Background Numerous case studies have reported spontaneous regression of recognized metastases following primary tumor excision, but underlying mechanisms are elusive. Here, we present a model of regression and latency of metastases following primary tumor excision and identify potential underlying mechanisms. Results Using MDA-MB-231HM human breast cancer cells that express highly sensitive luciferase, we monitored early development stages of spontaneous metastases in BALB/c nu/nu mice. Removal of the primary tumor caused marked regression of micro-metastases, but not of larger metastases, and in vivo supplementation of tumor secretome diminished this regression, suggesting that primary tumor-secreted factors promote early metastatic growth. Correspondingly, MDA-MB-231HM-conditioned medium increased in vitro tumor proliferation and adhesion and reduced apoptosis. To identify specific mediating factors, cytokine array and proteomic analysis of MDA-MB-231HM secretome were conducted. The results identified significant enrichment of angiogenesis, growth factor binding and activity, focal adhesion, and metalloprotease and apoptosis regulation processes. Neutralization of MDA-MB-231HM-secreted key mediators of these processes, IL-8, PDGF-AA, Serpin E1 (PAI-1), and MIF, each antagonized secretome-induced proliferation. Moreover, their in vivo simultaneous blockade in the presence of the primary tumor arrested the development of micro-metastases. Interestingly, in the METABRIC cohort of breast cancer patients, elevated expression of Serpin E1, IL-8, or the four factors combined predicted poor survival. Conclusions These results demonstrate regression and latency of micro-metastases following primary tumor excision and a crucial role for primary tumor secretome in promoting early metastatic growth in MDA-MB-231HM xenografts. If generalized, such findings can suggest novel approaches to control micro-metastases and minimal residual disease.

Numerous case studies have reported spontaneous regression of recognized metastases following primary tumor (PT) excision, but underlying mechanisms are elusive. Here we present a model of metastases regression and latency following PT excision, and identify potential underlying mechanisms. Using MDA-MB-231 HM human breast cancer cells that 5 express highly sensitive luciferase, we were able to monitor early stages of spontaneous metastases development in BALB/c nu/nu mice. Removal of the PT caused marked regression of the smallest micro-metastases, but not of larger metastases, and in vivo supplementation of tumor secretome diminished this regression, suggesting that PTsecreted factors promote early metastatic growth. Correspondingly, cancer cell conditioned 10 medium reduced apoptosis and enhanced MDA-MB-231 HM adhesion in vitro. To identify specific mediating factors, cytokine array and proteomic analysis of MDA-MB-231 HM secretome were conducted. Results identified significant enrichment of angiogenesis, growth factors binding and activity, focal adhesion, metalloprotease regulation, and apoptosis regulation processes. Simultaneous in vivo blockade of four secreted key 15 potential mediators of these processes, IL-8, PDGFaa, Serpin E1 (PAI-1), and MIF, arrested development of micro-metastases in the presence of the PT. Interestingly, using the public TCGA provisional dataset, high protein levels of these four factors were correlated with poor survival in a cohort of lung adenocarcinoma patients. These results demonstrate regression and latency of micro-metastases following PT excision, and a 20 crucial role for PT-secretome in promoting early metastatic stages in MDA-MB-231 HM xenografts. If generalized, such findings can suggest novel approaches to control minimal residual disease during and following PT excision.

Objective: In the era of widespread resistance, there are 2 time points at which most empiric prescription errors occur among hospitalized adults: (1) upon admission (UA) when treating patients at risk of multidrug-resistant organisms (MDROs) and (2) during hospitalization, when treating patients at risk of extensively drug-resistant organisms (XDROs). These errors adversely influence patient outcomes and the hospital’s ecology. Design and setting: Retrospective cohort study, Shamir Medical Center, Israel, 2016. Patients: Adult patients (aged >18 years) hospitalized with sepsis. Methods: Logistic regressions were used to develop predictive models for (1) MDRO UA and (2) nosocomial XDRO. Their performances on the derivation data sets, and on 7 other validation data sets, were assessed using the area under the receiver operating characteristic curve (ROC AUC). Results: In total, 4,114 patients were included: 2,472 patients with sepsis UA and 1,642 with nosocomial sepsis. The MDRO UA score included 10 parameters, and with a cutoff of ≥22 points, it had an ROC AUC of 0.85. The nosocomial XDRO score included 7 parameters, and with a cutoff of ≥36 points, it had an ROC AUC of 0.87. The range of ROC AUCs for the validation data sets was 0.7–0.88 for the MDRO UA score and was 0.66–0.75 for nosocomial XDRO score. We created a free web calculator (https://assafharofe.azurewebsites.net). Conclusions: A simple electronic calculator could aid with empiric prescription during an encounter with a septic patient. Future implementation studies are needed to evaluate its utility in improving patient outcomes and in reducing overall resistances.

An amendment to this paper has been published and can be accessed via the original article.