that SLNs (both malignant and normal) must be removed by navigation surgery, followed by a time-consuming pathological examination. The selective, non-invasive, and real-time diagnosis of metastatic status in SLNs is becoming essential.Methods: Here, we design two lanthanide-doped nanoparticles as a pair of NIR-II ratiometric fluorescence probes, one of which is conjugated with tumor-targeting moiety, while the other is conjugated with PEG as an internal reference. The NIR-II ratiometric fluorescence signal (I1060 nm/I1525 nm) from two well-separated channels were used to identify the tumor-draining SLNs. The precise navigation surgery of metastatic SLNs was performed and we further evaluated their surgery outcomes.Results: The NIR-II ratiometric fluorescence facilitates an ideal fluorescence-guided surgery with only resection of tumor-positive SLNs, thereby avoiding unnecessary removal of the normal SLNs. In addition, our system has a time-saving operation procedure and can be performed under the operation light without altering the appearance of surgical settings.Conclusion: The present study enables non-invasive and real-time detection metastatic status in SLNs with high sensitivity and selectivity. Our investigations will provide a new direction for SLN biopsy and substantially improve cancer surgery outcomes.

Technologic (R)Evolution Leads to Detection of More Sentinel Nodes in Patients with Melanoma in the Head and Neck Region.

Sentinel lymph node (SN) biopsy (SNB) has proven to be a valuable tool for staging melanoma patients. Since its introduction in the early 1990s, this procedure has undergone several technologic refinements, including the introduction of SPECT/CT, as well as radioguidance and fluorescence guidance. The purpose of the current study was to evaluate the effect of this technologic evolution on SNB in the head and neck region. The primary endpoint was the false-negative (FN) rate. Secondary endpoints were number of harvested SNs, overall operation time, operation time per harvested SN, and postoperative complications. Methods: A retrospective database was queried for cutaneous head and neck melanoma patients who underwent SNB at The Netherlands Cancer Institute between 1993 and 2016. The implementation of new detection techniques was divided into 4 groups: 1993-2005, with preoperative lymphoscintigraphy and intraoperative use of both a γ-ray detection probe and patent blue (n = 30); 2006-2007, with addition of preoperative road maps based on SPECT/CT (n = 15); 2008-2009, with intraoperative use of a portable γ-camera (n = 40); and 2010-2016, with addition of near-infrared fluorescence guidance (n = 192). Results: In total, 277 patients were included. At least 1 SN was identified in all patients. A tumor-positive SN was found in 59 patients (21.3%): 10 in group 1 (33.3%), 3 in group 2 (20.0%), 6 in group 3 (15.0%), and 40 in group 4 (20.8%). Regional recurrences in patients with tumor-negative SNs resulted in an overall FN rate of 11.9% (group 1, 16.7%; group 2, 0%; group 3, 14.3%; group 4, 11.1%). The number of harvested nodes increased with advancing technologies (P = 0.003), whereas Breslow thickness and operation time per harvested SN decreased (P = 0.003 and P = 0.017, respectively). There was no significant difference in percentage of tumor-positive SNs, overall operation time, and complication rate between the different groups. Conclusion: The use of advanced detection technologies led to a higher number of identified SNs without an increase in overall operation time, possibly indicating an improved surgical efficiency. Operation time per harvested SN decreased; the average FN rate remained 11.9% and was unchanged over 23 y. There was no significant change in postoperative complication rate.

Age-related transcriptome changes in melanoma patients with tumor-positive sentinel lymph nodes.

Age is an important factor for determining the outcome of melanoma patients. Sentinel lymph node (SLN) status is also a strong predictor of survival for melanoma. Paradoxically, older melanoma patients have a lower incidence of SLN metastasis but a higher mortality rate when compared with their younger counterparts. The mechanisms that underlie this phenomenon remain unknown. This study uses three independent datasets of RNA samples from patients with melanoma metastatic to the SLN to identify age-related transcriptome changes in SLNs and their association with outcome. Microarray was applied to the first dataset of 97 melanoma patients. NanoString was performed in the second dataset to identify the specific immune genes and pathways that are associated with recurrence in younger versus older patients. qRT-PCR analysis was used in the third dataset of 36 samples to validate the differentially expressed genes (DEGs) from microarray and NanoString. These analyses show that FOS, NR4A, and ITGB1 genes were significantly higher in older melanoma patients with positive SLNs. IRAK3- and Wnt10b-related genes are the major pathways associated with recurrent melanoma in younger and older patients with tumor-positive SLNs, respectively. This study aims to elucidate age-related differences in SLNs in the presence of nodal metastasis.

Sentinel lymph node biopsy in acral melanoma: A Korean single-center experience with 107 patients (2006-2018).

Sentinel lymph node biopsy (SLNB) of primary cutaneous melanoma as an important staging method has not been popularly undertaken in Korea and only a few studies with small patient numbers have been published. We examined the clinical feasibility and overall outcomes of SLNB in acral melanoma (AM) of Korean in Kyungpook National University Hospital (KNUH) over the past 13 years. SLNB in AM patients during 2006-2018 were analyzed retrospectively for sentinel lymph node (SLN) harvesting rate, positivity rate, positivity-relevant overall survival (OS) and disease-free survival (DFS), and its side effects. A total of 109 AM patients who underwent SLNB were enrolled. Harvested nodes were identified from 107 patients and SLN harvesting rate was 98.2%. The mean Breslow thickness (±standard deviation) was 3.38 ± 3.03mm, and the proportion of ulcerated melanomas was 64%. Twenty-two (20.6%) had a tumor-positive SLN and, among them, 82% (18/22) underwent immediate complete lymph node dissection (CLND). The metastasis-positive nodal basin after CLND was detected in 16.7% of cases (3/18). Tumor-negative SLN cohorts showed significantly better OS and DFS than tumor-positive ones (P=0.006 and P<0.001 for each). Two side effects, one seroma and one lymphocele, were observed without major sequelae. SLNB, crucial management of melanoma, proved its efficacy to predict patients' prognosis and could be performed successfully and safely in Korean AM patients by interdisciplinary cooperation between dermatology and other surgical departments. SLN(-) showed significantly better OS and DFS than SLN(+). Significant risk factors for DFS were Breslow thickness, the presence of ulceration and the presence of SLN metastasis. SLNB should be encouraged in order to stage melanoma accurately and direct the proper management in Korean AM.

Performance of models predicting residual lymph node disease in melanoma patients following sentinel lymph node biopsy

BackgroundAmong melanoma patients with a tumor-positive sentinel node biopsy (SNB), approximately 20% harbor disease in non-sentinel nodes (nSN), as determined by a completion lymph node dissection (CLND). CLND lacks a survival benefit and has high morbidity. This study assesses predictive factors for nSN metastasis and validates five models predicting nSN metastasis. MethodsPatients with invasive melanoma were identified from the BC Cancer Agency (2005–2015). Clinicopathological data were collected from 296 patients who underwent a CLND after a positive SNB. Multivariate analysis was completed to assess predictive variables in the study population. Five models were externally validated using overall model performance (Brier score [calibration and discrimination]) and discrimination (area under the ROC curve [AUC]). ResultsSeventy-three patients had nSN metastasis at the time of CLND. The variable most predictive of nSN involvement was lymphovascular invasion (odds ratio [OR] 3.99; 95% confidence interval [CI] 1.67–9.54; p = 0.002). The highest discrimination was Lee et al. (2004) (AUC 0.68 [95% CI 0.61–0.75]), Rossi et al. (2018) (AUC 0.68 [95% CI 0.57–0.77]), and Bertolli et al. (2019) (AUC 0.68 [95% CI 0.60–0.75]). Rossi et al. (2018) had the lowest overall model performance (Brier score 0.44). Rossi et al. (2018) and Bertolli et al. (2019) had the ability to stratify patients to a risk of nSN involvement up to 99% and 95%, respectively. ConclusionBertolli et al. (2019) had amongst the highest overall model performance, was the most clinically meaningful and is recommended as the preferred model for predicting nSN metastasis.

Anatomical localization of radiocolloid tracer deposition affects outcome of sentinel node procedures in prostate cancer.

Diagnostic imaging modalities have moderate sensitivity for the identification of lymph node (LN) metastases in prostate cancer (PCa) patients. Mapping the lymphatic drainage from the prostate can help to identify the LNs directly draining from the tumour (sentinel nodes (SNs)); the LNs stated to have the highest chance of containing metastatic cancer cells. Although the lymphatic drainage may differ between segments within the prostate, the location of the primary tumour is not routinely taken into account during peripheral zone-aimed tracer administration. This study evaluates whether linking the SN procedure to the primary cancer deposits increases the identification accuracy of lymphatic metastases. Sixty-seven PCa patients, scheduled for robot-assisted laparoscopic prostatectomy (RALP) and extended lymph node dissection (ePLND) with subsequent SN biopsy, were included in this retrospective study. After injection of the hybrid tracer ICG-99mTc-nanocolloid in the prostate, SN mapping was performed based on lymphoscintigraphy and SPECT/CT. SNs were resected using a combination of radio- and fluorescence guidance. Pathology was used to determine the primary tumour location and metastatic spread. Fluorescence imaging of paraffin-embedded prostate tissue was used to determine the location of the tracer deposits in the prostate. This deposition was related to the primary tumour location, the lymphatic drainage pattern of the injected tracer, and the metastatic spread. In total 265 radioactive LNs (211 SNs and 54 higher-echelon nodes in 64 patients; 4.3 LNs per patient; IQR: 2-6) were identified. In three patients (4%) preoperative imaging did not allow identification of SNs. Tumour-positive SN visualization within the pelvis was shown to be influenced by intraprostatic location of tracer administration. This could be concluded from (1) a clear correlation between lymphatic drainage to the right or left side of the body and tracer deposition on the right or left side of the prostate, (2) visualization of a higher number of LNs after dorsal tracer deposition compared with ventral tracer deposition, (3) different drainage patterns observed for tracer deposition into the base or apex of the prostate, and (4) the indication that intratumoural tracer deposition increases the chance of visualizing nodal metastases compared with extratumoural tracer deposition. The correlation between the location of the tracer deposits, the location of the primary tumour, and the visualization of the (tumour-positive) SNs indicated that placement of tracer deposits is of influence on the visualized lymphatic drainage pattern. This suggests that tracer injection near or into the primary tumour site is beneficial for the identification of metastatic spread.

Axillary Dissection vs. no Axillary Dissection in Breast Cancer Patients With Positive Sentinel Lymph Node: A Single Institution Experience.

Axillary surgery of breast cancer patients is undergoing a paradigm shift, as axillary lymph node dissection's (ALND) usefulness is being questioned in the treatment of patients with tumor-positive sentinel lymph node biopsy (SLNB). The aim of this study was to investigate the overall survival (OS) and relapse-free survival (RFS) of patients with positive SLNB treated with ALND or not. We investigated 617 consecutive patients with cN0 operable breast cancer with positive SLNB undergoing mastectomy or conservative surgery. A total of 406 patients underwent ALND and 211 were managed expectantly. No significant difference in OS and RFS was found between the two groups. The incidence of loco-regional recurrence in the SLNB-only group and the ALND group was low and not significant. The type of breast cancer surgery and the omission of ALND does not improve OS or RSF rate in cases with metastatic SLN.

A unique gene expression signature is significantly differentially expressed in tumor-positive or tumor-negative sentinel lymph nodes in patients with melanoma: Erratum.

A unique gene expression signature is significantly differentially expressed in tumor-positive or tumor-negative sentinel lymph nodes in patients with melanoma: Erratum.

Intraoperative Imaging with a Portable Gamma Camera May Reduce the False-Negative Rate for Melanoma Sentinel Lymph Node Surgery

BackgroundPreoperative imaging and intraoperative gamma probe (GP) localization is standard for identifying sentinel lymph nodes (SLNs) in melanoma patients. The aim of this prospective Institutional Review Board-approved study was to investigate whether an intraoperative portable gamma camera (PGC) improves SLN detection over the GP.MethodsLymphoscintigraphy and single photon emission computed tomography/computed tomography were performed after injection of 99mTc-Tilmanocept in melanoma patients (≥ 18 years, Breslow thickness ≥ 1.0 mm). A GP was used to localize the SLNs in each basin, which was explored by the GP to ensure that the operative field was < 10% counts of the hottest SLN. The PGC was then used after a negative GP screening. Any residual hotspots identified by the PGC were considered as additional SLNs and were removed following the 10% rule.ResultsPreoperative imaging of 100 patients identified 138 SLN basins, with 306 SLNs being identified by conventional surgery. The PGC localized 89 additional SLNs in 54 patients. Thus, the PGC identified an additional 23% of SLNs [95% confidence interval (CI) 18–27%]. Four of these 89 SLNs showed micrometastasis in four patients, in two of whom the only tumor-positive SLN was identified by the PGC, preventing two false-negative cases. Thus, the null hypothesis that the PGC did not detect additional positive SLNs was rejected (p = 0.000). The overall SLN positive rate was 9.9% (39/395, 95% CI 6–12), and the overall patient positive rate was increased using the PGC, from 25 to 27% (27/100).ConclusionsIntraoperative PGC imaging yielded additional SLNs in a significant number of patients over GP alone. Identification of these additional SLNs resulted in upstaging of four patients with two patients being converted from a negative to a positive status, thus, preventing two false-negative cases.

Unique Genes in Tumor-Positive Sentinel Lymph Nodes Associated with Nonsentinel Lymph Node Metastases in Melanoma.

Current risk assessment tools to estimate the risk of nonsentinel lymph node metastases after completion lymphadenectomy for a positive sentinel lymph node (SLN) biopsy in cutaneous melanoma are based on clinical and pathologic factors. We identified a novel genetic signature that can predict non-SLN metastases in patients with cutaneous melanoma staged with a SLN biopsy. RNA was collected for tumor-positive SLNs in patients staged by SLN biopsy for cutaneous melanoma. All patients with a tumor-positive SLN biopsy underwent completion lymphadenectomy. A 1:10 case:control series of positive and negative non-SLN patients was analyzed by microarray and quantitative RT-PCR. Candidate differentially expressed genes were validated in a 1:3 case:control separate cohort of positive and negative non-SLN patients. The 1:10 case:control discovery set consisted of 7 positive non-SLN cases matched to 70 negative non-SLN controls. The cases and controls were similar with regards to important clinicopathologic factors, such as gender, primary tumor site, age, ulceration, and thickness. Microarray and RT-PCR identified six potential differentially expressed genes for validation. In the 40-patient separate validation set, 10 positive non-SLN patients were matched to 30 negative non-SLN controls based on gender, ulceration, age, and thickness. Five of the six genes were differentially expressed. The five gene panel identified patients at low (7.1%) and high risk (66.7%) for non-SLN metastases. A novel, non-SLN gene score based on differential expressed genes in a tumor-positive SLN can identify patients at high and low risk for non-SLN metastases.

Abstract 4692: Local adjuvant treatment of clinical stage I-II melanoma with low dose CpG-B and/or GM-CSF: Long-term follow-up of three randomized controlled phase II trials

Abstract Introduction: Currently, there is no widely used adjuvant treatment available to improve survival after surgical excision of localized melanoma. Here, we present the clinical outcome of patients who participated in three randomized phase-II trials and received low-dose local immunotherapy, which was shown to be safe and to boost loco-regional and systemic anti-melanoma T cell immunity. Patients and Methods: In three single-center, single-blinded, randomized and placebo (saline) controlled phase-II clinical trials, patients with early stage melanoma were treated with 1) Granulocyte/Macrophage-Colony Stimulating Factor (GM-CSF), 2) unmethylated CpG type-B oligodeoxynucleotide CpG7909 (CpG-B), and 3) CpG-B, alone or combined with GM-CSF, through 1-4 intradermal injections at the site of the primary melanoma excision scar, within 7 days preceding re-excision and sentinel lymph node (SLN) biopsy. For clinical follow-up analysis, all treated patients were grouped together (treated group n=36) as were the patients who received saline (saline group n=28). Results: 10-year recurrence-free survival rate in the treated group was 94% (95% CI 78-98) versus 48% (95% CI 21-71) in the saline group (P=0.005), hazard ratio (HR) for recurrence was 0.15 (95% CI 0.06-0.60) for the treated group. This apparent antitumor efficacy was in line with the observation upon pathological examination of less tumor positive SLN in the treated group (P=0.05). The 10-year distant recurrence-free survival rate in treated patients was also higher (94%, 78-98 versus 59%, 28-81, HR 0.22, 0.07-0.93; P=0.04). Conclusion: Local low-dose immunotherapy in patients with early-stage melanoma may offer durable protection against distant recurrences. These findings warrant further clinical exploration of this local non-toxic immune potentiating regimen. Citation Format: Bas D. Koster, Mari F. van den Hout, Berbel J. Sluijter, Barbara G. Molenkamp, Ronald J. Vuylsteke, Arnold Baars, Paul A. van Leeuwen, Rik J. Scheper, Monique P. van den Tol, Alfons J. van den Eertwegh, Tanja D. de Gruijl. Local adjuvant treatment of clinical stage I-II melanoma with low dose CpG-B and/or GM-CSF: Long-term follow-up of three randomized controlled phase II trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4692. doi:10.1158/1538-7445.AM2017-4692

The intraoperative assessment of sentinel nodes – Standards and controversies

Intraoperative assessment of sentinel lymph nodes (SLNs) has the advantage of allowing breast cancer patients with tumor-positive SLNs to avoid a second surgery by immediately proceeding to axillary lymph node dissection (ALND). However, there are several reasons why the use of intraoperative assessment should be questioned. Whereas ALND was traditionally advised for all breast cancer patients with tumor-positive lymph nodes for axillary staging and locoregional control, more recent studies have demonstrated safety of omitting ALND in a substantial number of patients.In addition, there are concerns about the accuracy of intraoperative assessment methods including frozen section analysis, touch preparation cytology and one-step nucleic acid amplification. Moreover, intraoperative assessment of SLNs denies patients the opportunity to contribute to their treatment planning. In our opinion, intraoperative assessment of axillary lymph nodes should be reserved for patients who still have a strict indication for ALND. Patients with clinical node negative disease (cN0) and one or two positive SLNs can be safely treated with breast conserving surgery and radiotherapy. There has been more controversy for cN0 patients who are treated with mastectomy since radiotherapy is not routinely administered in these patients. However, there is increasing evidence that ALND may be omitted in patients undergoing mastectomy who have a low tumor-burden in their SLNs. Therefore, we defend the position that in cN0 patients undergoing mastectomy, SLNB should be performed and full pathologic evaluation of the SLN should be awaited. In cN0 patients undergoing neoadjuvant systemic therapy (NST) intraoperative assessment of SLNs can be omitted since ALND will not provide therapeutic benefit. It is being hypothesized that patients with limited axillary disease prior to NST who remain node-positive after NST could be treated safely with axillary radiotherapy instead of ALND. In these patients, omitting intraoperative assessment might be a reasonable option. In patients with extensive nodal disease prior to NST intraoperative assessment of axillary lymph nodes should be performed.

Are the ACOSOG Z0011 Trial Findings Being Applied to Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy?

In 2010, the ACOSOG Z0011 trial showed equivalent survival and recurrence between sentinel lymph node biopsy (SLNB) alone versus axillary lymph node dissection (ALND) for those with a tumor positive sentinel node (SN). We examined national trends in axillary surgery following neoadjuvant chemotherapy (NAC) for clinically node positive disease in the years prior to and after the Z0011 trial publication. 12,063 women with cT1-4N1M0 invasive breast cancer who underwent NAC from 2006 to 2013 and had 1-3 positive nodes on pathology were selected from the National Cancer Data Base. We defined SLNB as 1-4 nodes and ALND as ≥10 nodes examined. 2,704 women (22.4%) underwent SLNB alone and 9,359 (77.6%) underwent ALND. The rate of SLNB increased from 25.6% in 2006 to 33.3% in 2012 in patients that underwent lumpectomy (p < 0.01) and increased from 20.6% to 22.8% in patients that underwent mastectomy (p = 0.25). Patients treated at Community centers (30.4% versus 19.2% at Academic centers) and those with less positive nodes (32.2% for 1 positive node versus 10.1% for 3 positive nodes, p < 0.01) were more likely to have SLNB alone compared to ALND. On multivariate analysis, treatment with lumpectomy (OR 1.46, CI 1.28-1.67), lower number of positive nodes (OR 3.98, CI 3.29-4.82) and lobular subtype (OR 1.82, CI 1.42-2.34) were independent predictors of receiving SLNB alone after NAC. Approximately 22% of patients with cN1 breast cancer underwent SLNB alone for pN1 disease after NAC. Ongoing clinical trials will determine if recurrence and survival rates are equivalent between SLNB and ALND groups.

Abstract B02: Immune events in the sentinel lymph node in melanoma predict local and systemic response to disease

Abstract Background: The sentinel node (SN) has become the standard diagnostic tool for staging cutaneous melanoma. With the recent development of anti-CTLA-4 and anti-PD-1 antibodies as immunotherapies we hypothesized that the early immune events in melanoma maybe first observed in the SN and be related to the response to disease. Methods: 81 SN from 79 patients were evaluated with microarray technology, qPCR, routine H&amp;E &amp; IHC. We identified 10 immune genes that are present by qPCR in SNs from a random section of the SN. Statistical analysis assessed the utility of these markers to predict tumor-positive SN and survival. Results: Of the 79 patients, 48 (61%) were men. Median age was 59 (range 6-95 years). Primary melanomas were most commonly from the trunk (51%) and extremities (40%). The median thickness of the primaries was 0.95mm. 13% of the patients had ulcerated primaries. 29% of the primary tumors had at least 1 mitosis/mm2 . 9 (11%) patients had SN metastasis, as determined by conventional H&amp;E and IHC. The incidence of SN positivity was directly related to tumor thickness; the higher the T-stage the greater percentage of SN positivity: 2% T1, 19% T2, 20% T3 and 60% T4 melanoma. 33% of ulcerated primaries and 30% with increased mitotic rate had a tumor-positive SN. The microarray did not identify specifc immune related genes when comparing tumor-positive to tumor-negative SN. We then evaluated the gene expression of CD80, CD86, CD28, CD40, IDO, Arginase, IL-2, IL-10, PD-1 and CTLA-4 by qPCR. By univariate analyses: patient age (p&amp;lt;0.001), primary site (&amp;lt;0.001), decreasing gene expression of CTLA-4 (p&amp;lt;0.001) and PD-1 (p&amp;lt;0.001) in SN were predictive of SN positivity. Multivariate analyses confirmed the down-regulation of CTLA-4 and PD-1 gene expression in the SN were predictive of metastases in the SN and the AUC values of predicting SN positivity were 0.808 and 0.731 respectively . The positive and negative predictive values of the tests were 100 and 89.5%. Further the down-regulation of CTLA-4 and PD-1 gene expression in the SN correlated with diminished survival, while the up-regulation of IL-10 correlated with poor survival. Conclusions: Our results demonstrate the significance of CTLA-4, PD-1 and IL-10 gene expression in the SN of melanoma patients. The expression of these genes may be early events in the immune dysfunction that occurs with melanoma metastases. Citation Format: Richard Essner, Ke-Wei Gong, David Z. Kaufman, Alexandra Gangi, Myung Shin Sim. Immune events in the sentinel lymph node in melanoma predict local and systemic response to disease. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B02.