Sentinel Node Tumor Research Articles

Long-term multimodal imaging of tumor draining sentinel lymph nodes using mesoporous silica-based nanoprobes

The imaging of sentinel lymph nodes (SLNs), the first defense against primary tumor metastasis, has been considered as an important strategy for noninvasive tracking tumor metastasis in clinics. In this study, we report the development and application of mesoporous silica-based triple-modal nanoprobes that integrate multiple functional moieties to facilitate near-infrared optical, magnetic resonance (MR) and positron emission tomography (PET) imaging. After embedding near-infrared dye ZW800, the nanoprobe was labeled with T1 contrast agent Gd3+ and radionuclide 64Cu through chelating reactions. High stability and long intracellular retention time of the nanoprobes was confirmed by in vitro characterization, which facilitate long-term in vivo imaging. Longitudinal multimodal imaging was subsequently achieved to visualize tumor draining SLNs up to 3 weeks in a 4T1 tumor metastatic model. Obvious differences in uptake rate, amount of particles, and contrast between metastatic and contra-lateral sentinel lymph nodes were observed. These findings provide very helpful guidance for the design of robust multifunctional nanomaterials in SLNs' mapping and tumor metastasis diagnosis.

EORTC Melanoma Group achievements

Since its inception in 1969, the EORTC Melanoma Group has employed a multidisciplinary approach in the fight against melanoma and has registered significant achievements in many areas of melanoma treatment and research. The group showed that sentinel node (SN) tumor burden according to the Rotterdam Criteria and the microanatomic location were the most important prognostic factors for melanoma-specific survival and non-SN positivity in the completion lymph node dissection specimen. They demonstrated that extended schedule escalated dose temozolomide is feasible and has an acceptable safety profile. They also showed that the interferon-a targeted therapy should occur in a targeted patient population, and should probably not be offered to 70% of the patients that are currently being given this treatment. Through EORTC trial 18991, Sylatron™, pegylated interferon a-2b, for the treatment of melanoma patients with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy, was approved by the US FDA. The present article describes the achievements and future strategies of the Melanoma Group.

Reliability of Whole Sentinel Lymph Node Analysis by One-Step Nucleic Acid Amplification for Intraoperative Diagnosis of Breast Cancer Metastases

To assess the reliability of using the One-Step Nucleic Acid Amplification (OSNA) assay as a single test on whole sentinel lymph nodes (SLN) as a method of intraoperative diagnosis and staging of SLNs in breast cancer. Combining histological and molecular assessment of metastasis on the same SLN may not fully reproduce the actual load of cancer cells present in the SLN and create problems in decisions regarding axillary dissection. Selection criteria for the whole SLN OSNA test required that the primary tumor expressed CK19 in more than 80% of tumor cells. Imprint cytology analysis of SLNs was performed together with the OSNA. Of the 279 patients enrolled for SLN evaluation, 123 gave consent to the OSNA protocol and 156 to the standard histology. Thirteen patients were excluded from OSNA evaluation because of low CK19 gene expression in the primary tumor; only 2.3% were truly negative. The kappa of concordance between the imprint cytology and OSNA results was 0.52. The rate of macrometastases determined by OSNA was 11% versus 20% determined by histology, whereas the rate of OSNA-micrometastases (18%) was significantly higher than that determined by histology (8%). The rate of SLN-negative cases was similar between the 2 protocols. Macrometastases correlated with the presence of vascular invasion in both protocols. The rate of axillary lymph node metastases was consistent with SLN tumor load. Intraoperative OSNA assay performed on the whole SLN gave objective and reproducible results that were useful for directing decisions regarding axillary dissection and for accurately defining the SLN stage.

Sentinel Lymph Nodes Containing Very Small (<0.1 mm) Deposits of Metastatic Melanoma Cannot Be Safely Regarded as Tumor-Negative

Some authors have suggested that patients with very small (<0.1mm) deposits of metastatic melanoma in sentinel lymph nodes (SLNs) should be considered SLN-negative, whereas others have reported that such patients can have adverse long-term outcomes. The aims of the present study were to determine whether extensive sectioning of SLNs resulted in more accurate categorization of histologic features of tumor deposits and to assess prognostic associations of histologic parameters obtained using more intensive sectioning protocols. From patients with a single primary cutaneous melanoma who underwent SLN biopsy between 1991 and 2008, those in which the maximum size of the largest tumor deposit (MaxSize) in SLNs was <0.1mm in the original sections were identified. Five batches of additional sections were cut from the SLN tissue blocks at intervals of 250μm. The 1st batch was cut from the blocks without any trimming; these sections were therefore immediately adjacent to the original sections. Each batch included 5 sequential sections, the 1st and 5th stained with hematoxylin-eosin, and the 2nd, 3rd, and 4th stained immunohistochemically with S-100, HMB-45, and Melan-A, respectively. In each batch of sections, the following histologic features of tumor deposit(s) in the SLNs were evaluated: MaxSize; tumor penetrative depth (TPD) (defined as the maximum depth of tumor deposit(s) from the inner margin of the lymph node capsule), and intranodal location (classified as subcapsular if the tumor deposit(s) were confined to the subcapsular zone or parenchymal if there was any involvement of the nodal parenchyma beyond the subcapsular zone). The measured histologic parameters were compared in each batch of sections. The association of histologic parameters with overall survival was assessed for the parameters measured in each batch of sections. There were 20 eligible patients (15 females, 5 males, median age 60years). After a median follow-up duration of 40months, 4 patients had died from melanoma and 2 patients of unknown causes. Completion lymph node dissection (CLND) was performed in 13 cases (65%) and was negative in all cases. Relative to the measured values on the original sections, all 3 parameters were upstaged in subsequent batches of sections, but no further upstaging of MaxSize, TPD, or location was seen beyond batch 3, batch 4, and batch 2, respectively. Increasing MaxSize was associated with significantly poorer overall survival in batches 1, 2, and 3. Parenchymal involvement was significantly associated with poorer survival in batches 2-5. TPD was not significantly associated with overall survival. The results of this study indicate that very small (<0.1mm) deposits of melanoma in SLNs may be associated with adverse clinical outcomes and that this is due, at least in part, to the underestimation of SLN tumor burden in the initial sections. Our evidence does not support clinical decision-making on the assumption that patients with very small melanoma deposits in SLNs have the same outcome as those who are SLN-negative.

The size of Metastasis in the Sentinel Node Is a Predictor of Additional Non-Sentinel Node Positivity

Background: The need for axillary lymph node dissection (ALND) when sentinel lymph nodes (SLN) contain micrometastasis is controversial. The purpose of this study was to determine if the size of tumor in the SLN corresponds with additional positive non-sentinel lymph nodes (non-SLN) in pT1 breast cancer. Methods: This retrospective review of 483 patients with pT1 breast cancer identified 96 patients with tumor positive SLN biopsies between June 1999 and February 2010. The size of SLN metastasis and the number of tumor positive non-SLN were recorded using AJCC criteria. Receiver operating characteristic analysis was used to discriminate the SLN size with the optimal sensitivity, specificity and likelihood ratios (LR) for additional positive non-SLN. Results: Among 96 patients with a tumor positive SLN, 41% (n = 39) had micrometastasis, and 59% (n = 57) had macrometastasis. A positive non-SLN was identified after ALND among 18% (n = 7 of 39) with micrometastasis compared with 39% (n = 22 of 57) with macrometastasis (p = 0.04). The size of the SLN metastasis and presence of additional tumor positive non-SLNs corresponds to a positive likelihood ratio of 1.1 for micrometastasis and 1.6 for macrometastasis (95%CI: 0.56 - 0.74). Conclusions: Increased size of tumor in SLN is associated with greater likelihood of non-SLN positivity and should be considered for more aggressive follow-up and therapy.

Incorporation of Sentinel Lymph Node Metastasis Size Into a Nomogram Predicting Nonsentinel Lymph Node Involvement in Breast Cancer Patients With a Positive Sentinel Lymph Node

Sentinel lymph node (SLN) metastasis size is an important predictor of non-SLN involvement. The goal of this study was to construct a nomogram incorporating SLN metastasis size to accurately predict non-SLN involvement in patients with SLN-positive disease. We identified 509 patients with invasive breast cancer with a positive SLN who underwent completion axillary lymph node dissection (ALND). Clinicopathologic data including age, tumor size, histology, grade, presence of multifocal disease, estrogen and progesterone receptor status, HER2/neu status, presence of lymphovascular invasion (LVI), number of SLN(s) identified, number of positive SLN(s), maximum SLN metastasis size and the presence of extranodal extension were recorded. Univariate and multivariate logistic regression analyses identified factors predictive of positive non-SLNs. Using these variables, a nomogram was constructed and subsequently validated using an external cohort of 464 patients. On univariate analysis, the following factors were predictive of positive non-SLNs: number of SLN identified (P < 0.001), number of positive SLN (P < 0.001), SLN metastasis size (P < 0.001), extranodal extension (P < 0.001), tumor size (P = 0.001), LVI (P = 0.019), and histology (P = 0.034). On multivariate analysis, all factors remained significant except LVI. A nomogram was created using these variables (AUC = 0.80; 95% CI, 0.75-0.84). When applied to an external cohort, the nomogram was accurate and discriminating with an AUC = 0.74 (95% CI, 0.68-0.77). SLN metastasis size is an important predictor for identifying non-SLN disease. In this study, we incorporated SLN metastasis size into a nomogram that accurately predicts the likelihood of having additional axillary metastasis and can assist in personalizing surgical management of breast cancer.

The Impact of Primary Melanoma Thickness and Microscopic Tumor Burden in Sentinel Lymph Nodes on Melanoma Patient Survival

The primary objectives of this work are to (1) quantitate tumor burden in sentinel lymph nodes (SLNs), and (2) assess the independent contributions of SLN tumor burden and primary melanoma thickness (PMT) with respect to progression-free survival (PFS) and overall survival (OS). Sixty-three patients (41 male and 22 female) with one or more positive SLNs were available for review in this study, with median follow-up of 6.8 years. PMT was measured and SLN metastases were assessed for size, as maximum metastasis size (MMS) in mm, by hematoxylin and eosin (H&E) and immunohistochemistry (S100 and HMB45). PFS and OS were calculated from time of SLN resection until melanoma recurrence or death. Univariate and multivariate analyses and trend test were performed. Kaplan-Meier estimates of PFS and OS differed significantly by MMS (log-rank P = 0.031 for PFS and P = 0.016 for OS) and PMT (log-rank P = 0.036 for PFS and P < 0.001 for OS). After adjusting for age and gender, the hazard ratio (HR) associated with MMS was 1.09 per mm increase (P = 0.05) for PFS, and 6.30 (P = 0.014) and 5.41 (P = 0.048) for OS in patients, respectively, with MMS of 0.6-5.5 mm and MMS ≥5.5 mm compared with those with MMS <0.6 mm. When patients were stratified by their tumor characteristics of PMT, the risk for disease progression and worse OS was substantially higher for the group with PMT ≥ 4.5 mm (HR = 13.10 and P = 0.022 for PFS; HR = 17.26 and P < 0.001 for OS) relative to the baseline group with PMT <1.6 mm. All patients had completion lymph node dissection (CLND) except for four patients. Patients with positive CLND (14, 22.2%) showed significant worse PFS (P = 0.002) and OS (P = 0.0003) than the negative CLND group (45, 71.4%). PMT and MMS were independently prognostic of PFS and OS in melanoma patients. Patients with negative CLND had significantly better PFS and OS than those with positive CLND.

Radiation field design and regional control in sentinel lymph node‐positive breast cancer patients with omission of axillary dissection

Randomized data suggest that axillary clearance is not necessary in select, clinically lymph node-negative women with positive sentinel lymph node (SLN) biopsies (SLNBs) who undergo breast-conserving surgery or receive whole-breast radiotherapy and systemic therapy. The additional value of axillary radiotherapy in these patients is unknown. The authors identified 326 patients with positive SLNBs who underwent breast-conserving surgery without axillary lymph node dissection from 1997 to 2009. SLN tumor deposits measured ≤0.2 mm in 58% of patients, 0.3 to 2.0 mm in 35% of patients, and >2 mm in 7% Patients. Ninety-three percent of patients received adjuvant radiotherapy. Radiation fields were categorized as standard tangents, high tangents, comprehensive (tangents plus supraclavicular), or partial breast to reflect coverage of the axilla. Standard tangents included both prone and supine positions. Regional failure was defined as recurrence in the ipsilateral supraclavicular, axillary, or internal mammary lymph nodes. The median follow-up was 55 months (range, 1-158 months). The 4-year rates of regional control, local control, disease-free survival, and overall survival were 99%, 98%, 95%, and 91%, respectively. Three patients had regional recurrences. Two of those patients received adjuvant radiotherapy with standard supine tangents, and 1 patient did not receive radiotherapy. No regional recurrences occurred among 66 patients who received radiotherapy in the prone position. Regional control was high (99% at 4 years) in patients who had low-volume SLN disease who did not undergo axillary dissection, regardless of whether the axilla was irradiated. Whole-breast radiation alone, including in the prone position, is sufficient treatment after breast-conserving surgery for select patients with tumor-containing SLNs who omit axillary dissection.

No non‐sentinel node involvement in melanoma patients with limited Breslow thickness and low sentinel node tumour load

Most melanoma patients with a positive sentinel node (SN) undergo completion lymph node dissection and frequently experience associated morbidity. However, only 10-30% of SN-positive patients have further lymph node metastases. The aim of the present study was to predict the absence of non-SN metastases in a multicentre study of patients with a positive SN based on primary melanoma features and SN tumour load. Of 70 SN positive patients, 18 had non-SN metastases. Penetrative depth of metastatic cells into the SN and SN tumour load was assessed by morphometry. None of the 14 patients (20%) with a Breslow thickness <2.0 mm and an SN tumour load <0.2 mm2 had non-SN metastases. Similarly, none of the 15 patients (21%) with a Breslow thickness <2.0 mm and SN penetrative depth <600 μm had non-SN metastases. Lastly, none of the 14 patients (20%) with a Breslow thickness <2.0 mm and a diameter of the largest SN deposit <500 μm had non-SN metastases. A combination of limited Breslow thickness and low SN tumour load predicts absence of non-SN metastases in melanoma patients with a positive SN with high accuracy. We propose that this subgroup may be spared completion lymph node dissection.

Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer.

Immunochemical staining of sentinel lymph nodes (SLNs) and bone marrow identifies breast cancer metastases not seen with routine pathological or clinical examination. To determine the association between survival and metastases detected by immunochemical staining of SLNs and bone marrow specimens from patients with early-stage breast cancer. From May 1999 to May 2003, 126 sites in the American College of Surgeons Oncology Group Z0010 trial enrolled women with clinical T1 to T2N0M0 invasive breast carcinoma in a prospective observational study. All 5210 patients underwent breast-conserving surgery and SLN dissection. Bone marrow aspiration at the time of operation was initially optional and subsequently mandatory (March 2001). Sentinel lymph node specimens (hematoxylin-eosin negative) and bone marrow specimens were sent to a central laboratory for immunochemical staining; treating clinicians were blinded to results. Overall survival (primary end point) and disease-free survival (a secondary end point). Of 5119 SLN specimens (98.3%), 3904 (76.3%) were tumor-negative by hematoxylin-eosin staining. Of 3326 SLN specimens examined by immunohistochemistry, 349 (10.5%) were positive for tumor. Of 3413 bone marrow specimens examined by immunocytochemistry, 104 (3.0%) were positive for tumors. At a median follow-up of 6.3 years (through April 2010), 435 patients had died and 376 had disease recurrence. Immunohistochemical evidence of SLN metastases was not significantly associated with overall survival (5-year rates: 95.7%; 95% confidence interval [CI], 95.0%-96.5% for immunohistochemical negative and 95.1%; 95% CI, 92.7%-97.5% for immunohistochemical positive disease; P = .64; unadjusted hazard ratio [HR], 0.90; 95% CI, 0.59-1.39; P = .64). Bone marrow metastases were associated with decreased overall survival (unadjusted HR for mortality, 1.94; 95% CI, 1.02-3.67; P = .04), but neither immunohistochemical evidence of tumor in SLNs (adjusted HR, 0.88; 95% CI, 0.45-1.71; P = .70) nor immunocytochemical evidence of tumor in bone marrow (adjusted HR, 1.83; 95% CI, 0.79-4.26; P = .15) was statistically significant on multivariable analysis. Among women receiving breast-conserving therapy and SLN dissection, immunohistochemical evidence of SLN metastasis was not associated with overall survival over a median of 6.3 years, whereas occult bone marrow metastasis, although rare, was associated with decreased survival. clinicaltrials.gov Identifier: NCT00003854.

Factors Predicting Recurrence and Survival in Sentinel Lymph Node-Positive Melanoma Patients

Studies which have found that histologic features of metastatic melanoma in sentinel lymph nodes (SNs) were predictive of survival have differed considerably in their design and results. We investigated in detail the influence of SN tumor characteristics and clinical and primary tumor parameters on clinical outcomes in a large cohort of patients treated in a single center. In SN-positive melanoma patients, the association of clinical, primary tumor, and SN tumor features [maximum size (MaxSize), % cross-sectional area of SN occupied by tumor (%CS), tumor-penetrative depth (TPD), intranodal location of tumor, extranodal spread (ENS), and perinodal lymphatic invasion (PLI)] with disease-free (DFS), distant metastasis-free (DMFS), and melanoma-specific (MSS) survival was analyzed. In 409 SN-positive patients, independent predictors of poorer DFS were primary tumor features [anatomic site: head/neck (HR = 3.65, 95% CI 1.65-8.08) and limbs (HR = 2.46, 95% CI 1.21-4.98) compared with trunk; ulceration (HR = 1.70, 95% CI 1.15-2.51); satellites (HR = 2.85, 95% CI 1.49-5.44)], SN tumor features [MaxSize (HR = 1.53, 95% CI 1.04-2.26); ENS in SN (HR = 2.05, 95% CI 1.06-4.00); PLI (HR = 1.85, 95% CI 1.11-3.07)], and positive CLND (HR = 1.92, 95% CI 1.26-2.91). Factors independently predictive of poorer MSS were age ≥50 years (HR 1.64, 95% CI 1.01-2.67), primary tumor features [ulceration (HR = 2.55, 95% CI 1.44-4.52); satellites (HR = 3.95, 95% CI 1.83-8.49)], and ENS in SN (HR = 2.34, 95% CI 1.06-5.13). The use of clinical, primary tumor, and SN tumor characteristics shown to be independent predictors of clinical outcomes in melanoma patients will assist in accurate prediction of prognosis and optimize clinical management.

Mitotic Rate and Sentinel Lymph Node Tumor Burden Topography: Integration Into Melanoma Staging and Stratification Use in Clinical Trials

Mitotic Rate and Sentinel Lymph Node Tumor Burden Topography: Integration Into Melanoma Staging and Stratification Use in Clinical Trials

Seeing the invisible during surgery

Seeing the invisible during surgery

Molecular analysis of melanoma-induced sentinel lymph node immune dysfunction.

Sentinel lymph nodes (SLNs) of melanoma patients show evidence of tumor-induced immune dysfunction. Our previous works have shown that IL-10 and IFNγ co-regulate indoleamine-2,3-dioxygenase (IDO)-expressing immunosuppressive dendritic cells (DCs) in melanoma SLNs. The goal of this study is to examine the relationship between melanoma SLN tumor burden and the degree of SLN immune dysfunction as a model to study tumor-induced immune dysfunction. We hypothesize that SLN tumor burden correlates with the degree of SLN immune dysfunction. Patients undergoing SLN biopsy for clinical stages I and II melanomas were enrolled in the study under an IRB-approved protocol. During the SLN biopsy, non-hot and non-blue portion of the SLN was harvested, flash-frozen in liquid nitrogen, and mRNA was extracted. By using quantitative real-time PCR, gene expressions of cytokines (IL-4, IL-10, IFNγ, TGFβ, GM-CSF) and the surrogates of immunosuppressive regulatory and effector cells (IDO-expressing DCs and Foxp3-expressing T-regs, respectively) were measured and correlated against the SLN tumor burden (MART1) and against each other. The data were log transformed for normalization. Statistical test used Student's t-test and stepwise multivariate regression analysis. Statistical significance was determined at P<0.05. SLNs of 74 patients were analyzed in this analysis. Ten of seventy-four patients (13.5%) had tumor-positive SLNs. MART1 gene expression showed a significant difference between the SLN (+) and SLN (-) groups (P=0.04). Among the various cytokines, multivariate analysis showed that only IFNγ gene expression correlated independently with MART1 gene expression (P<0.0001, r=0.91). Similar multivariate analyses show that IFNγ (P<0.0001, r=0.78), IL-10 (P=0.0037, r=0.60), and TGFβ (P<0.0001, r=0.95) gene expressions correlated independently with IDO gene expression. IFNγ (P<0.0001, r=0.87) and GM-CSF (P=0.042, r=0.76) gene expressions correlated independently with Foxp3 gene expression. MART1 gene expression showed independent correlation with IDO (P=0.0002, r=0.75) and Foxp3 (P=0.0002, r=0.75) gene expressions. SLN tumor burden correlates with immunosuppressive IDO and Foxp3 expressions within the SLNs of melanoma patients. Our data are consistent with our theory that melanoma induces expressions of specific cytokines, which in turn, stimulate immune suppressors within the SLN. This study also supports our previous finding that IL-10 and IFNγ co-regulate IDO within the SLN. In our data, IFNγ is the sole cytokine that correlates with the SLN tumor burden and seems to play a central role in tumor-induced immunological changes in the SLN immune microenvironment.

33. Snore (non-Sentinel Node Risk score): a system for accurately stratifying risk of non-sentinel node positivity in cutaneous melanoma patients with positive sentinel lymph nodes

Background Completion lymph node dissection (CLND) is usually offered to all sentinel lymph node (SLN)-positive melanoma patients. However, metastatic melanoma is not present in ~80% of CLND specimens, and these patients are needlessly subjected to the operative risks and morbidities associated with CLND. In this study, we attempted to refine the criteria for selection of SLN-positive patients for CLND. Methods In SLN-positive patients managed at a single melanoma centre, the ability of clinical, primary tumour and SLN tumour features to predict NSLN positivity was investigated using logistic regression models. A weighted score (non- S entinel N ode sc ORE ) was derived from the models, and the efficacy of SNORE at stratifying risk of NSLN involvement was studied. Results There were 409 SLN-positive patients. Factors independently predictive of NSLN positivity included: regression, proportion of harvested SLNs involved by melanoma (%PosSLN), sex (trend), and SLN tumour burden indices [maximum size of largest deposit (MaxSize), % cross-sectional area of SLN occupied by tumour, tumour-penetrative depth, intranodal location of tumour) and perinodal lymphatic invasion (PLI). The final SNORE system included: sex, regression, %PosSLN, MaxSize, and PLI. SNOREs of 0, 1-3, 4-5, 6-7 and ≥8 were associated with very low (0%), low (5-10%), intermediate (15-20%), high (40-50%) and very high (70-80%) risk of NSLN involvement. Conclusions A weighted score (SNORE) based on clinico-pathological characteristics accurately stratifies the risk of NSLN involvement. If validated in future studies of large numbers of SLN-positive melanoma patients, SNORE will better inform patients and their treating physicians with regard to prognosis and aid in management decisions.

Abstract PD06-07: Sentinel Node Biopsy Alone for Node Positive Breast Cancer, Report from the American College of Surgeon's National Cancer Database, 1998-2007

Abstract Background: The decision to perform complete node dissection for a tumor positive sentinel node (SN) has become controversial especially in light of the results of a randomized trial of sentinel node biopsy alone for node positive disease. We report national trends in the United States of SN biopsy alone from 1998-2007 for node positive disease from the National Cancer Database (NCDB) of the American College of Surgeons. Patients and Methods: Utilizing the NCDB Participant User File we analyzed 994,883 patients diagnosed with invasive breast cancer from 1998 to 2007. Neoadjuvant cases and patients with clinically positive axillary nodes were excluded. All patients underwent breast surgery. After applying exclusion criteria, 104,548 SN tumor positive patients were identified. 15,643 (14.9%) patients underwent SN biopsy alone and 88,905 (85.1%) patients underwent SN biopsy followed by completion axillary node dissection. Cross tabulations with patient, tumor and hospital factors were performed. Results: Over the 10 year period, there was a statistically significant increase in the number of patients undergoing SN biopsy alone, with 488 (9%) in 1998, and 1798 (17%) in 2007 (P&amp;lt;0.001), and similar pattern was seen across age (all p&amp;lt;.0001), income (all p&amp;lt;.0001), census region (all p&amp;lt;.001), tumor stage (all p&amp;lt;.01), and facility type categories (all p&amp;lt;.0001). Overall there was a significant increase in the number of patients undergoing sentinel node biopsy alone according to age, with 756 (10.2%) for patients ages 30 to 40 versus 1368 (24.2%) for patients ages 80 to 90 (P&amp;lt;0.0001). 7,149 (15.3%) of patients in the highest income range had SN biopsy alone versus 1387 (13.8%) in the lowest income range (p=0.0002). There were significant differences according to the census region with the highest rate for SN alone in the Northeast region, 1263 (21%) and lowest in the Atlantic region, 2116 (12.8%) (26.5%) (P&amp;lt;0.001). There were significant differences in SN biopsy alone according to tumor stage, with 14441 (16.8%) Stage II patients had SN alone versus 577 (3.5%) for those with Stage III tumors (P&amp;lt;0.0001). There were minimal differences in the facility type, with 2090 (15%) patients treated at a community cancer program had SN alone versus 8646 (15%) at a comprehensive community cancer program versus 4907 (14%) at an academic/teaching program (p=0.501). Conclusions: The utilization of SN biopsy alone for patients with node positive breast cancer has significantly increased from 1998 to 2007. Patient age, tumor size, and socioeconomic status, were significant predictive variables but facility type was not. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD06-07.

Treatment combining RU486 and Ad5IL-12 vector attenuates the growth of experimentally formed prostate tumors and induces changes in the sentinel lymph nodes of mice

BackgroundTumor immune responses are first generated and metastases often begin in tumor sentinel lymph nodes (TSLN). Therefore, it is important to promote tumor immunity within this microenvironment. Mifepristone (RU486) treatment can interfere with cortisol signaling that can lead to suppression of tumor immunity. Here, we assessed whether treatment with RU486 in conjunction with an intratumor injection of Ad5IL-12 vector (a recombinant adenovirus expressing IL-12) could impact the TSLN microenvironment and prostate cancer progression.MethodsThe human PC3, LNCaP or murine TRAMP-C1 prostate cancer cell lines were used to generate subcutaneous tumors in NOD.scid and C57BL/6 mice, respectively. Adjuvant effects of RU486 were looked for in combination therapy with intratumor injections (IT) of Ad5IL-12 vector in comparison to PBS, DL70-3 vector, DL70-3 + RU486, RU486 and Ad5IL-12 vector treatment controls. Changes in tumor growth, cell cytotoxic activity and populations of CD4+/FoxP3+ T regulatory cells (Treg) in the TSLN were evaluated.ResultsTreatment of human PC3 prostate xenograft or TRAMP-C1 tumors with combination Ad5IL-12 vector and RU486 produced significantly better therapeutic efficacy in comparison to controls. In addition, we found that combination therapy increased the capacity of TSLN lymphocytes to produce Granzyme B in response to tumor cell targets. Finally, combination therapy tended towards decreases of CD4+/FoxP3+ T regulatory cell populations to be found in the TSLN.ConclusionInclusion of RU486 may serve as a useful adjuvant when combined with proinflammatory tumor killing agents by enhancement of the immune response and alteration of the TSLN microenvironment.

Non-Sentinel Node Risk Score (N-SNORE): A Scoring System for Accurately Stratifying Risk of Non-Sentinel Node Positivity in Patients With Cutaneous Melanoma With Positive Sentinel Lymph Nodes

Sentinel node (SN) biopsy allows identification of patients with melanoma at risk of further metastatic disease in regional non-sentinel nodes (NSN). We investigated clinicopathologic factors that predict NSN positivity in an attempt to identify patients who may be safely spared completion lymph node dissection (CLND). Clinicopathologic factors previously shown to be predictive of NSN positivity were analyzed in 409 patients with SN-positive disease (309 of whom underwent CLND) managed at a single melanoma center. A weighted score Non-Sentinel Node Risk Score [N-SNORE] incorporating predictive factors was derived, and the efficacy of N-SNORE at stratifying risk of NSN involvement was studied. Factors independently predictive of NSN positivity included primary tumor regression, proportion of harvested SNs involved by melanoma (%PosSN), sex (trend), and SN tumor burden indices (maximum size of largest deposit [MaxSize], % cross-sectional area of SN occupied by tumor, tumor penetrative depth, intranodal location of tumor) and perinodal lymphatic invasion (PLI). Of SN tumor burden criteria, MaxSize was the strongest predictor. N-SNORE was the sum of scores for five parameters: sex (female = 0, male = 1), regression (absent = 0, present = 2), %PosSN (absent = 0, present = 2), MaxSize (≤ 0.5 mm = 0, 0.51 to 2.00 mm = 1, 2.01 to 10.00 mm = 2, > 10.00 mm = 3), and PLI (absent = 0, present = 3). N-SNOREs of 0, 1 to 3, 4 to 5, 6 to 7, and ≥ 8 were associated with very low (0%), low (5% to 10%), intermediate (15% to 20%), high (40% to 50%), and very high (70% to 80%) risks of NSN involvement. A weighted score (N-SNORE) based on clinicopathologic characteristics accurately stratifies risk of NSN involvement in patients with melanoma. If validated in future studies, N-SNORE will better predict prognosis, aid in management decisions, and stratify patient groups for entry into clinical trials.

Re-evaluation of a Scoring System to Predict Nonsentinel-Node Metastasis and Prognosis in Melanoma Patients

We previously developed a scoring system based on patient age and total sentinel node (SN) tumor size to predict nonsentinel node (NSN) metastasis. The score relied on the cutoff values of 55 years for age and 5 mm total SN tumor size to stratify SN-positive patients into 3 categories. Its validity, however, remains in doubt given that it was developed by retrospective review of a single, relatively small cohort of SN-positive melanoma patients. The purpose of this study was to validate this scoring system and to determine its value in predicting patient survival. A review of melanoma patients who had undergone sentinel node biopsy and completion lymph node dissection (CLND) at the Melanoma Institute Australia from June 1992 until April 2009 was undertaken. The significance of the correlation of each of the score variables (age and total SN tumor size) with NSN metastasis, melanoma-specific survival, and overall survival was tested. Cox logistic regression analysis was used to determine the degree of correlation of the score system to each of the 3 outcomes. Six hundred six SN-positive patients were identified and included in this study. The score system did not significantly correlate with NSN metastasis (p = 0.1049). However, it did significantly correlate with both overall survival (p < 0.0001) and disease-specific survival (p = 0.0014). Our results revealed that the previously developed scoring system does not predict NSN metastasis; however, it was found to be a powerful predictive tool for overall and disease-free survival in SN-positive melanoma patients.

EORTC Melanoma Group sentinel node protocol identifies high rate of submicrometastases according to Rotterdam Criteria

Sentinel node (SN) status is the most important prognostic factor for disease-free survival (DFS) and overall survival (OS) in stages I–II melanoma. We evaluated the positive sentinel node identification rate of the EORTC Melanoma Group (MG) protocol as well as its capacity to identify minimal tumour burden, according to the Rotterdam Criteria in 421 consecutive patients. Correlations between primary tumour characteristics and SN tumour burden were investigated. The same 2 pathologists worked up all SNs according to the EORTC MG protocol and tumour burden was scored according to the Rotterdam Criteria (<0.1 mm, 0.1–1.0 mm and >1.0 mm for the largest diameter of the largest metastasis in the SN). The positive SN detection rate was 28.7% with a false negative rate of 10.4% at a median Breslow thickness of 2.1 mm. The high positive identification rate of about 30% of the EORTC MG protocol has been confirmed in this study. The protocol is sensitive and identifies submicrometastases (<0.1 mm) in a high percentage (18%). The variables SN tumour load, non-SN (NSN) status and ulceration of the primary were independent prognostic factors for DFS and OS in the multivariate analysis. At a median follow-up time of 4.3 years patients with minimal tumour burden (<0.1 mm) had a 5 year OS rate of 91%, virtually identical to 90% for SN-negative patients. The NSN positivity rate of 0% in these patients indicates that they may be spared a completion lymph node dissection (CLND) and its morbidity.