LN-negative Patients Research Articles

Multiscale deep learning framework captures systemic immune features in lymph nodes predictive of triple negative breast cancer outcome in large-scale studies.

The suggestion that the systemic immune response in lymph nodes (LNs) conveys prognostic value for triple-negative breast cancer (TNBC) patients has not previously been investigated in large cohorts. We used a deep learning (DL) framework to quantify morphological features in haematoxylin and eosin-stained LNs on digitised whole slide images. From 345 breast cancer patients, 5,228 axillary LNs, cancer-free and involved, were assessed. Generalisable multiscale DL frameworks were developed to capture and quantify germinal centres (GCs) and sinuses. Cox regression proportional hazard models tested the association between smuLymphNet-captured GC and sinus quantifications and distant metastasis-free survival (DMFS). smuLymphNet achieved a Dice coefficient of 0.86 and 0.74 for capturing GCs and sinuses, respectively, and was comparable to an interpathologist Dice coefficient of 0.66 (GC) and 0.60 (sinus). smuLymphNet-captured sinuses were increased in LNs harbouring GCs (p < 0.001). smuLymphNet-captured GCs retained clinical relevance in LN-positive TNBC patients whose cancer-free LNs had on average ≥2 GCs, had longer DMFS (hazard ratio [HR] = 0.28, p = 0.02) and extended GCs' prognostic value to LN-negative TNBC patients (HR = 0.14, p = 0.002). Enlarged smuLymphNet-captured sinuses in involved LNs were associated with superior DMFS in LN-positive TNBC patients in a cohort from Guy's Hospital (multivariate HR = 0.39, p = 0.039) and with distant recurrence-free survival in 95 LN-positive TNBC patients of the Dutch-N4plus trial (HR = 0.44, p = 0.024). Heuristic scoring of subcapsular sinuses in LNs of LN-positive Tianjin TNBC patients (n = 85) cross-validated the association of enlarged sinuses with shorter DMFS (involved LNs: HR = 0.33, p = 0.029 and cancer-free LNs: HR = 0.21 p = 0.01). Morphological LN features reflective of cancer-associated responses are robustly quantifiable by smuLymphNet. Our findings further strengthen the value of assessment of LN properties beyond the detection of metastatic deposits for prognostication of TNBC patients. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Discordance Between Conventional and Detailed Lymph Node Analysis in Resected, Node-negative Pancreatic or Ampullary Adenocarcinomas and Association With Adverse Survival Outcomes: A Single-institution Analysis.

To assess the frequency of occult metastases (OM) in patients with resected pancreatic ductal adenocarcinoma (PDAC) or ampullary adenocarcinoma (AA) discovered on detailed pathologic examination on lymph nodes (LNs) previously considered negative by conventional analysis and to examine the association between OM and overall survival (OS). Poor prognosis of patients with no pathologic evidence of LN metastases may be due to OM that is not detected on conventional LN analysis. Patients with LN-negative resected PDAC or AA (2010-2020) were identified from our institutional database. Original hematoxylin and eosin ( H and E ) slides were reanalyzed. In addition, selected LN were analyzed by H and E (3 sections/LN) and pan-cytokeratin (AE1-AE3/PCK26) immunohistochemistry. A total of 598 LNs from 74 LN-negative patients were reexamined. Nineteen patients (25.7%) had OM; 9 (47.4%) were found with immunohistochemistry but not on H and E . The number of positive LNs ranged from 1 to 3. No clinicodemographic, pathologic, or treatment-related factors were associated with OM. On conventional LN analysis, 3/19 patients (15.8%) had stage IA, 9/34 (26.5%) had stage IB, and 7/19 (36.8%) had stage IIA. On detailed LN analysis, 11/19 patients (57.9%) were upstaged to IIB, whereas 8/19 (42.1%) had isolated tumor cells only (N0i+). OM was associated with shorter OS (median OS: 22.3 vs 50.5 months; hazard ratio=3.95, 95% CI: 1.58-9.86). There is a 26% discordance rate between conventional and detailed LN pathologic analysis in resected PDAC and AA. The presence of OM is associated with shorter OS.

Association of lymph node metastases, grade and extent of mesenteric lymph node dissection in locoregional small intestinal neuroendocrine tumors with recurrence-free survival.

We aimed to assess the prognostic impact of tumor- and patient-related parameters in patients with stage I-III small intestinal neuroendocrine tumors (SI-NETs), who underwent locoregional resective surgery (LRS) with curative intent. We included 229 patients with stage I-III SI-NETs diagnosed from June 15, 1993, through March 8, 2021, identified using the SI-NET databases from five European referral centers. Mean ± SD age at baseline was 62.5 ± 13.6 years; 111/229 patients were women (49.3%). All tumors were well-differentiated; 160 were grade 1 (G1) tumors, 51 were G2, two were G3 and 18 tumors were of unspecified grade (median Ki-67: 2%, range 1%-50%). One-hundred and sixty-three patients (71.2%) had lymph node (LN) involvement. The median number of retrieved lymph nodes was 10 (0-63), whereas the median number of positive LNs was 2 (0-43). After a mean ± SD follow-up of 54.1 ± 64.1months, 60 patients experienced disease recurrence at a median (range) of 36.2 (2.5-285.1) months. The 5- and 10-year recurrence-free survival (RFS) rates were 66.6% and 49.3% respectively. In univariable analysis, there was no difference in RFS and overall survival (OS) between LN-positive and LN-negative patients (log-rank, p=.380 and .198, respectively). However, in stage IIIb patients who underwent mesenteric lymph node dissection (MLND) with a minimum of five retrieved LN (n=125), five or more LN metastases were associated with shorter RFS (median RFS [95% CI]=107.4 [0-229.6] vs. 73.7 [35.3-112.1]months; log-rank, p=.048). In addition, patients with G2 tumors exhibited shorter RFS compared to patients with G1 tumors (median RFS [95% confidence interval (CI)]=46.9 [36.4-57.3] vs. 120.7 [82.7-158.8]months; log-rank, p=.001). In multivariable Cox-regression RFS analysis in stage IIIb patients, the Ki-67 proliferation index (hazard ratio=1.08, 95% CI=1.035-1.131; p < .0001) and the number of LN metastases (hazard ratio=1.06, 95% CI=1.001-1.125; p=.047) were independent prognostic factors for RFS. In conclusion, LRS with a meticulous MLND and a minimum number of five harvested LNs appears to be critical in the surgical management of SI-NET patients with locoregional disease. In patients who underwent LRS and MLND, the Ki-67 proliferation index and the LN metastases count were independent predictors of RFS.

Effect of sentinel lymph node isolated tumor cells on recurrence free survival in patients with mismatch repair proficient vs. deficient stage I/II endometrioid endometrial adenocarcinoma (173)

Objectives: To assess associations between mismatch repair (MMR) status and recurrence-free survival (RFS) among early-stage endometrial cancer patients with and without isolated tumor cells (ITCs). Methods: We conducted a multi-institution, retrospective study of women with stage I/II endometrial cancer with endometrioid histology who underwent surgical staging with sentinel lymph node (SLN) mapping with or without completing the lymphadenectomy between 2016 and 2021. SLN mapping was performed following the NCCN SLN mapping guidelines. ITC patients and matched controls were identified through electronic medical records using keyword search. Patients were excluded if they had evidence of micro-or macro-metastases in any lymph node (LN). Categorical variables were analyzed using the Chi-square test and continuous variables were analyzed with Student’s t-test and the two-proportion Z-test. Kaplan–Meier method and log-rank tests were used for survival analysis. Results: Among 234 patients, 38 were found to have ITCs. The majority had grade 1 (82.1%), stage IA (67.0%), endometrioid adenocarcinoma. Overall, 22.2% of tumors were MMR deficient by immunohistochemistry. Patients with ITCs were more likely to demonstrate > 50% myometrial invasion (24.5% vs 52.5%, p=<0.001) and were more likely to receive adjuvant radiation therapy (14.8% vs 42.1%, p<0.001) and/or chemotherapy (2.6% vs 23.7%, p<0.001). Grade (p=0.923) and MMR status (p=0.850) were not significantly different between patients with ITCs and those with LN-negative disease. The Median follow-up time was 27 months. Overall, 11 patients we re diagnosed with recurrence (4.7%). The recurrence rate for patients with LN-negative disease was 4.6% (9/196) and the recurrence rate for ITC positive patients was 5.3% (2/38) (p=0.842). The 3-year RFS was 96% in patients with LN-negative disease and 88% in patients with ITC positive disease (log-rank p=0.712). Recurrence rates were comparable among patients with MMR proficient tumors, regardless of ITC status (LN-negative: 3.3% vs ITC-positive: 3.4%; p=0.975). This was also true among patients with MMR deficient tumors (LN-negative: 9.3% vs ITC-positive: 11.1%,p=0.175). RFS was not different between LN-negative and ITC-positive patients with MMR proficient tumors (log-rank p=0.846) as well as between LN-negative and ITC-positive patients with MMR deficient tumors (log-rank p=0.790). Conclusions: These preliminary data suggest that the presence of ITCs does not impact RFS in early-stage endometrial cancer patients with MMR proficient or MMR deficient tumors. However, a longer follow-up time and a larger sample size are needed to better explore the relationship between the presence of ITCs and tumor molecular characterization. Objectives: To assess associations between mismatch repair (MMR) status and recurrence-free survival (RFS) among early-stage endometrial cancer patients with and without isolated tumor cells (ITCs). Methods: We conducted a multi-institution, retrospective study of women with stage I/II endometrial cancer with endometrioid histology who underwent surgical staging with sentinel lymph node (SLN) mapping with or without completing the lymphadenectomy between 2016 and 2021. SLN mapping was performed following the NCCN SLN mapping guidelines. ITC patients and matched controls were identified through electronic medical records using keyword search. Patients were excluded if they had evidence of micro-or macro-metastases in any lymph node (LN). Categorical variables were analyzed using the Chi-square test and continuous variables were analyzed with Student’s t-test and the two-proportion Z-test. Kaplan–Meier method and log-rank tests were used for survival analysis. Results: Among 234 patients, 38 were found to have ITCs. The majority had grade 1 (82.1%), stage IA (67.0%), endometrioid adenocarcinoma. Overall, 22.2% of tumors were MMR deficient by immunohistochemistry. Patients with ITCs were more likely to demonstrate > 50% myometrial invasion (24.5% vs 52.5%, p=<0.001) and were more likely to receive adjuvant radiation therapy (14.8% vs 42.1%, p<0.001) and/or chemotherapy (2.6% vs 23.7%, p<0.001). Grade (p=0.923) and MMR status (p=0.850) were not significantly different between patients with ITCs and those with LN-negative disease. The Median follow-up time was 27 months. Overall, 11 patients we re diagnosed with recurrence (4.7%). The recurrence rate for patients with LN-negative disease was 4.6% (9/196) and the recurrence rate for ITC positive patients was 5.3% (2/38) (p=0.842). The 3-year RFS was 96% in patients with LN-negative disease and 88% in patients with ITC positive disease (log-rank p=0.712). Recurrence rates were comparable among patients with MMR proficient tumors, regardless of ITC status (LN-negative: 3.3% vs ITC-positive: 3.4%; p=0.975). This was also true among patients with MMR deficient tumors (LN-negative: 9.3% vs ITC-positive: 11.1%,p=0.175). RFS was not different between LN-negative and ITC-positive patients with MMR proficient tumors (log-rank p=0.846) as well as between LN-negative and ITC-positive patients with MMR deficient tumors (log-rank p=0.790). Conclusions: These preliminary data suggest that the presence of ITCs does not impact RFS in early-stage endometrial cancer patients with MMR proficient or MMR deficient tumors. However, a longer follow-up time and a larger sample size are needed to better explore the relationship between the presence of ITCs and tumor molecular characterization.

Lymph node dissection in thymic carcinomas and neuroendocrine carcinomas.

Although lymph node (LN) metastases are not uncommon in thymic carcinomas, preoperative LN evaluation, intraoperative lymph node dissection (LND) and postoperative outcomes remain unknown. The aim of this study was to elucidate the characteristics of and outcomes in patients with thymic carcinomas and thymic neuroendocrine carcinomas undergoing LND. A retrospective chart review was performed using our multi-institutional database to identify patients who underwent resection and LND for thymic carcinoma or thymic neuroendocrine carcinoma between 1991 and 2018. An enlarged mediastinal LN was defined as having a short-axis diameter >1 cm. We assessed survival outcomes using the Kaplan-Meier analysis. N1-level LND was performed in 41 patients (54.6%), N2-level LND in 14 patients (18.7%) and both-level LND in 16 patients (21.3%). Pathological LN metastasis was detected in 20 patients (26.7%) among the 75 patients undergoing LND. There was a significant difference in the number of LN stations (P = 0.015) and metastasis factor (P = 0.0042) between pathologically LN-positive and pathologically LN-negative patients. The sensitivity of enlarged LNs on preoperative computed tomography was 18.2%. There was a tendency towards worse overall survival of pathologically N2-positive patients, although the difference was not statistically significant (P = 0.15). Preoperative CT appears to play a limited role in detecting pathological LN metastases. Our findings suggest that the significance of N1- and N2-level LND should be evaluated in prospective studies to optimize the postoperative management of patients with thymic carcinomas and neuroendocrine carcinomas.

Abstract PS6-27: Secondary invasive breast events (SIBE) among patients with oncotype DX recurrence scores (RS) 26-30 and &amp;gt;31: Results from a large oncotype database

Abstract Background: Oncotype RS is a 21-gene assay used to predict the likelihood of distant recurrence and benefit of chemotherapy in patients with lymph node negative (LN-), hormone positive (HR+) breast cancer (BC). The Oncotype RS is used to identify patients who may be spared chemotherapy in the adjuvant setting without adverse impact on survival or secondary invasive breast events (SIBE). Results of the TAILORx trial (Sparano et al, 2018) provided evidence that chemotherapy can likely be spared for most patients with oncotype RS&amp;lt;25, with chemotherapy benefit potentially related to chemotherapy-induced menopause. More aggressive endocrine therapy with concurrent ovarian suppression in pre-menopausal women may mitigate the need for chemotherapy among patients with higher RS. We developed a large oncotype database to determine rates of SIBE (ipsilateral recurrence, contralateral breast cancer or metastatic recurrence) among patients with higher genomic risk (Oncotype RS 26-30 and &amp;gt; 31) to determine the benefit of chemotherapy among these groups. Methods:We identified 887 patients with early-stage, HR+ BC treated between 2006-2018. Among these patients, 515 had treatment and follow-up data available for SIBE analysis. Median follow-up for SIBE was 62 months with 41 SIBE (8%) including both LN+ and LN- patients. When stratified by RS using conservative cutoffs (Sparano et al, 2018): low risk (&amp;lt;10), intermediate risk (11-25), and high risk (&amp;gt;26), 5 year rates of SIBE were 4%, 6% and 16% respectively. The Kaplan Meier method was used to estimate the time to SIBE distributions overall and among different RS groups with the log rank test used to compare distributions between groups. Results: Among 887 patients, 616 (69%) were post-menopausal. A total of 654 (74%) patients had surgical management, of which 226 underwent mastectomy (35%) and 428 underwent lumpectomy (65%). Among the 630 patients who received adjuvant therapy, 14 (2%) received chemotherapy alone, 143 (23%) received a combination of chemotherapy/endocrine therapy and 473 (75%) received endocrine therapy alone. Twenty-four patients (3%) refused one or more recommended therapies. Three hundred fourteen patients (50%) also received radiation therapy. Rates of chemotherapy administration were 8% among low RS, 16% among intermediate RS and 82% among high RS patients (73% for RS 26-30 and 90% for RS &amp;gt;31). One-hundred eighty six of 887 patients were missing chemotherapy administration data as they were likely treated at another center. Patients with treatment data available and adequate follow up were included in the SIBE analysis (n=515). Among the 27 LN- patients with RS 26-30, twenty (74%) received chemotherapy and the remaining seven (26%) did not. The five year rate of SIBE was 25% among patients who received chemotherapy and 33% among those who did not receive chemotherapy; p=0.5489. Among the 23 LN negative patients with RS &amp;gt;31, twenty-one (91%) patients received chemotherapy and the remaining two (9%) did not. The five year rate of SIBE was 0% in both patients who received chemotherapy and in patients who did not receive chemotherapy; p-value not estimable in this subgroup due to no SIBE in either group. Conclusion: In this large oncotype database, there was no statistically significant difference in SIBE for patients with higher genomic risk (RS 26-30 and &amp;gt;31) whether or not they received chemotherapy. This data was limited by small numbers of patients in these sub-groups. More aggressive endocrine therapy with ovarian suppression has become an alternative option to spare chemotherapy in intermediate risk patients (RS 11-25). This approach may be useful among patients with even higher risk oncotype scores. Prospective randomized studies may be useful to determine utility of chemotherapy among patients with RS &amp;gt;26. Citation Format: Brittney S Zimmerman, Krystal Cascetta, Natalie Berger, Serena Tharakan, Kelly Suchman, Julia Blanter, Erin Moshier, Meng Ru, Shabnam Jaffer, Amy Tiersten. Secondary invasive breast events (SIBE) among patients with oncotype DX recurrence scores (RS) 26-30 and &amp;gt;31: Results from a large oncotype database [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-27.

Tumour-free distance: a novel prognostic marker in patients with early-stage cervical cancer treated by primary surgery

BackgroundModels predicting recurrence risk (RR) of cervical cancer are used to tailor adjuvant treatment after radical surgery. The goal of our study was to compare available prognostic factors and to develop a prognostic model that would be easy to standardise and use in routine clinical practice.MethodsAll consecutive patients with early-stage cervical cancer treated by primary surgery in a single referral centre (01/2007–12/2016) were eligible if assessed by standardised protocols for pre-operative imaging and pathology. Fifteen prognostic markers were evaluated in 379 patients, out of which 320 lymph node (LN)-negative.ResultsThe best predictive model for the whole cohort entailed a combination of tumour-free distance (TFD) ≤ 3.5 mm and LN positivity, which separated two subgroups with a substantially distinct RR 36% and 6.5%, respectively. In LN-negative patients, a combination of TFD ≤ 3.5 mm and adenosquamous tumour type separated a group of nine patients with RR 33% from the rest of the group with 6% RR.ConclusionsA newly identified prognostic marker, TFD, surpassed all traditional tumour-related markers in the RR assessment. Predictive models combining TFD, which can be easily accessed on pre-operative imaging, with LN status or tumour type can be used in daily practice and can help to identify patients with the highest RR.

Prognostic Impact of the Number of Examined Lymph Nodes in Stage II Colorectal Adenocarcinoma: A Retrospective Study.

Background Evaluation of lymph node status is critical in colorectal carcinoma (CRC) treatment. However, as patients with node involvement may be incorrectly classified into earlier stages if the examined lymph node (ELN) number is too small and escape adjuvant therapy, especially for stage II CRC. The aims of this study were to assess the impact of the ELN on the survival of patients with stage II colorectal cancer and to determine the optimal number. Methods Data from the US Surveillance, Epidemiology, and End Results (SEER) database on stage II resected CRC (1988-2013) were extracted for mathematical modeling as ELN was available since 1988. Relationship between ELN count and stage migration and disease-specific survival was analyzed by using multivariable models. The series of the mean positive LNs, odds ratios (ORs), and hazard ratios (HRs) were fitted with a LOWESS (Locally Weighted Scatterplot Smoothing) smoother, and the structural break points were determined by the Chow test. An independent cohort of cases from 2014 was retrieved for validation in 5-year disease-specific survival (DSS). Results An increased ELN count was associated with a higher possibility of metastasis LN detection (OR 1.010, CI 1.009-1.011, p < 0.001) and better DSS in LN negative patients (OR 0.976, CI 0.975-0.977, p < 0.001). The cut-off point analysis showed a threshold ELN count of 21 nodes (HR 0.692, CI 0.667-0.719, p < 0.001) and was validated with significantly better DSS in the SEER 2009 cohort CRC (OR 0.657, CI 0.522-0.827, p < 0.001). The cut-off value of the ELN count in site-specific surgeries was analyzed as 20 nodes in the right hemicolectomy (HR 0.674, CI 0.638-0.713, p < 0.001), 19 nodes in left hemicolectomy (HR 0.691, CI 0.639-0.749, p < 0.001), and 20 nodes in rectal resection patients (HR 0.671, CI 0.604-0.746, p < 0.001), respectively. Conclusions A higher number of ELNs are associated with more-accurate node staging and better prognosis in stage II CRCs. We recommend that at least 21 lymph nodes be examined for accurate diagnosis of stage II colorectal cancer.

Multidisciplinary Approach in Improving Survival Outcome of Early-Stage Gastric Cancer

BackgroundThe necessity of extensive lymph node (LN) dissection/examination and adjuvant therapy for patients with early gastric cancer (EGC, Tis-T1, any N) remains controversial. We aim to refine treatment recommendations for patients with EGC through a reflective analysis for the survival gap between Eastern and Western countries. MethodsEGC patients diagnosed between 2004 and 2014 were identified from the National Cancer Database (NCDB) and a large medical center in China. Adequate LN yield was defined as ≥25 LNs examined. ResultsIn the US cohort, 14.4% of (1104/7641) patients with EGC had ≥25 LNs examined. The 5-y overall survival (OS) was significantly better than those with <25 LNs (78.9% versus 68.5%, P < 0.001). Examination of ≥25 LNs was an independent predictor of better OS after adjusting all known prognostic factors. Patients with ≥25 LNs examined had significantly higher chance of having LN-positive disease compared to patients with <25 LNs (14.9% versus 10.7%, P < 0.001). A similar stage migration phenomenon was observed in Chinese cohort (LN positive: 25.2% versus 18.4% in ≥25 LNs and <25 LNs examined group, respectively, P = 0.02). In the US cohort, adjuvant therapy was associated with a significant survival benefit for LN-positive patients (5-y OS: 71.0% versus 43.0% for with/without adjuvant therapy, respectively, P < 0.001) but not in LN-negative patients (5-y OS: 71.2% versus 71.5%, P = 0.90). ConclusionsAdequate lymphadenectomy and LN examination are critical components of EGC management. Adjuvant therapy should be strongly encouraged for all EGC patients with LN-positive disease in the United States.

Chronic lymphocytic thyroiditis protects against recurrence in patients with cN0 papillary thyroid cancer

BackgroundChronic lymphocytic thyroiditis (CLT) frequently coexists with papillary thyroid carcinoma (PTC) that exhibits normal thyroid function. However, few studies have investigated the relationship between CLT and clinically lymph node (LN)-negative PTC. The aim of this study was to evaluate the relationship between subclinical central LN metastasis and CLT, and to assess the impact of CLT on the recurrence of clinically LN-negative PTC. MethodsWe investigated the medical records of 850 patients with PTC who underwent prophylactic bilateral central neck dissection as well as total thyroidectomy between 2004 and 2010; the median follow-up time was 95.5 months (range, 12–158 months). ResultsCLT was observed in 480 patients (56.5%). Female sex, a preoperative thyroid-stimulating hormone level >2.5 mU/L, a primary tumor ≤1 cm, no gross extrathyroidal extension, high number of harvested LNs, low number of metastatic LNs, and positive anti-thyroglobulin (Tg) antibody at 1 year post-initial treatment were significantly associated with the presence of CLT. Multivariate analysis revealed that patients with N1a stage (vs. N0 stage; hazard ratio [HR], 3.255; 95% confidence interval [CI], 1.290–8.213; p = 0.012) and positive anti-Tg antibody at 1 year post-initial treatment (vs. negative anti-Tg antibody; HR, 5.118; 95% CI, 2.130–12.296; p < 0.001) had poorer recurrence-free survival (RFS), while those with CLT (vs. no CLT; HR, 0.357; 95% CI, 0.157–0.812; p = 0.014) had favorable RFS outcomes. ConclusionsCLT is associated with less aggressive tumor characteristics and LN metastasis. Clinically LN-negative PTC patients with CLT experience longer RFS intervals than those without CLT.

Molecular lymph node staging for bladder cancer patients undergoing radical cystectomy with pelvic lymph node dissection

ObjectivePresence of lymph node (LN) metastasis in bladder cancer (BCa) is a main risk factor for tumor recurrence after radical cystectomy (RC). Molecular analysis facilitates detection of small-volume LN metastases with higher sensitivity than standard histopathology.The aim of the present study was to establish molecular LN analysis in BCa patients undergoing RC with lymph node dissection (LND) and to determine its ability to predict tumor recurrence. Patients and methodsFive transcripts with overexpression in BCa (FXYD3, KRT17, KRT20, SPINK1, UPKII) were evaluated for molecular LN analysis. We included 76 BCa patients from the prospective, randomized surgical phase-III trial (LEA AUO AB 25/02, NCT01215071) investigating extended vs. limited LND at RC. The primary endpoint was recurrence-free survival (RFS). As control, 136 LNs from 45 patients without BCa were analyzed to determine a threshold for pathologic gene expression. ResultsAbout 1,319 LNs were investigated with molecular and histopathologic examination. Histopathology detected 39 LN metastases in 17 (22%) patients. Of the tested genes FXYD3 performed best and classified all pN+-patients correctly as node-positive (pN+/molN+). In addition, FXYD3 reclassified 43 histopathologic negative LNs and 7 (9%) pN0-patients as molecular node-positive (pN0/molN+). Molecular and histopathologic LN status (pN0/molN0 vs. pN0/molN+ vs. pN+/molN+) was significantly associated with locally advanced disease (P = 0.006) and poor RFS (P < 0.001). Median RFS was not reached in LN-negative patients (pN0/molN0), 45 months (95%CI 8–83) in exclusively molecular positive patients (pN0/molN+) and 9 months (95%CI 5–13) in patients with histopathologic and molecular positive LNs (pN+/molN+). ConclusionsMolecular LN analysis with FXYD3 identified additional LN metastases in histopathologic negative LNs and identified patients with elevated risk of tumor recurrence after RC. Thus, molecular LN analysis improves LN staging and might serve as a tool to guide adjuvant treatment.

Multiple Level CT Radiomics Features Preoperatively Predict Lymph Node Metastasis in Esophageal Cancer: A Multicentre Retrospective Study.

Background: Lymph node (LN) metastasis is the most important prognostic factor in esophageal squamous cell carcinoma (ESCC). Traditional clinical factor and existing methods based on CT images are insufficiently effective in diagnosing LN metastasis. A more efficient method to predict LN status based on CT image is needed.Methods: In this multicenter retrospective study, 411 patients with pathologically confirmed ESCC were registered from two hospitals. Quantitative image features including handcrafted-, computer vision-(CV-), and deep-features were extracted from preoperative arterial phase CT images for each patient. A handcrafted-, CV-, and deep-radiomics signature were built, respectively. Then, multiple radiomics models were constructed by merging independent clinical risk factor into radiomics signatures. The performance of models were evaluated with respect to the discrimination, calibration, and clinical usefulness. Finally, an independent external validation cohort was used to validate the model's predictive performance.Results: Five, seven, and nine features were selected for building handcrafted-, CV-, and deep-radiomics signatures from extracted features, respectively. Those signatures were statistically significant different between LN-positive and LN-negative patients in all cohorts (p < 0.001). The developed multiple level CT radiomics model that integrates multiple radiomics signatures with clinical risk factor, was superior to traditional clinical factors and the results reported by existing methods, and achieved satisfactory discrimination performance with C-statistic of 0.875 in development cohort, 0.874 in internal validation cohort and 0.840 in independent external validation cohort. Nomogram and decision curve analysis (DCA) further confirmed our method may serve as an effective tool for clinicians to evaluate the risk of LN metastasis in patients with ESCC and further choose treatment strategy.Conclusions: The proposed multiple level CT radiomics model which integrate multiple level radiomics features into clinical risk factor can be used for preoperative predicting LN metastasis of patients with ESCC.

Is it possible to predict the prognostic values of Oncotype Dx using the results of web-based mathematical prognostic value models?

e12058 Background: The goal of the study was to determine whether the prognostic values for ER+ HER2- breast cancer can be calculated based on a test of gene expression profiles in tumors using Oncotype Dx or by entering clinicopathological factors into a web-based model. We evaluated the correlation between these results to shed light on whether the results from web-based models could serve as representative indices for Oncotype Dx. Patients: Two hundred two primary breast cancer patients whose prognostic value was evaluated using Oncotype Dx between May 2010 and October 2018 in St. Marianna University Hospital. Methods: The patients’ clinicopathological factors were extracted from their medical records. Then, the 5- and 10-year breast cancer-specific mortality rates were calculated using PREDICT (www.predict.nhs.uk/tool), while the 5–10 year distant recurrence rate was calculated using CTS5 (www.cts5-calculator.com/). The correlations with the Oncotype Dx prognostic values were evaluated by calculating the Spearman’s rank correlation coefficient, and JMP.ver13.0 (SAS Institute Inc., Cary, NC, USA) was employed for the analysis. Results: The patients’ median age was 49. There were 78 lymph node(LN)-negative patients and 124 LN-positive patients. For the disease stages, 51 patients were stage I, 99 patients were stage IIA, 41 patients were stage IIB, and 11 patients were stage III or above. All patients of the correlation between the Oncotype Dx recurrence score (RS) and the 10-year breast cancer-specific mortality rate was r = 0.1616. The correlation of LN-Negative patients of the 10-year distant recurrence rate between Oncotype Dx and CTS5 was r = 0.1768. The correlation of LN-Positive Cases of the 5-year distant recurrence rate between Oncotype Dx and CTS5 was r = 0.3374. The correlation of these cohort between the 5-year mortality rate from Oncotype Dx and PREDICT was r = 0.4298. Conclusions: There was no correlation between the Oncotype Dx RS and prognostic values calculated from web-based models, and there was also no correlation for prognostic values of lymph node-negative cases. However, there was a correlation for prognostic values of lymph node-positive cases, but the correlation was too weak to use the results from web-based models as representative indices for Oncotype Dx.

Defining the Role of Lymphadenectomy for Pancreatic Neuroendocrine Tumors: An Eight-Institution Study of 695 Patients from the US Neuroendocrine Tumor Study Group.

Preoperative factors that reliably predict lymph node (LN) metastases in pancreatic neuroendocrine tumors (PanNETs) are unclear. The number of LNs needed to accurately stage PanNETs has not been defined. Patients who underwent curative-intent resection of non-functional PanNETs at eight institutions from 2000 to 2016 were analyzed. Preoperative factors associated with LN metastases were identified. A procedure-specific target for LN retrieval to accurately stage patients was determined. Of 695 patients who underwent resection, 33% of tumors were proximal (head/uncinate) and 67% were distal (neck/body/tail). Twenty-six percent of patients (n = 158) had LN-positive disease, which was associated with a worse 5-year recurrence-free survival (RFS; 60% vs. 86%; p < 0.001). The increasing number of positive LNs was not associated with worse RFS. Preoperative factors associated with positive LNs included tumor size ≥ 2cm (odds ratio [OR] 6.6; p < 0.001), proximal location (OR 2.5; p < 0.001), moderate versus well-differentiation (OR 2.1; p = 0.006), and Ki-67 ≥ 3% (OR 3.1; p < 0.001). LN metastases were also present in tumors without these risk factors: < 2cm (9%), distal location (19%), well-differentiated (23%), and Ki-67 < 3% (16%). Median LN retrieval was 13 for pancreatoduodenectomy (PD), but only 9 for distal pancreatectomy (DP). Given that PD routinely includes a complete regional lymphadenectomy, a minimum number of LNs to accurately stage patients was not identified. However, for DP, removal of less than seven LNs failed to discriminate 5-year RFS between LN-positive and LN-negative patients (less than seven LNs: 72% vs. 83%, p = 0.198; seven or more LNs: 67% vs. 86%; p = 0.002). Tumor size ≥ 2cm, proximal location, moderate differentiation, and Ki-67 ≥ 3% are preoperative factors that predict LN positivity in resected non-functional PanNETs. Given the 9-23% incidence of LN metastases in patients without such risk factors, routine regional lymphadenectomy should be considered. PD inherently includes sufficient LN retrieval, while DP should aim to remove seven or more LNs for accurate staging.

A radiomics approach to predict lymph node metastasis and clinical outcome of intrahepatic cholangiocarcinoma.

This study was conducted in order to establish and validate a radiomics model for predicting lymph node (LN) metastasis of intrahepatic cholangiocarcinoma (IHC) and to determine its prognostic value. For this retrospective study, a radiomics model was developed in a primary cohort of 103 IHC patients who underwent curative-intent resection and lymphadenectomy. Radiomics features were extracted from arterial phase computed tomography (CT) scans. A radiomics signature was built based on highly reproducible features using the least absolute shrinkage and selection operator (LASSO) method. Multivariate logistic regression analysis was adopted to establish a radiomics model incorporating radiomics signature and other independent predictors. Model performance was determined by its discrimination, calibration, and clinical usefulness. The model was internally validated in 52 consecutive patients. The radiomics signature comprised eight LN-status-related features and showed significant association with LN metastasis in both cohorts (p < 0.001). A radiomics nomogram that incorporates radiomics signature and CA 19-9 level showed good calibration and discrimination in the primary cohort (AUC 0.8462) and validation cohort (AUC 0.8921). Promisingly, the radiomics nomogram yielded an AUC of 0.9224 in the CT-reported LN-negative subgroup. Decision curve analysis confirmed the clinical utility of this nomogram. High risk for metastasis portended significantly lower overall and recurrence-free survival than low risk for metastasis (both p < 0.001). The radiomics nomogram was an independent preoperative predictor of overall and recurrence-free survival. Our radiomics model provided a robust diagnostic tool for prediction of LN metastasis, especially in CT-reported LN-negative IHC patients, that may facilitate clinical decision-making. • The radiomics nomogram showed good performance for prediction of LN metastasis in IHC patients, particularly in the CT-reported LN-negative subgroup. • Prognosis of high-risk patients remains dismal after curative-intent resection. • The radiomics model may facilitate clinical decision-making and define patient subsets benefiting most from surgery.

The Prognostic Impact of the Aryl Hydrocarbon Receptor (AhR) in Primary Breast Cancer Depends on the Lymph Node Status.

Increasing evidence implicates the aryl hydrocarbon receptor (AhR) as a possible regulator of mammary carcinogenesis. This study aims to clarify its prognostic impact in breast cancer (BC). Meta-analyses performed at the mRNA level demonstrated that the predictive value of AhR expression in BC depends on the lymph node (LN) status. AhR expression and sub-cellular location were then analyzed by immunohistochemistry in 302 primary BC samples. AhR was expressed in almost 90% of cases with a predominant nuclear location. Nuclear and cytoplasmic AhR levels were significantly correlated and associated with the expression of RIP140 (receptor-interacting protein of 140 kDa), an AhR transcriptional coregulator and target gene. Interestingly, total and nuclear AhR levels were only significantly correlated with short overall survival in node-negative patients. In this sub-group, total and nuclear AhR expression had an even stronger prognostic impact in patients with low RIP140-expressing tumors. Very interestingly, the total AhR prognostic value was also significant in luminal-like BCs and was an independent prognostic marker for LN-negative patients. Altogether, this study suggests that AhR is a marker of poor prognosis for patients with LN-negative luminal-like BCs, which warrants further evaluation.

Poor prognostic and staging value of tumor deposit in locally advanced rectal cancer with neoadjuvant chemoradiotherapy.

Tumor deposit (TD) was associated with poor survival in colorectal cancer. However, its prognostic and staging value in locally advanced rectal cancer (LARC) patients following neoadjuvant chemoradiotherapy (neo‐CRT) is controversial. Four hundred and ninety‐five LARC patients following neo‐CRT and surgery were retrospectively analyzed. Univariate and multivariate analyses were performed using Kaplan‐Meier method and Cox proportional hazards regression in all lymph node (LN) ‐negative and LN‐positive patients. Next, we used three methods to classify the counts of LNs and TDs (oN, only LN counts; n1N, counts according to the N1c standards; n2N, total counts of LNs and TDs) to evaluate the impact of TD on N staging. TD‐positive patients were associated with more aggressive clinicopathological features. In multivariate analyses, TD was an independent poor prognostic factor of overall survival (OS), disease‐free survival (DFS), and local recurrence‐free survival in all patients. In LN‐negative patients, TD was an independent poor prognostic factor of OS, DFS and distant metastasis‐free survival (DMFS). In LN‐positive patients, TD has poor prognostic value only in patients with one positive LN. Three multivariate analyses according to three N staging methods showed that oN was not an independent prognostic factor, whereas n1N and n2N were independently associated with poor survival in OS, DFS and DMFS. The n2N method seemed to be better than n1N method. TD is an independent poor prognostic factor in LARC patients following neo‐CRT, especially in patients with no more than one positive LN. TD probably should be considered as one positive LN when performing N staging.

Abstract P2-07-07: Development of a machine learning-based classifier for Oncotype DX® category prediction in a population of lymph node positive breast carcinoma patients

Abstract INTRODUCTION: Oncotype DX® (ODX) Assay is a valuable prognostic and predictive tool in ER+, Her2- invasive breast cancer (IBC). Initially tested and validated in lymph node (LN) negative patients, the indications of this test have been expanded to include patients with limited LN-positive disease. Several prediction systems have been developed to predict the ODX Recurrence Score (RS) with substantial performance in predicting a high vs low RS score but with low performance when predicting the 3 classes that compose the standard ODX. Additionally, many of these prediction systems have not been developed and/or tested for a population of LN+ patients. OBJECTIVES: The primary objective of this study was to evaluate the performance of several previously published ODX RS predictive systems in a population of LN+ patients. Furthermore, we developed a machine-learning based classification system to accurately predict the ODX 3 category RS for this specific population. METHODS: We conducted a retrospective search of Stanford's pathology database for all patients with LN+ IBC diagnosed between January 2013 and December 2017 with an ODX RS available. A total of 119 patients were identified for inclusion in this cohort. Our multivariate pathologic feature-based discriminatory model aimed to classify each case as belonging to the low, intermediate or high ODX RS category. We performed model validation by the 10-fold cross validation (10F-CV) method. The model's performance was assessed by comparing simple accuracy, balanced accuracy, F1 score (harmonic average of the precision and recall) and several concordance classification metrics. RESULTS: Of the evaluated methods, Magee equations performed well in this population of LN+ patients with the modified Magee equation 2 displaying the best accuracy (70.9%) which was surprisingly better than originally reported (55.8%, in Klein et al. Mod Path. 2013). After an initial screen of methods and tuning of the best performing model, our model achieved an overall accuracy of 78.1% on 10F-CV with a 79.1 % balanced accuracy and no two-step discordances. This corresponded to an increase of weighted Cohen's kappa of 30% versus the best performing Magee equation in this cohort and an increase of 103% versus the modified Magee 1 equation (which uses the same features as our model except for tumor grade). DISCUSSION: Classifiers aimed at providing an alternative to Oncotype DX testing are available and perform consistently across datasets. We are currently validating our approach in a population of 1000 LN-negative patients from the MSKCC and the SEER database. Due to the substantial performance of our machine learning-based classifier based on standard reported pathologic features, our model may be considered an alternative to the ODX standard testing or a screening method for ODX testing, especially for cases with where the cost and availability of the ODX test are a concern. Citation Format: Beca F, Yang S-R, Gruber JG, Barry-Holson K, West R, Wen HY, Allison KH. Development of a machine learning-based classifier for Oncotype DX® category prediction in a population of lymph node positive breast carcinoma patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-07-07.

MiR-126: An indicator of poor prognosis and recurrence in histologically lymph node-negative gastric cancer.

Few biomarkers are available for the prediction of prognosis and recurrence in lymph node (LN)-negative gastric cancer (GC) currently. miR-126 functions as a tumor suppressor in GC, however, its clinical significance in LN-negative GC remains unknown. To investigate the associations of tissue miR-126 level with the clinicopathological characteristics and clinical outcome of LN-negative GC patients. Quantitative real-time polymerase chain reaction was performed to examine the tissue miR-126 level in 315 LN-negative GC patients who underwent curative gastrectomy with D2 lymphadenectomy. The associations of tissue miR-126 level with clinicopathological characteristics and clinical outcome were evaluated. Compared with matched adjacent non-tumor tissues, miR-126 expression was significantly down-regulated in tumor tissues. A reduced tissue miR-126 level statistically correlated with aggressive clinicopathological characteristics, including larger tumor size, deeper local invasion, and poorer prognosis. Notably, multivariate analysis identified advanced T stage and low miR-126 level as independent predictors of the unfavorable prognosis and recurrence of LN-negative GC. These results indicate for the first time that advanced T stage and low miR-126 level are predictors of unfavorable prognosis and recurrence in LN-negative GC patients. These parameters should be taken into account to stratify patients for adjuvant therapy and close follow-up.

A Radiomics Approach Predicts Lymph Node Metastasis and Clinical Outcomes in Intrahepatic Mass-Forming Cholangiocarcinoma

Background: To develop and validate a radiomics model for predicting lymph node (LN) metastasis in intrahepatic mass-forming cholangiocarcinoma (IMCC), and to determine its prognostic value. Methods: A radiomics model was developed in a primary cohort of 103 IMCC patients who underwent curative-intent resection and regional lymphadenectomy. Radiomic features were extracted from arterial-phase computed tomography (CT) scans. A radiomics signature was built based on high reproducible features using the Lasso method. Multivariate logistic regression analysis was adopted to establish a radiomics model incorporating radiomics signature and other independent predictors. Model performance was determined by its discrimination, calibration, and clinical usefulness. The model was internally validated in 52 consecutive patients. Findings: The radiomics signature comprised eight LN-status-related features and showed significant association with LN metastasis in both cohorts (P<0.001). A radiomics nomogram that incorporates radiomics signature and CA 19-9 level showed good calibration and discrimination in primary cohort (AUC 0.8462) and validation cohort (AUC 0.8921). Promisingly, the radiomics nomogram yielded an AUC of 0.9224 in CT-reported LN-negative subgroup. Decision curve analysis confirmed the clinical utility of this nomogram. High-risk metastasis portended significantly lower overall and recurrence-free survival than low-risk metastasis (both P<0.001). The radiomics nomogram represented an independent preoperative predictor of overall and recurrence-free survival. Interpretation: Our radiomics nomogram provides an individualized approach for preoperative detection of LN metastasis in IMCC patients, especially in CT-reported LN-negative patients. This model allows prediction of the metastasizing potential of IMCCs with poor prognosis even after curative-intent resection and thus may improve clinical decision-making. Funding: This study was supported by the Natural Science Foundation of China (81530048, 81470901, 81670570), and the Key research and development program of Jiangsu Province (BE2016789). Declaration of Interest: All authors declare no potential conflicts of interest. Ethical Approval: The ethics committee of Nanjing Medical University approved this retrospective analysis and waived the requirement for informed consent.