Does Angiosarcoma of the Breast Need Nodal Staging?

Breast angiosarcoma is a rare malignancy classically associated with hematogenous metastases. We sought to determine the prevalence of pathologic nodal involvement in patients with nonmetastatic, resected breast angiosarcoma and its association with overall survival. The National Cancer Database was used to identify patients with nonmetastatic angiosarcoma of the breast who underwent surgical resection from 2004 to 2017. The prevalence of regional lymph node operation and nodal positivity was calculated. The Kaplan-Meier method was used to evaluate overall survival among node-positive and node-negative patients. Cox proportional hazard modeling was used to evaluate the adjusted association of nodal positivity with overall survival. We included 991 patients with angiosarcoma. The median age was 69 years (interquartile range 57 to 78), and the cohort was 99% female. A total of 298 patients (30%) had pathologic regional nodal evaluation. Of those, 15 (5.0%) had positive regional lymph nodes. Node-positive patients had significantly worse survival than patients with negative regional lymph nodes. After adjusting for patient, tumor, and treatment factors, a positive regional lymph node was associated with worse overall survival compared with patients with no nodal evaluation (hazard ratio 3.20; 95% CI 1.75 to 5.86; p < 0.001). Patients with nonmetastatic angiosarcoma of the breast have a 5% regional lymph node positivity rate, which is at a common threshold to consider evaluation, and identifies patients with poor survival. A prospective study to determine performance characteristics of sentinel lymph node biopsy is warranted

Differential effects of VEGFR-1 and VEGFR-2 inhibition on tumor metastases based on host organ environment

Tumors induce new blood vessel growth primarily from host organ microvascular endothelial cells (ECs), and microvasculature differs significantly between the lung and liver. Vascular endothelial growth factor (VEGF or VEGF-A) promotion of tumor angiogenesis is thought to be mediated primarily by VEGF receptor (VEGFR) 2. In this study, VEGFR-2 antibody (DC101) inhibited growth of RenCa renal cell carcinoma lung metastases by 26% while VEGFR-1 antibody (MF-1) had no effect. However, VEGFR-2 neutralization had no effect on RenCa liver metastases while VEGFR-1 neutralization decreased RenCa liver metastases by 31%. For CT26 colon carcinoma liver metastases, inhibition of both VEGFR-1 and VEGFR-2 was required to induce growth delay. VEGFR-1 or VEGFR-2 inhibition decreased tumor burden not by preventing the establishment of micrometastases but rather by preventing vascularization and growth of micrometastases by 55% and 43%, respectively. VEGF induced greater phosphorylation of VEGFR-2 in lung ECs and of VEGFR-1 in liver ECs. EC proliferation, migration, and capillary tube formation in vitro were suppressed more by VEGFR-2 inhibition for lung EC and more by VEGFR-1 inhibition for liver EC. Collectively, our results indicate that liver metastases are more reliant on VEGFR-1 than lung metastases to mediate angiogenesis due to differential activity of VEGFRs on liver EC versus lung EC. Thus, therapies inhibiting specific VEGF receptors should consider the targeted sites of metastatic disease

New Metastatic Lymph Node Ratio System Reduces Stage Migration in Patients Undergoing D1 Lymphadenectomy for Gastric Adenocarcinoma

Background: The American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) staging system for gastric cancer incorporates the absolute number of metastatic lymph nodes (N status) and is optimally used when ≥15 nodes are examined. The ratio of metastatic to examined nodes (N ratio) is an effective prognostic tool, but has not been examined in Western patients undergoing primarily D1 lymphadenectomy. Methods: Two hundred and fifty seven patients with gastric adenocarcinoma who underwent gastric resection between 1995 and 2005 at our institution were examined. Novel N ratio intervals were determined using the best cutoff approach (Nr0: N ratio = 0 and ≥15 nodes examined; Nr1: 0 ≤ N ratio ≤ 0.3; Nr2: 0.3 0.7). Overall survival was examined according to N status and N ratio. Results: 83% of patients underwent D1 lymphadenectomy with a median of 14 lymph nodes examined. Overall survival stratified by N status was significantly different in patients with <15 nodes examined compared with those with ≥15 nodes examined. When we stratified by N ratio intervals, there was no significant difference in overall survival in patients with <15 versus ≥ 15 nodes examined. On multivariate analysis, N ratio but not N status was retained as an independent prognostic factor. Conclusions: The use of N status for staging patients undergoing primarily D1 lymphadenectomy results in significant stage migration due to varying numbers of nodes examined. Use of N ratio reduces stage migration and may be a more reliable method of staging these patients

Comparison of a Lymph Node Ratio–Based Staging System With the 7th AJCC System for Gastric Cancer

OBJECTIVES: The American Joint Committee on Cancer (AJCC) staging system for gastric cancer bases N status on absolute number of metastatic nodes, regardless of the number of examined nodes. We examined a modified staging system utilizing node ratio (Nr), the ratio of metastatic to examined nodes. METHODS: A total of 18,043 gastric cancer patients who underwent gastrectomy were identified from the US Surveillance, Epidemiology, and End Results (SEER) database. A training set was divided into 5 Nr groups, and a TNrM staging system was constructed. Median survival and overall survival, based on 7th edition AJCC and TNrM staging systems, were compared, and the analysis was repeated in a validation set. RESULTS: Median examined nodes were 10 to 11. For the training set, overall survival for all 5 AJCC N categories was significantly different when subgrouped into 15 or fewer versus more than 15 examined nodes, but overall survival was similar regardless of the number of examined nodes in 4 of 5 Nr categories. Seven AJCC stages had statistically different overall survival between subgroups, whereas only 1 TNrM stage had statistically different overall survival between subgroups. When misclassification was defined as any subgroup in which median survival fell outside the 95% confidence interval of the group's overall median survival, AJCC staging misclassified 57% of patients and TNrM staging misclassified only 12%. Similar results were found in the validation set. CONCLUSIONS: The AJCC system classifies SEER gastric cancer patients into stages in which subgroups often have wide variations in survival. For patients undergoing limited lymph node analysis, the proposed TNrM system may predict survival more accurately

Differential Effects of VEGFR-1 and VEGFR-2 Inhibition on Tumor Metastases Based on Host Organ Environment

Tumors induce new blood vessel growth primarily from host organ microvascular endothelial cells (ECs), and microvasculature differs significantly between the lung and liver. Vascular endothelial growth factor (VEGF or VEGF-A) promotion of tumor angiogenesis is thought to be mediated primarily by VEGF receptor (VEGFR) 2. In this study, VEGFR-2 antibody (DC101) inhibited growth of RenCa renal cell carcinoma lung metastases by 26% while VEGFR-1 antibody (MF-1) had no effect. However, VEGFR-2 neutralization had no effect on RenCa liver metastases while VEGFR-1 neutralization decreased RenCa liver metastases by 31%. For CT26 colon carcinoma liver metastases, inhibition of both VEGFR-1 and VEGFR-2 was required to induce growth delay. VEGFR-1 or VEGFR-2 inhibition decreased tumor burden not by preventing the establishment of micrometastases but rather by preventing vascularization and growth of micrometastases by 55% and 43%, respectively. VEGF induced greater phosphorylation of VEGFR-2 in lung ECs and of VEGFR-1 in liver ECs. EC proliferation, migration, and capillary tube formation in vitro were suppressed more by VEGFR-2 inhibition for lung EC and more by VEGFR-1 inhibition for liver EC. Collectively, our results indicate that liver metastases are more reliant on VEGFR-1 than lung metastases to mediate angiogenesis due to differential activity of VEGFRs on liver EC versus lung EC. Thus, therapies inhibiting specific VEGF receptors should consider the targeted sites of metastatic disease

D2 Lymphadenectomy with Surgical Ex Vivo Dissection into Node Stations for Gastric Adenocarcinoma Can Be Performed Safely in Western Patients and Ensures Optimal Staging

BACKGROUND: The AJCC recommends examination of >16 nodes to stage gastric adenocarcinoma. D2 lymphadenectomy (LAD) followed by surgical ex vivo dissection (SEVD) into nodal stations is standard at many high-volume Asian centers, but potential increases in morbidity and mortality have slowed adoption of D2 LAD in some Western centers. METHODS: A total of 331 patients with gastric adenocarcinoma who underwent surgical resection at one Western institution from 1995 to 2010 were examined. RESULTS: Median age of patients was 69 years old, 65% were male, and 84% were white. D1 LAD was performed in 285 patients (86%) and D2 LAD in 46 patients (14%), with SEVD being performed in 17 patients (37%) in the D2 group. D2 LAD with or without SEVD was performed much more commonly between 2006 and 2010. For the D1, D2 without SEVD, and D2 with SEVD groups, the median number of examined nodes and percentage with >16 examined nodes were 16 and 51%, 27 and 93%, and 40 and 100%, respectively. Major complications occurred in 16% of the D1 group and 17% of the D2 group (p>0.05), and 30-day mortality was 3% for the D1 group and 0% for the D2 group. D2 LAD was a positive prognostic factor for overall survival on univariate (p=0.027) and multivariate analyses (p=0.005), but there were several possible confounding variables. CONCLUSIONS: D2 LAD at our Western institution was performed with low morbidity and no mortality. Optimal staging occurred after D2 LAD combined with SEVD, where a median of 40 nodes were examined and all patients had >16 examined nodes

Automated machine learning (AutoML) can predict 90-day mortality after gastrectomy for cancer

Abstract Early postoperative mortality risk prediction is crucial for clinical management of gastric cancer. This study aims to predict 90-day mortality in gastric cancer patients undergoing gastrectomy using automated machine learning (AutoML), optimize models for preoperative prediction, and identify factors influential in prediction. National Cancer Database was used to identify stage I–III gastric cancer patients undergoing gastrectomy between 2004 and 2016. 26 features were used to train predictive models using H2O.ai AutoML. Performance on validation cohort was measured. In 39,108 patients, 90-day mortality rate was 8.8%. The highest performing model was an ensemble (AUC = 0.77); older age, nodal ratio, and length of inpatient stay (LOS) following surgery were most influential for prediction. Removing the latter two parameters decreased model performance (AUC 0.71). For optimizing models for preoperative use, models were developed to first predict node ratio or LOS, and these predicted values were inputted for 90-day mortality prediction (AUC of 0.73–0.74). AutoML performed well in predicting 90-day mortality in a larger cohort of gastric cancer patients that underwent gastrectomy. These models can be implemented preoperatively to inform prognostication and patient selection for surgery. Our study supports broader evaluation and application of AutoML to guide surgical oncologic care

Proton-Beam, Intensity-Modulated, and/or Intraoperative Electron Radiation Therapy Combined with Aggressive Anterior Surgical Resection for Retroperitoneal Sarcomas

BACKGROUND: We sought to reduce local recurrence for retroperitoneal sarcomas by using a coordinated strategy of advanced radiation techniques and aggressive en-bloc surgical resection. METHODS: Proton-beam radiation therapy (PBRT) and/or intensity-modulated radiation therapy (IMRT) were delivered to improve tumor target coverage and spare selected adjacent organs. Surgical resection of tumor and adjacent organs was performed to obtain a disease-free anterior margin. Intraoperative electron radiation therapy (IOERT) was delivered to any close posterior margin. RESULTS: Twenty patients had primary tumors and eight had recurrent tumors. Tumors were large (median size 9.75 cm), primarily liposarcomas and leiomyosarcomas (71%), and were mostly of intermediate or high grade (81%). PBRT and/or IMRT were delivered to all patients, preferably preoperatively (75%), to a median dose of 50 Gy. Surgical resection included up to five adjacent organs, most commonly the colon (n = 7) and kidney (n = 7). Margins were positive for disease, usually posteriorly, in 15 patients (54%). IOERT was delivered to the posterior margin in 12 patients (43%) to a median dose of 11 Gy. Surgical complications occurred in eight patients (28.6%), and radiation-related complications occurred in four patients (14%). After a median follow-up of 33 months, only two patients (10%) with primary disease experienced local recurrence, while three patients (37.5%) with recurrent disease experienced local recurrence. CONCLUSIONS: Aggressive resection of retroperitoneal sarcomas can achieve a disease-negative anterior margin. PBRT and/or IMRT with IOERT may possibly deliver sufficient radiation dose to the posterior margin to control microscopic residual disease. This strategy may minimize radiation-related morbidity and reduce local recurrence, especially in patients with primary disease

DNA Damage Repair Classifier Defines Distinct Groups in Hepatocellular Carcinoma

DNA repair pathways have been associated with variability in hepatocellular carcinoma (HCC) clinical outcomes, but the mechanism through which DNA repair varies as a function of liver regeneration and other HCC characteristics is poorly understood. We curated a panel of 199 genes representing 15 DNA repair pathways to identify DNA repair expression classes and evaluate their associations with liver features and clinicopathologic variables in The Cancer Genome Atlas (TCGA) HCC study. We identified two groups in HCC, defined by low or high expression across all DNA repair pathways. The low-repair group had lower grade and retained the expression of classical liver markers, whereas the high-repair group had more clinically aggressive features, increased p53 mutant-like gene expression, and high liver regenerative gene expression. These pronounced features overshadowed the variation in the low-repair subset, but when considered separately, the low-repair samples included three subgroups: L1, L2, and L3. L3 had high DNA repair expression with worse progression-free (HR 1.24, 95% CI 0.81&ndash;1.91) and overall (HR 1.63, 95% CI 0.98&ndash;2.71) survival. High-repair outcomes were also significantly worse compared with the L1 and L2 groups. HCCs vary in DNA repair expression, and a subset of tumors with high regeneration profoundly disrupts liver biology and poor prognosis