Hypoxia derived exosomes promote the proliferation and metastasis of colorectal cancer through the regulation of HIF-1α/miR-4299/ZBTB4.

AIMS: The biological functions of colorectal cancer (CRC) cell derived exosomes responding to hypoxic microenvironment and its underlying mechanisms remain unclear. MAIN METHODS: Extracted exosomes were confirmed. CRC cells were incubated with hypoxic and normoxic exosomes and its biological behavior were analyzed. miRNA microarray were conducted. Cells were incubated with miRNAs mimics, inhibitors, or small interfering RNAs; expression of reporter constructs was measured in luciferase assays. Cells were transfected with Lentivirus vectors containing eGFP-miR-4299 overexpression (or ZBTB4 siRNA expression plasmid) and they were injected into BALB/C nude mice subcutaneously or by tail vein and the growth of xenograft tumors or lung metastasis were measured. The clinical significance of ZBTB4 was measured in tumor tissues and adjacent non-tumor tissues. KEY FINDINGS: Hypoxic exosomes could tranfer to the recipient normoxic cells and promote the cell proliferation and migration. We found several miRNAs were significantly up-regulated in hypoxic exosomes and the expression levels of miR-4299 increased in both hypoxic cells and hypoxic exosomes. We observed that miR-4299 was upregulated in a HIF-1α dependent way. In addition, ectopic expression of miR-4299 promoted the tumor growth and metastasis in vitro and in vivo. ZBTB4, an identified direct target of miR-4299, could abrogate the effect on tumor growth and distant metastasis. The expression of ZBTB4 were decreased in tumor tissues compared with non-tumor colon tissues from patients. SIGNIFICANCE: We demonstrated that in response to hypoxia, CRC cells had an increased production of exosomes. The hypoxia derived exosomes promote the proliferation and metastasis of colorectal cancer by exporting miR-4299 and modulating its target gene ZBTB4.

Adequate Number of Lymph Nodes Sampled May Determine Appropriate Surgical Modality for Early-Stage NSCLC: A Population-Based Real-World Study.

BACKGROUND: The standard surgical procedure for ≤ 2 cm non-small cell lung cancer (NSCLC), including the number of lymph nodes sampled (nLN) and surgical modality, remains controversial. This study was designed to determine the optimal cohort in which sublobectomy could be an alternative to lobectomy. MATERIALS (OR PATIENTS) AND METHODS: Patients from 1998 to 2017 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The optimal cutoff value of nLN was identified using a restrictive cubic spline graph (RCS). Kaplan-Meier analysis was used to determine cancer-specific survival (CSS). The COX proportional hazard regression model was used to identify the influence of clinical and demographic variables on survival, and propensity score matching (PSM) was used to balance differences in baseline characteristics. Finally, we used an external cohort from a single-center medical institution to verify the conclusions drawn from the SEER database. RESULTS: A total of 6150 patients were included. The sublobectomy subgroup included segmentectomy (308, 5.0%) and wedge resection (1611, 26.2%). The cutoff value for nLN was 7. In the nLN ≥7 subgroup of the PSM cohort, the CSS of segmentectomy and wedge resection was close to that of the lobectomy subgroup (P = .12), whereas in the nLN <7 subgroup, the CSS of the lobectomy subgroup was significantly higher than that of the sublobectomy with P < .001). Surgical methods, nLN, age, sex, and differentiated grade were independent predictors of CSS. External cohort validation: A total of 1106 patients from the Affiliated Jinhua Hospital of Zhejiang University School of Medicine between 2013 and 2020 were included. The grouping criteria were consistent with the SEER database. In the nLN≥7 subgroup, sublobectomy had a survival outcome similar to that of lobectomy (P = .81). CONCLUSION: Sublobectomy and nLN < 7 were strongly associated with poorer CSS for early-stage NSCLC. On the premise of nLN ≥ 7, sublobectomy could provide similar survival outcomes to lobectomy for these patients.

Estrogen receptor-negative/progesterone receptor-positive and her-2-negative breast cancer might no longer be classified as hormone receptor-positive breast cancer.

BACKGROUND: The single progesterone receptor (PR)-positive phenotype (estrogen receptor (ER)-/PR + , sPR positive) is an infrequent and independent biological entity. However, the prognosis of patients with sPR-positive and her-2-negative phenotype is still controversial, and it is not always easy to decide treatment strategies for them. METHODS: Patients during 2010-2014 were identified from Surveillance, Epidemiology, and End Results (SEER) database. The Kaplan-Meier method was used to evaluate cancer-specific survival (CSS). The propensity score matching (PSM) method was used to balance differences of characteristics in groups. The Life-Table method was used to calculate 5-year CSS rates and the annual hazard rate of death (HRD). RESULTS: A total of 97,527 patients were included, and only 745 (0.76%) patients were sPR-positive phenotype. The majority of sPR-positive breast cancer were basal-like subtype. Survival analysis showed that the sPR-positive breast cancer had similar prognosis comparing to double hormonal receptor-negative (ER-/PR-, dHoR-negative) breast cancer, and had the highest HRD during the initial 1-2 years of follow-up, then maintained the HRD of almost zero during the late years of follow-up. CONCLUSIONS: The patients with sPR-positive and her-2-negative breast cancer, similar to dHoR-negative breast cancer, had a worse survival, and could benefit from chemotherapy significantly. However, the escalating endocrine therapy was not recommended for sPR-positive patients. The patients with sPR positive should be excluded from future clinical trials concerning endocrine therapy.

Competing Nomogram for Late-Period Breast Cancer-Specific Death in Patients with Early-Stage Hormone Receptor-Positive Breast Cancer.

BACKGROUND: More than half of early breast cancer recurrences occur after 5 years from the initial diagnosis. An individualized estimate of the risk of late-period breast cancer-specific death (LP-BCSD) after 5 years of endocrine therapy (ET) can improve decision-making for extended endocrine therapy (EET). MATERIALS AND METHODS: A total of 147,059 eligible patients with breast cancer who survived 5+ years after diagnosis between 1990 and 2007 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate analyses based on the competing risk regression model were used to evaluate predictive factors for high risk of LP-BCSD or late-period non-breast cancer-specific death (LP-non-BCSD). Significant factors were used to build a nomogram to individualize estimates of LP-BCSD or LP-non-BCSD. RESULTS: The 5- and 10-year LP-BCSD rates were 5.7% and 10.1%, respectively, and the 5- and 10-year LP-non-BCSD rates were 6.7% and 15.5%, respectively. Young age, black race, single marital status, poor differentiation, large tumor size, lymph node metastasis, and estrogen receptor-positive/progesterone receptor-negative (ER+/PR-) status were independent predictive factors for high risk of LP-BCSD. Age was the most important factor for predicting high risk of LP-non-BCSD. The nomograms, which were based on significant factors identified by the competing risk regression model. A risk score system based on the competing risk nomogram was established to describe the relative risk of LP-BCSD and LP-non-BCSD. CONCLUSION: This study explored the novel endpoint of LP-BCSD for further clinical trials. The risk score system might be highly useful for patient counseling, especially in discussing EET options with elderly or comorbid patients.

A clinical model to predict distant metastasis in patients with superficial gastric cancer with negative lymph node metastasis and a survival analysis for patients with metastasis.

BACKGROUND: Distant metastasis (DM) is relatively rare in superficial gastric cancer (SGC), especially in patients without lymph node metastasis. This study aimed to explore the main clinical risk factors for DM in patients with superficial gastric cancer-no lymph node metastasis (SGC-NLNM) and the prognostic factors for patients with DM. METHODS: Records of patients with SGC-NLNM between 2004 and 2015 were collected from the public Surveillance, Epidemiology, and End Results (SEER) database. Both univariate and multivariate logistic regressions were performed to analyze the clinical risk factors for DM. The Kaplan-Meier method and Cox regression model were used to identify prognostic factors for patients with DM. A nomogram was built based on multivariate logistic regression and evaluated by the C-index, the calibration, and the area under the receiver operating characteristic curve (AUC). RESULTS: We developed and validated a nomogram to predict DM in patients with SGC-NLNM, showing that race, age, primary site, depth, size, and grade were independent risk factors. The built nomogram had a good discriminatory performance, with a C-index of 0.836 (95% confidence interval [CI]: 0.813-0.859). Calibration plots showed that the predicted DM probability was identical to the actual observations in both the training and validation sets. AUC was 0.846 (95% CI: 0.820-0.871) and 0.801 (95% CI: 0.751-0.850) in the training and validation sets, respectively. The results of the survival analysis revealed that surgery (hazard ratio [HR] = 0.249; 95% CI, 0.125-0.495), chemotherapy (HR = 0.473; 95% CI, 0.353-0.633), and grade (HR = 1.374; 95% CI, 1.018-1.854) were independent prognostic factors associated with cancer-specific survival (CSS), but radiotherapy was not (log-rank test, p = 0.676). CONCLUSIONS: We constructed a sensitive and discriminative nomogram to identify high-risk patients with SGC-NLNM who may harbor dissemination at initial diagnosis. The tumor size and primary site were the largest contributors to DM prediction. Compared with radiotherapy, aggressive surgery, and chemotherapy may be better options for patients with DM.

Establishing a Competing Risk Regression Nomogram Model for Survival Data.

The Kaplan-Meier method and Cox proportional hazards regression model are the most common analyses in the survival framework. These are relatively easy to apply and interpret and can be depicted visually. However, when competing events (e.g., cardiovascular and cerebrovascular accidents, treatment-related deaths, traffic accidents) are present, the standard survival methods should be applied with caution, and real-world data cannot be correctly interpreted. It may be desirable to distinguish different kinds of events that may lead to the failure and treat them differently in the analysis. Here, the methods focus on using the competing regression model to identify significant prognostic factors or risk factors when competing events are present. Additionally, nomograms based on a proportional hazard regression model and a competing regression model are established to help clinicians make individual assessments and risk stratifications in order to explain the impact of controversial factors on prognosis.

Early T Stage Is Associated With Poor Prognosis in Patients With Metastatic Liver Colorectal Cancer.

Clinically, a considerable portion of patients with early T stage who were supposed to have a low distant metastatic probability were diagnosed with metastatic liver colorectal cancer (CRLM). Our study aims to evaluate the prognostic value of the T stage for metastatic patients and establish a convenient individual assessment model for clinicians to explore preoperative predictors. The mRNA profiles of colorectal tumors (N = 19) were obtained by microarray at our clinical center. A total of 5,618 patients with CRLM from 2010 to 2015 were enrolled for the Surveillance, Epidemiology, and End Results (SEER) database. The cDNA microarray analyses showed that gene expression pattern in the T2N0M1 subgroup was significantly different from the T3/4N0M0 subgroup. In the survival analysis, metastatic patients with T1 stage surprisingly had much poorer prognosis than those with T3/T4 stage. Specifically, metastatic patients with early T stage were observed with higher frequency occurring at the rectum, better differentiation, less metastases in the lymph nodes, and a higher CEA level. Further survival analysis indicated that early T classification was an independent prognostic factor for a poor survival. When the lymph node (N) status was taken into consideration, patients with T1/2N+ had better survival than T1/2N0 patients. A clinical nomogram was constructed based on preoperative factors. The calibration curves showed a good concordance between nomogram prediction and actual observation. In conclusion, CRLM with early T stage had a different biological background. The prognosis of patients at T1/2M1 was poorer than at T3/4M1. More attention should be paid to the surveillance of high-risk factors and the screening of early T stage.

Zic1 suppresses gastric cancer metastasis by regulating Wnt/ß-catenin signaling and epithelial-mesenchymal transition.

Gastric cancer (GC) patients with metastasis had limited treatment options and dismal outcome. We have previously reported the aberrant expression of Zic family member 1 (Zic1) in GC. However, the functional roles and underlying mechanism of Zic1 in GC metastasis remain unknown. Here, we demonstrate that lower expression of Zic1 was correlated with more lymph node metastasis and poor outcome of GC patients. Ectopic expression of Zic1 suppressed both lung metastasis and peritoneal tumor dissemination of GC in mice. The metastatic suppressing ability of Zic1 was mediated by regulating the process of cell invasion, adhesion and epithelial-mesenchymal transition (EMT). Mechanistically, Zic1 could downregulate Wnt targets including c-Myc and Cyclin D1 by inhibiting LEF transcriptional activity in GC cells. Notably, Zic1 was inversely related to the expression of Cyclin D1 in GC tissues tested. In addition, Zic1 could physically interact with ß-catenin/transcription factor 4 (TCF4) and disrupt their complex formation, while not affecting ß-catenin nuclear localization. Collectively, our study indicated that Zic1 suppressed GC metastasis through attenuating Wnt/ß-catenin signaling and the EMT process. Our work may provide novel therapeutic strategies for the metastasis of GC.

Klotho-mediated targeting of CCL2 suppresses the induction of colorectal cancer progression by stromal cell senescent microenvironments.

Senescent microenvironments play an important role in tumor progression. Here, we report that doxorubicin (DOX)-pretreated or replicative senescent stromal cells (WI-38 and HUVEC) promote colorectal cancer (CRC) cell growth and invasion in vitro and in vivo. These pro-tumorigenic effects were attenuated by exogenous administration of Klotho, an anti-aging factor. We subsequently identified several senescence-associated secretory phenotype (SASP)-associated genes, including CCL2, which were significantly upregulated in both types of senescent stromal cells during replication and DNA damage-induced senescence. Importantly, we found that the secretion of CCL2 by senescent stromal cells was significantly higher than that seen in nonsenescent cells or in senescent cells pretreated with Klotho. Notably, CCL2 was found to accelerate CRC cell proliferation and invasion, while this effect could be blocked by administration of a specific CCR2 antagonist. We further show that Klotho can suppress NF-κB activation during DOX-induced senescence and thus block CCL2 transcription. Low expression of Klotho, or high expression of CCL2 in patient tumor tissues, correlated with poor overall survival of CRC patients. Collectively, our findings suggest that senescent stromal cells are linked to progression of CRC. Klotho can suppress the senescent stromal cell-associated triggering of CRC progression by inhibiting the expression of SASP factors including CCL2. The identification of key SASP factors such as CCL2 may provide potential therapeutic targets for improving CRC therapy.

De-escalating chemotherapy for stage II colon cancer?

BACKGROUND: Although adjuvant chemotherapy is recommended for patients with stage II colon cancer characterized by poor prognostic features, its pros and cons remain a controversial issue. We aim to evaluate the real effectiveness of chemotherapy on stage II colon cancer as well as select suitable patients. METHODS: Patients during 1988-2013 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The competing risk regression model and propensity score matching method were used to evaluate colon-cancer-specific death (CCSD) and non-CCSD. Also, a competing-risk nomogram was constructed to identify risk of patients. Risk score (RS) was calculated according to nomogram. RESULTS: A total of 58,133 patients were included, 25.66% received chemotherapy, and 74.34% were without chemotherapy. In total, 19.95% and 25.78% of patients died of CCSD and non-CCSD, respectively. Univariate and multivariate analyses showed that receiving chemotherapy appears to be associated with more CCSD and less non-CCSD (HR 1.23, 95% CI 1.18-1.28; HR 0.45, 95% CI 0.43-0.47, respectively), even after adjustment for covariates and propensity score weighting. A competing-risk nomogram was established; the model was relatively good with a C-index of 0.661. Based on the RS, risk stage could only predict prognosis but failed to predict the benefit from chemotherapy. CONCLUSIONS: The value of chemotherapy is much less than we thought. It is time to de-escalate chemotherapy for stage II colon cancer. CCSD, rather than overall survival, should be considered as an appropriate primary end point for future trials in stage II colon cancer.

Young-onset breast cancer: a poor prognosis only exists in low-risk patients.

The number of reported young breast cancer cases has increased dramatically recently. The impact of age on the outcomes of breast cancers remains controversial. Our study aimed to explore the factors that can stratify the impact of young age on the prognosis of early breast cancer patients. In total, 244,324 patients with early breast cancer in the Surveillance, Epidemiology, and End Results database were identified from 1990 to 2007. Survival curves were generated using the Kaplan-Meier method. The 5- and 10-year cancer-specific survival (CSS) rates were calculated using the Life-Table method. Multivariable analyses were used to identify prognosti c variables (without age) to construct the nomograms. The risk score developed from the nomogram was used to classify the cohort into three subgroups (low-, medium- and high-risk subgroup). Approximately 8.89% of women were diagnosed with breast cancer at a young age (≤ 40 years). Clinical nomogram had the potential ability to predict CSS accurately with a well C-index (0.785). Subgroup analysis indicated that the risk score as the sole factor can stratify the impact of young age on the prognosis of early breast cancer patients. Young breast cancer patients had a worse prognosis in the low-risk (HR=0.61; 95% CI: 0.57-0.65; P<0.001) or medium-risk subgroup (HR=0.89; 95% CI: 0.85-0.93; P<0.01) than in the high-risk subgroup (P=0.431). In conclusion, the worse prognosis of young women only appeared in the low- and medium-risk subgroups rather than in the high-risk subgroup. The risk score yielded from the nomogram model can assist clinical decision making for young breast cancer patients.

Young Patients with Hormone Receptor-Positive Breast Cancer Have a Higher Long-Term Risk of Breast Cancer Specific Death.

PURPOSE: Although it is widely accepted that hormone receptor (HR) status is associated with later post-diagnostic periods, a debate exists as to whether the association is independent of age. The aim of our study was to confirm the impact of HR status on later period breast cancer-specific death (LP-BCSD) and later period non-breast cancer-specific death (LP-non-BCSD) in different age subgroups. METHODS: Surveillance, Epidemiology, and End Results databases were utilized to identify 181,108 breast cancer patients with > 5 years survival. The cumulative incidence of LP-BCSD and LP-non-BCSD was calculated using the Gray method. The subdistribution hazard ratio (SHR) of variables was estimated via the Fine and Gray proportional hazard regression model. Subgroup analyses for LP-BCSD and LP-non-BCSD were performed according to the HR status. RESULTS: The risk of LP-BCSD was exceeded by that of LP-non-BCSD at > 5 years since the diagnosis, particularly in old women. The competing risk regression model indicated that hormone receptor-positive (HR+) was an independent factor for more LP-BCSD (hazard ratio, 1.54; 95% confidence interval, 1.44-1.54; p < 0.001). However, stratified analysis indicated that HR+ was only associated with more LP-BCSD in the young women subgroup. Although HR+ was associated with more LP-non-BCSD, the predictive value of HR+ for LP-non-BCSD was eliminated after adjusting for age. CONCLUSIONS: HR+ was related to LP-BCSD in the premenopausal population. LP-BCSD should be an optimal endpoint in future trials designed to evaluate the role of extended adjuvant endocrine therapy.

The Lymph Node Ratio Optimizes Staging in Patients with Small Intestinal Neuroendocrine Tumors.

BACKGROUND: The effectiveness of the current Tumor, Lymph node, Metastases (TNM) staging system in small intestinal neuroendocrine tumors (SiNETs) is unsatisfactory. Current N classification only distinguishes between node-negative and node-positive status. We aim to refine the N classification for updated TNM stage. METHODS: During the period from 1988 to 2012, patients with non-metastatic -SiNETs were enrolled in the Surveillance, Epidemiology, and End Results database. Using the X-tile program, we calculated an optimal cutoff value for lymph node ratio (LNR) and proposed a novel Nr category. Survival outcomes were estimated using the Kaplan-Meier method and Cox regression model. Adjusted hazard ratio (HR) and cluster analysis were performed to differentiate TNrM stages. RESULTS: Patients with existing TNM stage I and II had equivalent survival prognosis (p = 0.214). Current N classification was not a significant predictor of patient survival (p = 0.372). Multivariate analyses identified the revised Nr classification, based on LNR of 0.6 optimal cutoff value, as an independent prognostic factor (p = 0.020). By incorporating the Nr classification, a revised TNrM, which categorized patients into 3 new stages was proposed: stage I (T1-2Nr0-1), stage II (T3Nr0-1), and stage III (TxNr2 or T4Nrx). TNrM stage had better stratification according to the survival outcome (primary cohort: stage I: reference, II: HR 3.852, 95% CI 1.731-8.575; III: HR 7.169, 95% CI 3.220-15.963, p < 0.001; validation cohort: stage I: reference, II: HR 2.034; III: HR 3.815; p < 0.001). CONCLUSIONS: The Nr classification more accurately stratifies SiNET patients than current N classification. The new TNrM staging system could improve the ability to predict survival outcome of SiNET patients.

How Young Is Too Young in Breast Cancer?-Young Breast Cancer Is Not a Unique Biological Subtype.

BACKGROUND: There is no uniformly adopted cutoff value to define "young patients" with breast cancer. This study was designed to determine an optimal cutoff value, to investigate prognostic factors and to explore gene expression profiles of young female breast cancer. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results database was examined to identify cases of female breast cancer diagnosed between 2000 and 2007. The optimal cutoff value for young age was determined using the X-tile program (Yale University, version 3.6.1). Age-specific gene expression profiles were explored using RNA sequence data from the Cancer Genome Atlas database. RESULTS: The age of 40 years was determined as the optimal cutoff value. Among 94,087 patients, 12,755 were aged 40 years or younger (younger group), and 81,332 were older (older group). The 5- and 10-year cancer-specific survival rates in younger and older groups were 88.74% and 80.65%, respectively, and 93.22% and 88.43%, respectively (P < .001). Univariate and multivariate analyses indicated younger patients had worse prognosis. Subgroup analysis according to estrogen receptor (ER) showed the risk for cancer-specific death of ER-positive (ER+) younger patients increased by approximately 2 times (hazard ratio, 1.96) compared with ER+ older patients. We failed to find any age-related gene in 509 patients after adjusting according to subtype (50-gene prediction analysis of a microarray) and histological type. CONCLUSION: The age of 40 years is a reasonable cutoff value for defining "young." Young patients with breast cancer, especially those in the ER+ subgroup, have worse prognosis. However, we found that young breast cancer is not a unique biological entity, and therefore, a lack of new potential targets.

Real-world impact of non-breast cancer-specific death on overall survival in resectable breast cancer.

BACKGROUND: The real-world occurrence rate of non-breast cancer-specific death (non-BCSD) and its impact on patients with breast cancer are poorly recognized. METHODS: Women with resectable breast cancer from 1990 to 2007 in the Surveillance, Epidemiology, and End Results database (n = 199,963) were analyzed. The outcome events of breast cancer were classified as breast cancer-specific death (BCSD), non-BCSD, or survival. Binary logistics was used to estimate the occurrence rates of non-BCSD and BCSD with different clinicopathological factors. The Gray method was used to measure the cumulative incidence of non-BCSD and BCSD. The ratio of non-BCSDs to all causes of death and stacked cumulative incidence function plots were used to present the impact of non-BCSD on overall survival (OS). Models of Cox proportional hazards regression and competing risk regression were compared to highlight the suitable model. RESULTS: There were 12,879 non-BCSDs (6.44%) and 28,784 BCSDs (14.39%). The oldest age group (>62 years), black race, and a single or divorced marital status were associated with more non-BCSDs. With adjustments for age, a hormone receptor-positive (HoR+) status was no longer related to increased non-BCSDs. In patients with grade 1, stage I disease and an HoR+ status as well as the oldest subgroup, a great dilution of non-BCSD on all causes of death could be observed, and this led to incorrect interpretations. The inaccuracy, caused by the commonly used Cox proportional hazards model, could be corrected by a competing risk model. CONCLUSIONS: OS was largely impaired by non-BCSD during early breast cancer. For some future clinical trial planning, especially for the oldest patients and those with HoR+ breast cancer, non-BCSD should be considered a competing risk event. Cancer 2017;123:2432-43. © 2017 American Cancer Society.

Survival outcomes and surgical intervention of small intestinal neuroendocrine tumors: a population based retrospective study.

BACKGROUND: Small intestinal neuroendocrine tumors (SiNETs) without distant metastasis typically behave in an indolent manner, but there can be heterogeneity. We aimed to define the survival outcomes and impacts of surgical intervention. METHODS: A retrospective cohort study was conducted by using data from the Surveillance, Epidemiology, and End Results (SEER) database. Clinicopathologic features were analyzed in 4407 patients between 2000 and 2012. The cancer specific survival (CSS) was calculated by the Kaplan-Meier method. Multivariable Cox regression models with hazard ratios (HRs) were constructed to analyze survival outcomes and risk factors. RESULTS: The adjusted incidence of early SiNETs is 1.3/100,000. Tumors are most commonly located in the ileum and are small (≤ 2 cm). The 5-year and 10-year CSS rates were 95.0% and 88.5%, respectively. Age > 50 years, large tumor size (> 2cm), poor differentiation, advanced T classification, and absence of surgical treatment were independent predictors of poor survival. Stratified analysis indicated that surgery significantly improved survival in patients that were white (HR, 0.45), > 50 years old (HR, 0.61), had duodenal tumors (HR, 0.43), large tumors (> 2cm) (HR, 0.32), advanced T classification (T3: HR, 0.29; T4: HR, 0.18) or well differentiation (HR, 0.55). There was no significant survival difference between local resection and radical resection (P =0.884). CONCLUSIONS: Early SiNETs have a favorable prognosis. Surgical resection may improve outcomes, particularly in older patients and those with large tumors. More aggressive resections couldn't improve outcomes.

Signet ring cell carcinoma of resectable metastatic colorectal cancer has rare surgical value.

BACKGROUND AND OBJECTIVES: Signet ring cell carcinoma (SRCC) is a uniquely separated subgroup in metastatic colorectal cancer (mCRC). The aims are to investigate the value of resection in patients with resectable metastatic signet ring cell colorectal cancer. METHODS: Patients with mCRC who underwent resection in Surveillance, Epidemiology, and End Results database during 1998-2010 were retrospectively analyzed. Kaplan-Meier and COX models were used to analyze the differences in the survival. Logistic regression models were used to evaluate the relationship between SRCC and other clinicopathological factors. RESULTS: Among the 3,568 patients, 94 (2.63%) patients had SRCC. The median survival time of patients with SRCC and non-SRCC were 17 and 29 months, respectively (P < 0.001). Multivariate analysis indicated that SRCC was an independent prognostic factor for poor overall survival. Logistic regression model based on variables identified by univariate analysis indicated that younger age (≤50 years old) (P = 0.005), female (P < 0.001), location in colon (P = 0.012), and N positive status (P = 0.003) were independent variables correlated with the SRCC subgroup. SRCC had a dramatically higher invalid surgical outcome rate than non-SRCC (P = 0.001). CONCLUSION: SRCC patients might benefit little from the resection of primary and metastatic lesions with a high rate of undergoing invalid operations. J. Surg. Oncol. 2016;114:1004-1008. © 2016 Wiley Periodicals, Inc.

Clinical Nomogram for Predicting Survival Outcomes in Early Mucinous Breast Cancer.

BACKGROUND: The features related to the prognosis of patients with mucinous breast cancer (MBC) remain controversial. We aimed to explore the prognostic factors of MBC and develop a nomogram for predicting survival outcomes. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was searched to identify 139611 women with resectable breast cancer from 1990 to 2007. Survival curves were generated using Kaplan-Meier methods. The 5-year and 10-year cancer-specific survival (CSS) rates were calculated using the Life-Table method. Based on Cox models, a nomogram was constructed to predict the probabilities of CSS for an individual patient. The competing risk regression model was used to analyse the specific survival of patients with MBC. RESULTS: There were 136569 (97.82%) infiltrative ductal cancer (IDC) patients and 3042 (2.18%) MBC patients. Patients with MBC had less lymph node involvement, a higher frequency of well-differentiated lesions, and more estrogen receptor (ER)-positive tumors. Patients with MBC had significantly higher 5 and10-year CSS rates (98.23 and 96.03%, respectively) than patients with IDC (91.44 and 85.48%, respectively). Univariate and multivariate analyses showed that MBC was an independent factor for better prognosis. As for patients with MBC, the event of death caused by another disease exceeded the event of death caused by breast cancer. A competing risk regression model further showed that lymph node involvement, poorly differentiated grade and advanced T-classification were independent factors of poor prognosis in patients with MBC. The Nomogram can accurately predict CSS with a high C-index (0.816). Risk scores developed from the nomogram can more accurately predict the prognosis of patients with MBC (C-index = 0.789) than the traditional TNM system (C-index = 0.704, P< 0.001). CONCLUSIONS: Patients with MBC have a better prognosis than patients with IDC. Nomograms could help clinicians make more informed decisions in clinical practice. The competing risk regression model, as a more rational model, is recommended for use in the survival analysis of patients with MBC in the future.

Synchronous Resectable Metastatic Colorectal Cancer: Lymph Node Involvement Predicts Poor Outcome.

To evaluate the value of lymph node status of primary tumors in predicting the prognosis of synchronous resectable metastatic colorectal cancer (mCRC).The characteristics of resectable mCRC are substantially different from other cancers, and the prognostic factors of resectable mCRC are still controversial.The data of 2007 patients with mCRC who received resection of the primary tumors and metastatic lesions synchronously were reviewed from the Surveillance, Epidemiology and End-Result database. The Kaplan-Meier method was used to evaluate the capacity of different prognostic factors. Univariate and multivariate logistic regression models were used to evaluate the relationship between the lymph node status and other factors. The mRNA profiles of primary resectable mCRC tumors were obtained by microarray at our center.The median survival times were 50, 36, 32, 27, and 19 months in the N0-stage, N1a-stage, N1b-stage, N2a-stage, and N2b-stage subgroups according to the 7th American Joint Committee on Cancer (AJCC) Tumor Lymph Node Metastasis (TNM) N-classification (P = 0.000), and 40, 29, 22, and 15 months in patients with metastatic lymph node ratio (LNR) <0.25, 0.25-0.49, 0.5-0.74, and ≥0.75 subgroups (P = 0.000). In the COX model, the 7th AJCC TNM N-stage and LNR were independent prognostic factors. The mRNA profile was not associated with lymph node involvement.Both the N-stage according to the 7th AJCC TNM staging system and LNR had the capacity to subclassify synchronous resectable mCRC with different prognoses. The lymph node might be integrated into the AJCC staging system as a diagnose-delay prognostic factor for stage IV disease.