[Corrigendum] Long non­coding RNA LINC00238 suppresses the malignant phenotype of liver cancer by sponging miR­522.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that two pairs of data panels featured in Figs. 2E and 6D, portraying the results from cell invasion and migration assay experiments, appeared to contain overlapping sections, such that data which were intended to show the results from differently performed experiments had apparently been derived from a smaller number of original sources. The authors were able to re­examine their original data (which was also presented to the Editorial Office), and realized that errors has been made in the compilation of Fig. 2. The proposed revised version of Fig. 2, now showing the results from the 'field 1' view of the data, is shown on the next page. Note that these errors did not significantly affect either the results or the conclusions reported in this paper,.All the authors agree to the publication of this Corrigendum, and are grateful to the Editor of Molecular Medicine Reports for allowing them the opportunity to correct this error; furthermore, they apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 25: 71, 2022; DOI: 10.3892/mmr.2022.12587].

Volume-based 18F-FDG PET/CT predicts prognosis and outcome of active surveillance for intra-abdominal desmoid tumor.

PURPOSE: Desmoid tumor (DT) is a rare monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Initial active surveillance is recommended by current guideline, and surgery is one of the main therapies for DT. Predicting the prognosis and outcome of active surveillance for intra-abdominal DT is pressing issue. METHODS: The study included eighteen patients with intra-abdominal DT. Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum standardized uptake value (SUVmax) were measured. We analyzed their relationship with the outcome of active surveillance, as well as clinical, prognostic, and pathological data. RESULTS: The MTV and TLG of recurrent DT were significantly higher than those of non-recurrent DT (P < 0.001 and P = 0.00, respectively). The ROC curve suggested that the appropriate cutoff values for distinguishing recurrent DT from non-recurrent DT were 760.8 for MTV (sensitivity = 1, specificity = 0.857 and AUC = 0.929), and 1318.4 for TLG (sensitivity = 1, specificity = 0.786, and AUC = 0.911). The cutoff values of MTV and TLG significantly correlated with PFS using the Kaplan-Meier method (P = 0.002 and P = 0.007, respectively). MTV and TLG could distinguish DTs with subsequent progression from stable ones (P = 0.004 and P = 0.004, respectively). The ROC curve suggested that the appropriate cutoff values for distinguishing DTs with subsequent progression from stable ones were 197.1 for MTV (sensitivity = 0.9, specificity = 1, and AUC = 0.900), and 445.45 for TLG (sensitivity = 0.9, specificity = 1, and AUC = 0.900). CONCLUSION: Volume-based 18F-FDG-PET can predict prognosis of intra-abdominal DT. MTV and TLG can predict the outcome of active surveillance for intra-abdominal DT. MTV and TLG can potentially be predictors of surgical risk and difficulty.

Auranofin inhibits the occurrence of colorectal cancer by promoting mTOR-dependent autophagy and inhibiting epithelial-mesenchymal transformation.

Colorectal cancer (CRC) is one of the world's most common and deadly cancers. According to GLOBOCAN2020's global incidence rate and mortality estimates, CRC is the third main cause of cancer and the second leading cause of cancer-related deaths worldwide. The US Food and Drug Administration has approved auranofin for the treatment of rheumatoid arthritis. It is a gold-containing chemical that inhibits thioredoxin reductase. Auranofin has a number of biological activities, including anticancer activity, although it has not been researched extensively in CRC, and the mechanism of action on CRC cells is still unknown. The goal of this research was to see how Auranofin affected CRC cells in vivo and in vitro . The two chemical libraries were tested for drugs that make CRC cells more responsive. The CCK-8 technique was used to determine the cell survival rate. The invasion, migration, and proliferation of cells were assessed using a transwell test and a colony cloning experiment. An electron microscope was used to observe autophagosome formation. Western blotting was also used to determine the degree of expression of related proteins in cells. Auranofin's tumor-suppressing properties were further tested in a xenograft tumor model of human SW620 CRC cells. Auranofin dramatically reduced the occurrence of CRC by decreasing the proliferation, migration, and invasion of CRC cells, according to our findings. Through a mTOR-dependent mechanism, auranofin inhibits the epithelial-mesenchymal transition (EMT) and induces autophagy in CRC cells. Finally, in-vivo tests revealed that auranofin suppressed tumor growth in xenograft mice while causing no harm. In summary, auranofin suppresses CRC cell growth, invasion, and migration. Auranofin inhibits the occurrence and progression of CRC by decreasing EMT and inducing autophagy in CRC cells via a mTOR-dependent mechanism. These findings suggest that auranofin could be a potential chemotherapeutic medication for the treatment of human CRC.

Preoperative assessment of retroperitoneal Liposarcoma using volume-based 18F-FDG PET/CT: implications for surgical strategy and prognosis.

PURPOSE: Retroperitoneal liposarcoma (RLPS) poses a challenging scenario for surgeons due to its unpredictable biological behavior. Surgery remains the primary curative option for RLPS; however, the need for additional information to guide surgical strategies persists. Volume-based 18F-FDG PET/CT may solve this issue. METHODS: We analyzed data from 89 RLPS patients, measuring metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum standardized uptake value (SUVmax) and explored their associations with clinical, prognostic, and pathological factors. RESULTS: MTV, TLG of multifocal and recurrent RLPS were significantly higher than unifocal and primary ones (P < 0.001, P < 0.001, P = 0.003 and P = 0.002, respectively). SUVmax correlated with FNCLCC histological grade, mitotic count and Ki-67 index (P for G1/G2 = 0.005, P for G2/G3 = 0.017, and P for G1/G3 = 0.001, P < 0.001 and P = 0.024, respectively). MTG, TLG and SUVmax of WDLPS were significantly lower than DDLPS and PLPS (P for MTV were 0.009 and 0.022, P for TLG were 0.028 and 0.048, and P for SUVmax were 0.027 and < 0.001, respectively). Multivariable Cox analysis showed that MTV > 457.65 (P = 0.025), pathological subtype (P = 0.049) and FNCLCC histological grade (P = 0.033) were related to overall survival (OS). CONCLUSIONS: Our findings indicate that MTV is an independent prognostic factor for RLPS, while MTV, TLG, and SUVmax can preoperatively predict multifocal lesions, histological grade, and pathological subtype. Volume-based 18F-FDG PET/CT offers valuable information to aid in the decision-making process for RLPS surgical strategies.

Short- and long-term surgical outcomes of pancreatic resection for retroperitoneal sarcoma: A long-term single-center experience of 90 cases.

BACKGROUND AND OBJECTIVES: Resection of retroperitoneal sarcoma (RPS) en bloc with pancreas is challenging and controversial. This single-center retrospective study aimed to analyze the impact of pancreatic resection (PR) and its different types on short- and long-term outcomes in patients with RPS. METHODS: Data from 242 consecutive patients with RPS who underwent surgical treatment at the Peking University Cancer Hospital Sarcoma Center between January 2010 and February 2021 were analyzed. Out of these, 90 patients underwent PR, including pancreaticoduodenectomy (PD) in 31 and distal pancreatectomy (DP) in 59. RESULTS: Patients in the PR group had a higher major morbidity (37.8% vs. 14.5%) and mortality (8.9% vs. 1.3%) than those in the non-PR group, with a similar 5-year overall survival (OS) rate (46.9% vs. 53.6%). Patients in the PD and DP groups had a slight difference in major morbidity (48.4% vs. 32.2%), mortality (6.4% vs. 10.2%), and 5-year OS rates (43.3% vs. 49.3%). The PR type was not an independent risk factor for major morbidity or OS. CONCLUSIONS: PR in RPS resection was associated with increased morbidity and mortality with minimal influence on survival. Patients with RPS undergoing PD and DP showed slight differences in terms of safety and OS.

Multidimensional characteristics, prognostic role, and preoperative prediction of peritoneal sarcomatosis in retroperitoneal sarcoma.

Background: Peritoneal sarcomatosis (PS) could occur in patients with retroperitoneal sarcomas (RPS). This study aimed to expand the understanding of PS on its characteristics and prognostic role, and develop a nomogram to predict its occurrence preoperatively. Methods: Data of 211 consecutive patients with RPS who underwent surgical treatment between 2011 and 2019 was retrospectively reviewed. First, the clinicopathological characteristics of PS were summarized and analyzed. Second, the disease-specific survival (DSS) and recurrence-free survival (RFS) of patients were analyzed to evaluate the prognostic role of PS. Third, preoperative imaging, nearly the only way to detect PS preoperatively, was combined with other screened risk factors to develop a nomogram. The performance of the nomogram was assessed. Results: Among the 211 patients, 49 (23.2%) patients had PS with an incidence of 13.0% in the primary patients and 35.4% in the recurrent patients. The highest incidence of PS occurred in dedifferentiated liposarcoma (25.3%) and undifferentiated pleomorphic sarcoma (25.0%). The diagnostic sensitivity of the preoperative imaging was 71.4% and its specificity was 92.6%. The maximum standardized uptake value (SUVmax) was elevated in patients with PS (P<0.001). IHC staining for liposarcoma revealed that the expression of VEGFR-2 was significantly higher in the PS group than that in the non-PS group (P = 0.008). Survival analysis (n =196) showed significantly worse DSS in the PS group than in non-PS group (median: 16.0 months vs. not reached, P < 0.001). In addition, PS was proven as one of the most significant prognostic predictors of both DSS and RFS by random survival forest algorithm. A nomogram to predict PS status was developed based on preoperative imaging combined with four risk factors including the presentation status (primary vs. recurrent), ascites, SUVmax, and tumor size. The nomogram significantly improved the diagnostic sensitivity compared to preoperative imaging alone (44/49, 89.8% vs. 35/49, 71.4%). The C-statistics of the nomogram was 0.932, and similar C-statistics (0.886) was achieved at internal cross-validation. Conclusion: PS is a significant prognostic indicator for RPS, and it occurs more often in recurrent RPS and in RPS with higher malignant tendency. The proposed nomogram is effective to predict PS preoperatively.

Patients with first recurrent retroperitoneal sarcoma that can be macroscopically completely resected can achieve comparable outcomes with that of primary patients after en bloc resection of tumor and adjacent organs.

The outcomes of patients with primary retroperitoneal sarcoma (RPS) are significantly superior to those with recurrence. En bloc resection of tumor and adjacent organs is recommended in primary RPS. However, whether en bloc resection of tumor and adjacent organs can benefit recurrent patients or some recurrent patients is unclear. We compared the outcomes of patients with primary RPS, first recurrence (RPS-Rec1), and ≥2 recurrences (≥RPS-Rec2) to evaluate the value and criteria for en bloc resection of tumor and adjacent organs in recurrent cases. We evaluated the safety of en bloc resection of tumor and adjacent organs by assessing operation time, blood loss volume, postoperative morbidities (POM), and efficacy by comparing local recurrence and peritoneal metastasis (LR-PM), distant metastasis, progression-free survival (PFS), and overall survival (OS). A total of 101, 47, and 30 patients with primary RPS, RPS-Rec1, and ≥RPS-Rec2 were included, respectively. Recurrent RPS invaded more adjacent organs and surrounding fat tissue than primary RPS. The operation time, amount of blood loss, incidence of grade III-V POM, LR-PM rate, PFS, and OS in the RPS-Rec1 group were similar to those of the primary group, both of which were significantly superior to those of the ≥RPS-Rec2 group. Macroscopically incomplete resection and high-grade RPS rather than first recurrence were independent risk factors for LR-PM, PFS, and OS. In conclusion, the safety and efficacy of en bloc resection of tumor and adjacent organs in RPS-Rec1 were comparable with those in primary RPS but significantly superior to those of ≥RPS-Rec2. For RPS-Rec1, comparable outcomes to patients with primary RPS can be achieved, particularly in those in whom a macroscopically complete resection is achieved.

Treatment algorithm and surgical outcome for primary and recurrent retroperitoneal sarcomas: A long-term single-center experience of 242 cases.

BACKGROUND AND OBJECTIVES: Retroperitoneal sarcomas (RPSs) are difficult to manage, rare malignant tumors. This single-center, retrospective study aimed to analyze the treatment algorithm and outcomes of aggressive surgical treatment in patients with primary and recurrent RPS. METHODS: Data of 242 consecutive patients with RPS who underwent surgical treatment at the Peking University Cancer Hospital Sarcoma Center between January 2010 and February 2021 were collected and analyzed. Indications for surgery were based on the treatment algorithm. RESULTS: A total of 145 patients with primary RPS and 97 with recurrent RPS were included. The recurrent cohort comprised more patients with multifocal tumors than the primary cohort (64.9% vs. 15.2%). R0/R1 resection was achieved in 94.5% and 81.4% of the primary and recurrent RPS cases, respectively. Major complication rates in the primary and recurrent cohorts were 17.9% and 30.9%, respectively. During a median follow-up of 51 months, the estimated 5-year overall survival, local recurrence, and distant metastasis rates for patients with primary and recurrent RPS were 61.0% versus 37.1%, 47.4% versus 71.3%, and 18.4% versus 17.6%, respectively. CONCLUSIONS: Aggressive surgical treatment achieved good local control and long-term survival in patients with primary RPS, whereas the prognosis in patients with recurrence were significantly worse.

Long non­coding RNA LINC00238 suppresses the malignant phenotype of liver cancer by sponging miR­522.

Long non­coding RNAs can regulate the malignant tumor phenotype either as tumor suppressors or oncogenes. The present study investigated the underlying mechanism of LINC00238 in liver cancer. LINC00238 was identified as a downregulated molecule in The Cancer Genome Atlas liver hepatocellular carcinoma dataset through Gene Expression Profiling Interactive Analysis software. Through gain­ and loss­of­function experiments, LINC00238 was confirmed as a tumor suppressor that could not only decrease cell viability, migration and invasion in vitro, but also tumorigenesis and tumor metastasis in vivo. By cytoplasmic and nuclear RNA isolation, LINC00238 was confirmed to be predominantly cytoplasmic. Mechanistically, RNA pull­down assays showed that LINC00238 sponged microRNA (miR)­522 and then reversed the inhibitory effects on two downstream targets, secreted frizzled related protein 2 and dickkopf1. Collectively, LINC00238 was identified as a tumor suppressor that acts via sponging miR­522 followed by silencing of downstream targets, suggesting that LINC00238 may have a key role in suppressing the malignant phenotype of liver cancer cells.

Predictive Value of Preoperative Controlling Nutritional Status Score Combined with Fibrinogen-Albumin Ratio in Postoperative Local Recurrence-Free Survival of Patients with Retroperitoneal Liposarcoma.

BACKGROUND: Previous studies have shown that nutrition and systemic inflammation plays an essential role in the development of soft tissue sarcoma. However, few studies have explored the association of clinicopathologic features and local recurrence with nutritional and inflammatory markers in retroperitoneal liposarcoma (RPLS). This study sought to evaluate the prognostic value of the preoperative nutritional and inflammatory markers for local recurrence-free survival (LRFS) among surgical RPLS patients. METHODS: The study included 111 RPLS patients who underwent surgery between May 2010 and June 2019 at the Peking University Cancer Hospital Sarcoma Center. Time-dependent receiver operating characteristic (time-ROC) curve analysis was conducted to evaluate the ability of markers to predict LRFS. The associations of the CONUT-FAR score with clinicopathological variables and LRFS were evaluated. RESULTS: In the time-ROC curve analysis, the CONUT-FAR score was superior to other nutritional and inflammatory markers in predicting LRFS. The CONUT-FAR score was the only nutritional and inflammatory marker that independently predicted LRFS in the multivariate analysis, and patients with a high CONUT-FAR score (> 11) showed significantly decreased LRFS. Although the CONUT-FAR score failed to discriminate patients with low grade (G1) (p = 0.327) or undergoing incomplete (R2) resection (p = 0.072), it stratified patients with high grade (G2 and G3) or undergoing complete resection (R0/R1) into subgroups with significantly distinct LRFS (p < 0.001). The CONUT-FAR score also showed good clinical utility among patients with different clinical characteristics. CONCLUSION: The preoperative CONUT-FAR score reflects both nutritional and inflammatory factors and is an effective predictor of LRFS for surgical RPLS patients.

Prediction of Histologic Subtype and FNCLCC Grade by SUVmax Measured on 18F-FDG PET/CT in Patients with Retroperitoneal Liposarcoma.

This study aimed to evaluate the usefulness of maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET/CT) in differentiating the subtypes and tumor grades of retroperitoneal liposarcoma (RPLS). The data of RPLS patients who underwent surgical resection from November 2013 to December 2019 at the sarcoma center of our institute were reviewed. The demographics, clinical features, and SUVmax of 84 patients who underwent preoperative 18F-FDG PET/CT scans were analyzed. Of these, 19 patients (22.6%) were with well-differentiated liposarcoma (WDLPS), 60 patients (71.4%) were with dedifferentiated liposarcoma (DDLPS), and 5 patients (6.0%) were with pleomorphic liposarcoma (PMLPS). The median SUVmax of WDLPS, DDLPS, and PMLPS groups was 2.8 (IQR: 1.9-3.2), 6.2 (IQR: 4.1-11.3), and 4.5 (IQR: 4.0-7.4). The ROC curve suggested 3.8 as an approximate cutoff value of SUVmax for distinguishing WDLPS and non-WDLPS (sensitivity = 0.769; specificity = 0.895). The median SUVmax for FNCLCC Grades 1, 2, and 3 of RPLS was 2.5 (IQR: 1.9-3.2), 4.5 (IQR: 3.2-6.7), and 9.0 (IQR: 6.0-13.3). The ROC curves suggest that SUVmax of ≤3.8 and >5.3 can be used for predicting FNCLCC Grades 1 and 3, respectively. The result showed that 18F-FDG PET/CT exhibited high sensitivity and specificity for identifying the subtypes and FNCLCC grades of RPLS. Additionally, 18F-FDG PET/CT might be a useful complementary imaging modality for guiding suitable biopsy location of RPLS.

Comprehensive comparison of patient-derived xenograft models in Hepatocellular Carcinoma and metastatic Liver Cancer.

Patient-derived xenograft (PDX) models are effective preclinical cancer models that reproduce the tumor microenvironment of the human body. The methods have been widely used for drug screening, biomarker development, co-clinical trials, and personalized medicine. However, the low success rate and the long tumorigenesis period have largely limited their usage. In the present studies, we compared the PDX establishment between hepatocellular cancer (HCC) and metastatic liver cancer (MLC), and identified the key factors affecting the transplantation rate of PDXs. Surgically resected tumor specimens obtained from patients were subcutaneously inoculated into immunodeficient mice to construct PDX models. The overall transplantation rate was 38.5% (20/52), with the HCC group (28.1%, 9/32) being lower than MLC group (56.2%, 9/16). In addition, HCC group took significantly longer latency period than MLC group to construct PDX models. Hematoxylin and eosin staining results showed that the histopathology of all generations in PDX models was similar to the original tumor in all three types of cancer. The transplantation rate of PDX models in HCC patients was significantly associated with blood type (P=0.001), TNM stage (P=0.023), lymph node metastasis (P=0.042) and peripheral blood CA19-9 level (P=0.049), while the transplantation rate of PDX models in MLC patients was significantly associated with tumor size (P=0.034). This study demonstrates that PDX models can effectively reproduce the histological patterns of human tumors. The transplantation rate depends on the type of original tumor. Furthermore, it shows that the invasiveness of the original liver cancer affects the possibility of its growth in immunodeficient mice.

Dexamethasone inhibits pancreatic tumor growth in preclinical models: Involvement of activating glucocorticoid receptor.

Glucocorticoid receptor (GR) modulates extensive biological and pathological processes including tumor progression through diverse mechanisms. The regulatory effects of dexamethasone (DEX), a synthetic glucocorticoid, as well as its interaction with GR have been recognized beyond hematologic cancers. In the present study, we investigated the anti-cancer efficacy of DEX and the correlation with GR in pancreatic cancer, a most aggressive malignancy threatening human health. The differential levels of GR expression were examined in two human pancreatic cancer cell lines, PANC-1 and SW1990, as well as in xenografts and patient tumor tissues. DEX significantly inhibited colony formation, migration, and tumor growth of PANC-1 cells expressing abundant GR. The underlying mechanisms involved suppression of nuclear factor κB (NF-κB) phosphorylation and down-regulation of epithelial-to-mesenchymal transition (EMT), interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF). The anti-cancer effects of DEX were partially reversed by GR silencing or combinational administration of GR antagonist, RU486. The dose-dependent efficacy of DEX in tumor growth inhibition was also demonstrated in a GR-positive patient-derived xenograft model along with safety in mice. DEX was less potent, however, in SW1990 cells with poor GR expression. Our findings suggest that DEX effectively inhibits pancreatic tumor growth partially through GR activation. The potential correlation between GR expression and anti-cancer efficacy of DEX may have some clinical implications.

Establishment of pancreatic cancer patient-derived xenograft models and comparison of the differences among the generations.

Tumor samples of pancreatic ductal adenocarcinoma patients, who underwent resection surgery, were implanted into NOD/SCID mice to construct pancreatic cancer patient-derived xenograft (PDX) models and explore the biological changes in the different generations of PDXs. Ten PDXs were successfully generated, and the tumor formation rate of F1 PDXs was found to be 38.46%, which was lower than F2 (77.78%) and F3 (71.43%) PDXs. In addition, latent periods of tumorigenesis of F2 and F3 PDXs were significantly shorter, compared to that in F1 PDXs (P<0.05). Comparison of H&E staining of tumor tissue from primary pancreatic cancer and PDXs showed that all three generations of PDXs had similar histopathology to primary pancreatic cancer, indicating that PDXs may well reproduce the histological patterns of primary human cancer. Besides, Ki67 expression was increased in all three generations of PDXs compared to primary tumors of patients, and additionally, EpCAM expression was increased in F3 PDXs. These results were corroborated by the real-time qPCR and western blot results. Therefore, we concluded that PDXs are able to preserve the differentiation degree, morphological characteristics, and structural features of tumor cells. Furthermore, the latent periods of tumorigenesis are shortened after the first generation, which may be attributed to an increase in expression levels of tumor promoters such as Ki67 and EpCAM. PDX models may become an efficient tool for pancreatic cancer research.

Clinicopathological features and prognostic factors of solid pseudopapillary neoplasms of pancreas.

.To explore the clinicopathological features of solid pseudopapillary neoplasm (SPN) of pancreas and to analyze the related factors of SPNs with aggressive behavior. Clinical data of SPN patients admitted in the Single Center of Peking University Cancer Hospital from January 2007 to September 2017 were retrospectively analyzed. The correlations of clinicopathological features with aggressive SPNs and distant metastasis after curative resection were analyzed using univariate analysis. Twelve of the total 54 SPN patients were diagnosed as aggressive SPNs. Univariate analysis suggested clinical features had no correlations with aggressive SPNs. Patients were followed up for an average of 5.0 years, four of them developed distant metastases. Univariate analysis indicated that distant metastasis of SPNs was correlated with the aggressive behaviors (P=0.031). Moreover, vessels invasion (VI) and Ki-67>4% (P=0.012) were the independent risk factors of distant metastasis of SPNs. The aggressive SPNs, especially VI and Ki-67>4% are the independent factors correlated with distant metastases after SPNs surgery.

Anterior Approach to En Bloc Resection in Left-Sided Retroperitoneal Sarcoma with Adjacent Organ Involvement: A Study of 25 Patients in a Single Center.

BACKGROUND There is no standard surgical approach for the management of retroperitoneal sarcoma. The aim of this clinical study was to describe the experience of an anterior approach to en bloc resection in left-sided retroperitoneal sarcoma with adjacent organ involvement. MATERIAL AND METHODS This retrospective clinical study included 25 patients who were diagnosed with left-sided retroperitoneal sarcoma and underwent tumor resection at a single center between May 2012 and July 2017. All patients had tumors that were adjacent to the left colon, pancreas, left kidney, left adrenal gland, and psoas major; some of the tumors were adjacent to the diaphragm, stomach, and small intestine. An anterior approach was used to remove the left-sided retroperitoneal tumor with the adhesive organs en bloc, an approach that is described in detail. The value of this surgical approach was evaluated based on the histopathological findings, postoperative complications, and patient follow-up. RESULTS The median number of resected organs, in addition to the retroperitoneal tumor, was 8 (range, 6-10). Complete macroscopic tumor resection was achieved in 23 cases (92%). Twenty-four patients (96%) had tumor infiltration of at least one organ or the surrounding fat. Three patients (12%) experienced Grade III and IV postoperative morbidities. The one-year disease-free survival rate was 91.3% among patients with macroscopically complete resections. The one-year overall survival rate was 83.2%. CONCLUSIONS In selected patients, left-sided retroperitoneal sarcoma associated with local organ involvement can be surgically managed using an anterior approach with en bloc resection of adjacent organs.

Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model.

Dexamethasone (DEX) is the substrate of CYP3A. However, the activity of CYP3A could be induced by DEX when DEX was persistently administered, resulting in auto-induction and time-dependent pharmacokinetics (pharmacokinetics with time-dependent clearance) of DEX. In this study we investigated the pharmacokinetic profiles of DEX after single or multiple doses in human breast cancer xenograft nude mice and established a semi-mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for characterizing the time-dependent PK of DEX as well as its anti-cancer effect. The mice were orally given a single or multiple doses (8 mg/kg) of DEX, and the plasma concentrations of DEX were assessed using LC-MS/MS. Tumor volumes were recorded daily. Based on the experimental data, a two-compartment model with first order absorption and time-dependent clearance was established, and the time-dependence of clearance was modeled by a sigmoid Emax equation. Moreover, a semi-mechanism-based PK/PD model was developed, in which the auto-induction effect of DEX on its metabolizing enzyme CYP3A was integrated and drug potency was described using an Emax equation. The PK/PD model was further used to predict the drug efficacy when the auto-induction effect was or was not considered, which further revealed the necessity of adding the auto-induction effect into the final PK/PD model. This study established a semi-mechanism-based PK/PD model for characterizing the time-dependent pharmacokinetics of DEX and its anti-cancer effect in breast cancer xenograft mice. The model may serve as a reference for DEX dose adjustments or optimization in future preclinical or clinical studies.

Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drug-resistant and metastatic breast cancer.

Recent evidence shows that dopamine D2-like receptor (D2DR) antagonists, such as trifluoperazine and thioridazine, are effective for cancer therapy and inhibition of cancer stem-like cells (CSCs). In this study, we investigated the anti-cancer effects of combination therapy of dexamethasone (DEX) and sulpiride (SUL), an atypical antipsychotic, against drug-resistant and metastatic breast cancers and further explored the underlying mechanisms. Oral administration of SUL (25, 100 mg·kg-1·d-1) alone did not inhibit the tumor growth in human breast cancer MCF-7/Adr xenograft model, but dose-dependently decreased the proportion of CSCs in vitro and in vivo. In contrast, combination therapy of SUL (50 mg·kg-1·d-1) and DEX (8 mg·kg-1·d-1) markedly suppressed the tumor growth in MCF-7/Adr xenograft model with little systemic toxicity and lung metastasis in murine metastatic breast cancer 4T1 xenograft model. Among the metastasis-associated biomarkers analyzed, the combination therapy significantly decreased the levels of MMP-2, but increased E-cadherin levels in 4T1 xenograft tumors. Moreover, the combination therapy significantly inhibited the cell colony formation, migration and invasion of 4T1 and human breast cancer MDA-MB-231 cells in vitro. Addition of a specific D2DR agonist 7-OH-DPAT to the combination therapy reversed the enhanced anti-cancer effects in vivo and CSC population loss in tumor tissues. Our data demonstrate that SUL remarkably enhances the efficacy of DEX in the treatment of drug-resistant and metastatic breast cancer via the antagonism of D2DR, which might result from the eradication of CSCs.

Superior mesenteric artery margin in pancreaticoduodenectomy for pancreatic adenocarcinoma.

The aim of this study is trying to describe more details of superior mesenteric artery margin in pancreaticoduodenectomy for pancreatic ductal adenocarcinoma, to evaluate biological and prognostic implications of tumor budding in this margin, and to provide more evidence for evaluation of R0 surgery in pancreaticoduodenectomy. 46 patients in 5-years period are included in this study. Immunochemistry and immunofluorescence are used to analyze tumor budding and epithelial-mesenchymal transition. Superior mesenteric artery margin might be described from four aspects including location, gross appearance, microscopic appearance and tumor budding. We find that 1mm rule for R1 surgery is more appropriate to predict prognosis (P = 0.009) than 0mm rule (P = 0.141). Expression of cytokeratin in tumor budding is significantly lower than primary tumor (P = 0.001), and it suggests that tumor budding may participate the procedure of epithelial-mesenchymal transition. High-grade tumor budding and decreasing cytokeratin of tumor budding correlate with distant metastasis and has negative influence on prognosis. So superior mesenteric artery margin might be not only an area that tumor cells may invade, but also a pathway for distant metastasis. It is necessary to evaluate superior mesenteric artery margin in pancreaticoduodenectomy for pancreatic cancer.

MicroRNA-33a-3p suppresses cell migration and invasion by directly targeting PBX3 in human hepatocellular carcinoma.

MicroRNAs (miRNAs) have been shown to function as either oncogenes or tumor suppressors by negatively regulating target genes involved in tumor initiation and progression. In this study, we demonstrated that down-regulation of miR-33a-3p in human primary hepatocellular cancer (HCC) specimens was significantly associated with metastases and poor survival. Over-expression of miR-33a-3p in HepG2 cells remarkably suppressed not only cell growth, migration and invasion, but also tumor growth and metastases in the chick embryo chorioallantoic membrane (CAM) assay, and down-regulated Pre-B-Cell Leukemia Homeobox 3 (PBX3) expression. Conversely, inhibition of miR-33a-3p in Bel-7402 cells resulted in increased of cell growth, spreading and invasion. Furthermore, rescue experiments by over-expression PBX3 completely eliminated the inhibitory effects of miR-33a-3p on tumor growth and metastasis, both in vitro and in vivo. The luciferase assay showed that 3'-untranslated regions (3'-UTRs) of PBX3 were inhibited significantly by miR-33a-3p, while mutations in the miR-33a-3p pairing residues rescued the luciferase expression. Taken together, our findings suggest that miR-33a-3p suppressed the malignant phenotype while also inhibiting PBX3 expression in hepatocellular cancer, implying that miR-33a-3p may be a promising biomarkers and therapy target for HCC intervention.