Postoperative Lung Metastasis Research Articles

Targeting NEDD8 suppresses surgical stress-facilitated metastasis of colon cancer via restraining regulatory T cells

Regulatory T cells (Tregs) are a key determinant for the immunosuppressive and premetastatic niche for cancer progression after surgery resection. However, the precise mechanisms regulating Tregs function during surgical stress-facilitated cancer metastasis remain unknown. This study aims to unravel the mechanisms and explore potential strategies for preventing surgical stress-induced metastasis by targeting NEDD8. Using a surgical stress mouse model, we found that surgical stress results in the increased expression of NEDD8 in Tregs. NEDD8 depletion abrogates postoperative lung metastasis of colon cancer cells by inhibiting Treg immunosuppression and thereby partially recovering CD8+T cell and NK cell-mediated anti-tumor immunity. Furthermore, Treg mitophagy and mitochondrial respiration exacerbated in surgically stressed mice were attenuated by NEDD8 depletion. Our observations suggest that cancer progression may result from surgery-induced enhancement of NEDD8 expression and the subsequent immunosuppressive function of Tregs. More importantly, depleting or inhibiting NEDD8 can be an efficient strategy to reduce cancer metastasis after surgery resection by regulating the function of Tregs.

A Case of Immunodeficiency-associated Lymphoproliferative Disease Requiring Differentiation from Postoperative Lung Metastasis of Lung Cancer

A Case of Immunodeficiency-associated Lymphoproliferative Disease Requiring Differentiation from Postoperative Lung Metastasis of Lung Cancer

Tumor-Targeting Extracellular Vesicles Loaded with siS100A4 for Suppressing Postoperative Breast Cancer Metastasis.

S100A4 promotes the establishment of tumor microenvironment for malignant cancer cells, and knockdown of S100A4 can inhibit tumorigenesis. However, there is no efficient way to target S100A4 in metastatic tumor tissues. Here, we investigated the role of siS100A4-loaded iRGD-modified extracellular vesicles (siS100A4-iRGD-EVs) in postoperative breast cancer metastasis. siS100A4-iRGD-EVs nanoparticles were engineered and analyzed using TEM and DLS. siRNA protection, cellular uptake, and cytotoxicity of EV nanoparticles were examined in vitro. Postoperative lung metastasis mouse model was created to investigate the tissue distribution and anti-metastasis roles of nanoparticles in vivo. siS100A4-iRGD-EVs protected siRNA from RNase degradation, enhanced the cellular uptake and compatibility in vitro. Strikingly, iRGD-modified EVs significantly increased tumor organotropism and siRNA accumulation in lung PMNs compared to siS100A4-EVs in vivo. Moreover, siS100A4-iRGD-EVs treatment remarkedly attenuated lung metastases from breast cancer and increased survival rate of mice through suppressing S100A4 expression in lung. siS100A4-iRGD-EVs nanoparticles show more potent anti-metastasis effect in postoperative breast cancer metastasis mouse model. The online version contains supplementary material available at 10.1007/s12195-022-00757-5.

Effects of plant-based medicinal food on postoperative recurrence and lung metastasis of gastric cancer regulated by Wnt/β-catenin-EMT signaling pathway and VEGF-C/D-VEGFR-3 cascade in a mouse model

BackgroundThe plant-based medicinal food (PBMF) is a functional compound extracted from 6 medicinal and edible plants: Coix seed, L. edodes, A. officinalis L., H. cordata, Dandelion, and G. frondosa. Our previous studies have confirmed that the PBMF possesses anti-tumor properties in a subcutaneous xenograft model of nude mice. This study aims to further investigate the effects and potential molecular mechanisms of the PBMF on the recurrence and metastasis of gastric cancer (GC).MethodsPostoperative recurrence and metastasis model of GC was successfully established in inbred 615 mice inoculated with mouse forestomach carcinoma (MFC) cells. After tumorectomy, 63 GC mice were randomly divided into five groups and respectively subject to different treatments for 15 days as below: model control group, 5-Fu group, and three doses of PBMF (43.22, 86.44, 172.88 g/kg PBMF in diet respectively). The inhibition rate (IR) of recurrence tumor weights and organ coefficients were calculated. Meanwhile, histopathological changes were examined and the metastasis IR in lungs and lymph node tissues was computed. The mRNA expressions related to the canonical Wnt/β-catenin signaling pathway, epithelial-mesenchymal transition (EMT) and lymphangiogenesis were detected by RT-qPCR in recurrence tumors and/or lung tissues. Protein expressions of β-catenin, p-β-catenin (Ser33/37/Thr41), GSK-3β, p-GSK-3β (Ser9), E-cadherin, and Vimentin in recurrence tumors were determined by Western Blot. LYVE-1, VEGF-C/D, and VEGFR-3 levels in recurrence tumors and/or lung tissues were determined by immunohistochemistry staining.ResultsThe mRNA, as well as protein expression of GSK-3β were up-regulated and the mRNA expression of β-catenin was down-regulated after PBMF treatment. Meanwhile, the ratio of p-β-catenin (Ser33/37/Thr41) to β-catenin protein was increased significantly and the p-GSK-3β (Ser9) protein level was decreased. And PMBF could effectively decrease the mRNA and protein levels of Vimentin while increasing those of E-cadherin. Furthermore, PBMF markedly reduced lymphatic vessel density (LVD) (labeled by LYVE-1) in recurrence tumor tissues, and mRNA levels of VEGF-C/D, VEGFR-2/3 of recurrence tumors were all significantly lower in the high-dose group.ConclusionsPBMF had a significant inhibitory effect on recurrence and lung metastasis of GC. The potential mechanism may involve reversing EMT by inhabiting the Wnt/β-catenin signaling pathway. Lymphatic metastasis was also inhibited by PBMF via down-regulating the activation of the VEGF-C/D-VEGFR-2/3 signaling cascade.

Genetically engineered exosomes for targetedly preventing premetastatic niche formation and suppressing postoperative melanoma lung metastasis

Premetastatic niche (PMN) is a prerequisite for initiation of tumor metastasis. Targeting prevention of PMN formation in distant organs is becoming a promising strategy to suppress metastasis of primary tumor. Based on “organotropic metastasis”, melanoma tends to metastasize to lungs, where granulocytic myeloid-derived suppressor cells (G-MDSCs) recruitment in lungs significantly contributes to the PMN formation. Herein, functional exosomes (GExoI) were designed to present pulmonary targeting peptide GFE1 on the membrane and load PI3Kγ inhibitor (IPI549) inside, aiming at suppressing postoperative lung metastasis of melanoma. In postoperative mice model, intravenously injected GExoI could significantly accumulate in lungs and release IPI549 to block G-MDSCs recruitment through interfering with CXCLs/CXCR2/PI3Kγ signaling. The increased percentages of CD4+ T cells and CD8+ T cells in lungs could transform microenvironment from immunosuppression to immunostimulation, leading to metastasis inhibition. This study suggests an effective anti-metastasis strategy of targeting prevention of PMN formation through specifically blocking G-MDSCs recruitment.

The clinical features and prognostic outcomes of primary mediastinal yolk sac tumors: A retrospective analysis of 15 rare cases from multiple centers.

Primary mediastinal yolk sac tumors (PMYSTs) are a rare occurrence. As such, the clinicopathological features, treatment, and prognosis, of this disease still remain unclear. In this study, we aimed to provide further information relating to this rare malignancy in order to facilitate the creation of more specific clinical guidelines for the diagnosis and treatment of patients with PMYSTs.In this retrospective study, we recruited 15 patients who had been diagnosed with PMYST from four medical institutions to create a population-based cohort. We then used Kaplan-Meier analysis and the log-rank test to investigate and compare overall survival (OS) and progression-free survival (PFS).A total of 15 cases were identified. The mean age was 27.3 years (range: 19–34 years). The estimated 1- and 2-year PFS rates were 66.7% and 60.0%, respectively. The 1- and 2-year OS rates were both 73.3%. Computer tomography scans revealed tumors were located in the anterior middle mediastinum (5 cases), the anterior superior mediastinum (1 case), the left anterior mediastinum (3 cases), and the right anterior mediastinum (6 cases). Of the 15 patients receiving extended resections, the majority (40.0%) underwent tumor resection, partial pericardiotomy, pulmonary wedge resection, and mediastinal lymphadenectomy. R0 resections were achieved in eleven patients. Four patients underwent R2 resection and experienced postoperative complications, including pneumonia (2 cases), atelectasis (1 case), and bronchopleural fistula (1 case). Four patients developed postoperative lung metastasis. Three patients died due to progressive diseases. Disease recurred in all patients at a median of 8.0 months (range: 6.0–11.0 months).PMYST is a rare but highly malignant tumor with a poor prognosis. Tumor resection, with optimal extended surgical management, may provide patients with the best chance of a cure although postoperative complications relating to the pulmonary systems should be treated with caution.

Analysis of related risk factors of lung metastasis after laparoscopic radical hysterectomy of cervical cancer.

To explore the risk factors of lung metastasis in patients after laparoscopic radical hysterectomy (LRH) of cervical cancer (CC).The clinical data of CC patients with clinical stage of IA1–IIA2 diagnosed in our hospital from April 2007 to October 2015 were collected. According to the situation of metastasis, the patients were divided into lung metastasis (n = 73) and non-lung metastasis group (n = 2076). The clinical data were compared between 2 groups, and logistic stepwise regression model was used to analyze the risk factors of lung metastasis in patients with CC after LRH.The incidence of lung metastasis after LRH of CC was 3.39%, and 67.13% of patients with lung metastases had no obvious clinical symptoms. 15.06% patients had lung metastasis in the first year, 38.35% in the second year, 43.83% in the third year and later. The postoperative lung metastasis of CC was related to tumor diameter (P < .001), pathological type (P < .001), interstitial invasion depth (P < .001), pelvic lymph node metastasis (PLNM, P < .001), vascular tumor thrombus (P = .011), tumor uterine invasion (P = .002), and abnormal preoperative tumor markers (P = .015). However, it was not related to age, clinical stage, tumor growth pattern, tumor differentiation, and para-aortic lymph node metastasis (P > .05). Logistic regression analysis revealed non-squamous cell carcinoma (P = .022), tumor diameter ≥4 cm (P = .008), interstitial invasion depth >2/3 (P = .003), PLNM (P = .007), and tumor uterine invasion (P = .037) is an independent risk factor for lung metastasis after LRH of CC.Non-squamous cell carcinoma, tumor diameter ≥4 cm, tumor interstitial invasion depth >2/3, PLNM, and tumor uterine invasion are independent risk factors for lung metastasis after LRH of CC.

Prognostic value of apical lymph node metastasis at the inferior mesenteric artery in sigmoid and rectal cancer patients who undergo laparoscopic surgery.

Evidence supporting the importance of apical lymph nodes (LNs) and the potential long-term impact of LN metastases at the inferior mesenteric artery (IMA) lymphectomy remains limited. This study aimed to evaluate the prognostic value of LNs at the IMA (IMA-LN) in sigmoid and rectal cancer patients undergoing laparoscopic surgery. We retrospectively evaluated 265 consecutive patients who underwent laparoscopic sigmoid or rectal cancer surgery between August 2016 and May 2020. They were divided into two groups according to the pathological results of the IMA LNs: IMA-LN negative (n = 248) and IMA-LN positive (n = 17). The IMA-LN negative group had significantly better overall survival (OS) (p = .020) and disease-free survival (DFS) (p = .000) than did the IMA-LN positive group. IMA-LN metastasis was associated with worse OS and DFS regardless of the pN stage. Patients with IMA-LN metastasis had a higher risk of postoperative recurrence, especially liver (p = .000) and lung (p = .025) metastasis, than did those without metastasis. However, there was no significant difference in the local recurrence rate between the two groups. IMA-LN metastasis is an independent risk factor for poor prognosis in sigmoid and rectal cancer. Dissecting and evaluating IMA-LN separately is a more accurate and practical method for predicting prognosis.

Combination Immunotherapy with Cytotoxic T-Lymphocyte-Associated Antigen-4 and Programmed Death Protein-1 Inhibitors Prevents Postoperative Breast Tumor Recurrence and Metastasis.

Postoperative tumor recurrence and metastasis remain an extreme challenge in breast cancer. Therapies that target cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have provided unprecedented clinical benefits in various types of cancer. The aim of this study was to determine whether the combination of anti-CTLA-4 and anti-PD-1 could prevent postoperative breast tumor recurrence and metastasis in breast tumor-bearing mice. The results indicated that the combination of CTLA-4 and PD-1 inhibitors was more effective compared with single inhibitors for mammary tumor growth and prevention of postsurgical tumor recurrence and pulmonary metastasis (P < 0.05), which resulted in prolonged survival (P < 0.05). Analysis of the underlying mechanism revealed that anti-CTLA-4 and anti-PD-1 in combination synergistically promoted the infiltration of CD8+ and CD4+ T cells into tumors (P < 0.05 vs. single inhibitors), thus boosting the antitumor immune responses. In summary, our results revealed that combination immunotherapy with anti-CTLA-4 and anti-PD-1 may present a new, promising regimen to inhibit postoperative breast cancer relapse and lung metastasis and improve patient outcomes, which warrants further investigation in clinical settings.

Loss of CDH1 promotes the metastasis of hypopharyngeal squamous cell carcinoma through the STAT3-MMP-9 signaling pathway.

BackgroundDistant metastasis is the major cause of death in patients with hypopharyngeal squamous cell carcinoma (HSCC). CDH1 is correlated with tumor invasion and metastasis; however, its function in HSCC remains unclear.MethodsWe used immunohistochemistry (IHC) staining to evaluate the expression of CDH1 in 31 and 78 specimens from primary HSCC patients with and without postoperative lung metastases respectively. Sulforhodamine B (SRB) and CCK-8 assays were used to test the proliferation of HSCC cells. Motility of HSCC cells was investigated by migration and invasion assays. Western blot analysis was used to measure the levels of CDH1 and other proteins.ResultsWe found that the low expression of CDH1 was significantly associated with postoperative lung metastasis in HSCC (P<0.001). Moreover, CDH1 was reduced concomitantly with the upregulation of MMP-9 in the same HSCC sample. Further mechanistic investigation showed that silencing CDH1 elevated the level of MMP-9, which was coupled with the phosphorylation of STAT3. Subsequently, inhibiting STAT3 either by siRNA transfection or by pharmacological suppression with AG490 attenuated MMP-9 upregulation and prevented the enhanced proliferation and invasion caused by CDH1 loss in FaDu cells.ConclusionsCDH1 plays vital roles in HSCC metastasis and might serve as a potential therapeutic target for the clinical treatment of HSCC.

How to optimize the therapeutic effect of free autogenous fibula graft and wrist arthroplasty for giant cell tumors of distal radius?

The purpose of this study is to retrospectively analyze the clinical efficacy of free fibula autograft and wrist arthroplasty in the treatment of giant cell tumors (GCT) of distal radius. We retrospectively reviewed 26 patients with GCT of distal radius who underwent free autogenous fibula graft and wrist arthroplasty for repairing residual defect after en-block resection. The length of the fibula graft was 8.2 cm (6-10 cm). Postoperative follow-up regularly for an mean of 66.9 months. Bone healing was assessed by radiographs, pain was assessed by Visual Analog Scale (VAS) score and limb function was evaluated by Musculoskeletal Tumor Society (MSTS) score and disabilites of the arm, shoulder and hand (DASH) score. The range of motion (ROM) of wrist and grip strength were also evaluated. There were four males and 22 females with an mean age of 36.7 years (19-60 years); the mean length of lesions was 4.8 cm (2.3-6.6 cm); 21 primary cases and five recurrent cases; eight cases of Campanacci Grade II, 18 cases of Grade III. We had no postoperative lung metastasis and only one case had a local recurrence, three cases (11%) with subluxation of lower ulnoradial joints and five cases (19%) showed narrowing of wrist joint space. The mean postoperative VAS pain score was 0.7 ± 0.7 and grip strength retained 71% of the normal hand, MSTS score was 27.7 ± 1.1 and DASH score was 9.0 ± 3.7. The ROM of the involved wrist only slightly restricted and no donor complications. Postoperative wrist joint function was significantly improved. Strict surgical resection boundary and solid reconstruction of wrist joint capsule are the key to achieving excellent oncological prognosis and function of distal radius GCT.

Correlations between the Recurrence Patterns and Sizes of Lateral Pelvic Lymph Nodes before and after Chemoradiotherapy in Patients with Lower Rectal Cancer

Objective: Factors that predict rectal cancer metastasis to the lungs remain undefined. We investigated whether the lateral pelvic lymph node (LPN) sizes before and after chemoradiotherapy (CRT) correlate with lung metastasis after surgery for lower rectal cancer. Methods: Two hundred and forty patients with lower rectal cancer who received preoperative CRT and curative surgery between 2003 and 2017 were examined. Computed tomography-measured LPN sizes before and after CRT were retrospectively determined by 1 colorectal surgeon who was blinded to the patients’ clinical and pathological outcomes. Results: The 5-year cumulative lung metastasis rates were 15.2%. The mean LPN sizes in patients who developed lung metastasis were larger than those in patients who did not (pre-CRT: 8.7 vs. 6.3 mm, p = 0.003; post-CRT: 6.8 vs. 4.5 mm, p = 0.001). The cumulative lung metastasis rate in patients with large LPNs was higher than in those with small LPNs both before and after CRT. On multivariate analysis, lung metastasis was independently correlated with the LPN size only after CRT (hazard ratio [HR]: 5.58), together with the ypT stage (HR: 2.96) and the tumor location (HR: 0.38). Conclusions: LPN size after CRT is strongly predictive of postoperative lung metastasis in patients with lower rectal cancer.

A case report of resection for postoperative lung metastasis of pancreatic cancer after systemic chemotherapy

We often encounter recurrence after surgery for pancreatic cancer. Systemic chemotherapy is usually undergone for such recurrence, however, prognosis is very poor. We reported a case whose postoperative lung metastasis of pancreatic cancer was able to resect after systemic chemotherapy. The patient was a 56-year-old female who underwent distal pancreatectomy for invasive ductal carcinoma of the pancreatic body in 2012. Pathological examination of the resected specimen demonstrated that moderately differentiated tubular adenocarcinoma invaded into splenic vein and diagnosed as Stage IIA (pT3 pN0 M0) according to the seventh edition of TNM classification. Postoperative course was uneventful and she received standard adjuvant chemotherapy with gemcitabine for six months. One year after operation, bilateral and multiple lung metastases were shown on computed tomography. Consequently, we started systemic chemotherapy with S-1 and continued for 2 years and 6 months. No other distant metastases than lung presented and the number of lung metastases decreased by chemotherapy. Finally, only one nodule remained in right lung on computed tomography, therefore, we considered to be resectable. She underwent surgery for lung metastasis after four years of the operation for primary pancreatic cancer, and pathological examination confirmed lung metastasis of pancreatic cancer. Now, one year has passed since lung metastasis was resected, there was no evidence of recurrence. In conclusion, we reported a case that postoperative lung metastasis of pancreatic cancer became resectable by systemic chemotherapy and successfully treated by surgery.

Metformin Enhances the Effect of Regorafenib and Inhibits Recurrence and Metastasis of Hepatic Carcinoma After Liver Resection via Regulating Expression of Hypoxia Inducible Factors 2α (HIF-2α) and 30 kDa HIV Tat-Interacting Protein (TIP30).

BackgroundRegorafenib (RGF) is the drug of choice for treating hepatic carcinoma (HCC), but the drug has drawbacks due to resistance and associated adverse effects. Thus, it becomes crucial to understand the causal ‘map’ of the resistance conferred by RGF, so that its clinical potency can be amplified, resulting in enhanced efficacy with reduced adverse effects. Metformin (MTF) has been reported to target NLK (Nemo-like kinase) to inhibit non-small lung cancer cells. Based on the literature, the present investigation was carried out to reveal the effect of RGF and MTF, with an expectation that MTF can synergize therapeutic potential as well reduce chances of resistance.Material/MethodsProtein expression of hypoxia inducible factors (HIF)-2α, 30 kDa HIV Tat-interacting protein (TIP30), E-cadherin, N-cadherin, and pAMPK were assessed by Western blot analysis. RGF and MTF were exposed to MHCC97H cell and proliferation was quantified by assay of cell viability. Gene silencing and chromatin immunoprecipitation assay were done to reveal the relationship between TIP30 and HIF-2α. The impact of RGF and MTF together on postoperative recurrence and lung metastasis of hepatocellular carcinoma was investigated using tumor engrafted mice after administration of MTF and RGF once daily for 35 days. Immunohistochemistry was used to reveal CD31, Ki67, and TUNEL.ResultsThe results suggested MTF-RGF combination lowered expression of HIF-2α gene silencing and suggested increased TIP30 after reduction of HIF-2α. The chromatin immunoprecipitation study indicated that under hypoxia, HIF-2α could bind with TIP30 promoter. Cell number quantification (CCK8), viable cell count, and apoptosis data (using Annexin V-FITC) indicated co-administration of RGF and MTF reduced cell proliferation, encouraging cell apoptosis, and reduced epithelial-mesenchymal transition course. Thus, in orthotopic mice, the RGF-MTF combination exhibited substantial reduction of HCC in lung metastasis and postoperative relapse.ConclusionsMTF can enhance the potential of RGF and inhibit the recurrence and metastasis of HCC after postoperative liver section by regulating the levels of TIP30 and HIF-2α.

Mechanical ventilation promotes lung metastasis in experimental 4T1 breast cancer lung-metastasized models.

Background/purposeThe aim of this study was to test the hypothesis that mechanical ventilation (MV) during cancer surgery induces lung stroma/tissue milieu changes, creating a favorable microenvironment for postoperative lung metastatic tumor establishment.Materials and methodsIn Protocol A, female BALB/c mice were divided into an MV group and a control (no MV) group, both of which were anesthetized and subjected to intravenous injection of green fluorescent protein (GFP)-labeled mouse mammary carcinoma cell line (4T1) cells. After 24 h, the lung tissue was removed and the number of GFP-labeled 4T1 cells was calculated. In Protocol B, the clinically relevant mouse model of spontaneous breast cancer lung metastasis was used with surgical resection of the primary tumor to investigate the MV event that dictates postoperative lung metastasis. Female BALB/c mice were inoculated in the mammary fat pad with 4T1 cells. After 14-d growth, mice were anesthetized and divided into an MV group and a control (no MV) group during surgical procedures (mastectomy). Metastatic tumor burden was assessed two weeks after mastectomy by both macroscopic metastatic nodule count, hematoxylin–eosin histology, immunohistochemistry for the macrophage marker (CD68), and epithelial cell adhesion molecule (EpCAM).ResultsMV was associated with a significant increase in the number of circulating breast tumor cells (GFP-labeled 4T1 cells) remaining in the microvasculature of the lung (P<0.01). Immunohistochemical results showed increased infiltration of CD68-positive macrophages within injured lung parenchyma and metastatic tumor as well as increased expression of EpCAM in metastatic nodules. Postoperative metastases were more prevalent in the mechanically ventilated mice group compared to the non-ventilated group (P<0.05).ConclusionMV-induced lung metastasis occurs by attracting circulating tumor cells to the site of the lung injury and by accelerating the proliferation of preexisting micro-metastases in the lung. These observations indicate that the metastasis-enhancing effect of MV should be considered in general anesthesia during cancer surgery.

Circulating Tumor Cells from Different Vascular Sites Exhibit Spatial Heterogeneity in Epithelial and Mesenchymal Composition and Distinct Clinical Significance in Hepatocellular Carcinoma.

Purpose: The spatial heterogeneity of phenotypic and molecular characteristics of CTCs within the circulatory system remains unclear. Herein, we mapped the distribution and characterized biological features of CTCs along the transportation route in hepatocellular carcinoma (HCC).Experimental Design: In 73 localized HCC patients, blood was drawn from peripheral vein (PV), peripheral artery (PA), hepatic veins (HV), infrahepatic inferior vena cava (IHIVC), and portal vein (PoV) before tumor resection. Epithelial and mesenchymal transition (EMT) phenotype in CTCs were analyzed by a 4-channel immunofluorescence CellSearch assay and microfluidic quantitative RT-PCR. The clinical significance of CTCs from different vascular sites was evaluated.Results: The CTC number and size gradient between tumor efferent vessels and postpulmonary peripheral vessels was marked. Tracking the fate of CTC clusters revealed that CTCs displayed an aggregated-singular-aggregated manner of spreading. Single-cell characterization demonstrated that EMT status of CTCs was heterogeneous across different vascular compartments. CTCs were predominantly epithelial at release, but switched to EMT-activated phenotype during hematogeneous transit via Smad2 and β-catenin related signaling pathways. EMT activation in primary tumor correlated with total CTC number at HV, rather than epithelial or EMT-activated subsets of CTCs. Follow-up analysis suggested that CTC and circulating tumor microemboli burden in hepatic veins and peripheral circulation prognosticated postoperative lung metastasis and intrahepatic recurrence, respectively.Conclusions: The current data suggested that a profound spatial heterogeneity in cellular distribution and biological features existed among CTCs during circulation. Multivascular measurement of CTCs could help to reveal novel mechanisms of metastasis and facilitate prediction of postoperative relapse or metastasis pattern in HCC. Clin Cancer Res; 24(3); 547-59. ©2017 AACR.

Comparison of clinical efficacy and complications of 125I seed brachytherapy and stereotactic body radiation therapy for recurrent pulmonary metastases from colorectal carcinoma.

PurposeTo evaluate the efficacies of 125I seed implantation and stereotactic body radiation therapy (SBRT) in treatment of recurrent lung metastases from colorectal cancer, to compare the tolerance of lung tissue to both forms of radiotherapy, and to analyze the factors that affect the prognosis.Material and methodsAccording to treatment received, thirty colorectal cancer patients with post-operative lung metastases were separated into two groups: 125I seed implantation group (group A; n = 16) and SBRT group (group B; n = 14). Patients were followed up, and local control rate, survival, and post-operative complications were analyzed retrospectively. Kaplan-Meier method was used for survival analysis. Cox proportional hazards model was used to identify the independent predictors of poor prognosis.ResultsSurvival was significantly different between group A and group B (median survival, 15 months and 11.5 months, respectively; p = 0.015). Local control rates at the first, third, sixth, and twelfth months after treatment were all > 80%, with no significant difference between the two groups (p = 0.829). Significant differences were seen between the two groups in the number of treatments received (p = 0.009) and the incidence of radiation pneumonitis (p < 0.001) as well as radiation-induced pulmonary fibrosis (p = 0.005). On multivariate regression analysis radiation pneumonitis was an independent predictor of poor prognosis (HR = 3.356, 95% CI: 1.518-7.421; p = 0.003).Conclusions125I seeds brachytherapy and SBRT are both effective for control of lung metastases but the former causes milder lung tissue damage. It can be repeated after short intervals, and appears to be a safe and efficient treatment for lung metastases.

Long-term survival of high-grade primary peritoneal papillary serous adenocarcinoma: a case report and literature review

BackgroundPrimary peritoneal papillary serous carcinoma (PPPSC) is an uncommon disease which has a high malignancy and a poor prognosis.Case presentationWe report here a long-term survival case of PPPSC with postoperative lung metastasis. A 62-year-old female patient with PPPSC was administered two cycles of neoadjuvant chemotherapy (NAC) followed by cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) and six cycles of platinum-based (docetaxel + carboplatin) intraperitoneal chemotherapy postoperatively. The patient reached a complete remission at the completion of primary treatment. Malignant thoracic effusion and lung metastasis developed 5 months after the treatment. The patient underwent video-assisted thoracoscopic surgery plus hyperthermic intrapleural chemotherapy.ConclusionsUp to present, the patient has been survived with tumor for over 86 months with a good performance status, with only encapsulated effusion found at the latest follow-up. As a relatively new regime, the application of CRS + HIPEC in our patient has been proved example for MPE management, although more large-scale studies are needed to substantiate its efficiency and safety.

Metformin sensitizes sorafenib to inhibit postoperative recurrence and metastasis of hepatocellular carcinoma in orthotopic mouse models

BackgroundSorafenib is recognized as a standard treatment for advanced hepatocellular carcinoma (HCC). However, many patients have to adopt dose reduction or terminate the use of sorafenib because of side effects. In addition, a large number of patients are resistant to sorafenib. Thus, it is essential to investigate the underlying mechanisms of the resistance to sorafenib and seek potential strategy to enhance its efficacy.MethodsThe protein expression of hypoxia-inducible factors (HIF)-2α, 30-kDa HIV Tat-interacting protein (TIP30), E-cadherin, N-cadherin, and pAMPK was detected by Western blot. Cell viability assays were performed to study the influence of metformin and sorafenib on cell proliferation. Annexin V-FITC apoptosis assays were used to detect the influence of metformin and sorafenib on cell apoptosis. The relationship between HIF-2α and TIP30 was studied using gene silencing approach and chromatin immunoprecipitation assay. To investigate the effect of metformin and sorafenib on postoperative recurrence and lung metastasis of HCC in tumor-bearing mice, the mice were orally treated either with metformin or sorafenib once a day for continuous 37 days after the operation to remove the lobe where the tumor was implanted. CD31, Ki67, and TUNEL were examined by immunohistochemistry.ResultsOur study demonstrated that metformin synergized with sorafenib reduced HIF-2α expression as examined by Western blot. Gene silencing approach indicated TIP30 was upregulated after knocking-down of HIF-2α and chromatin immunoprecipitation assay revealed that HIF-2α could bind to TIP30 promoter under hypoxic condition. Cell Counting Kit-8 (CCK8) cell viability assay and Annexin V-FITC apoptosis assay showed that metformin in combination with sorafenib suppressed cell proliferation and promoted cell apoptosis. Besides, combined therapy suppressed epithelial-mesenchymal transition (EMT) process both in vitro and in vivo. Moreover, metformin in combination with sorafenib significantly minimized postoperative recurrence and lung metastasis of HCC in orthotopic mouse model. Combined therapy inhibited CD31 and Ki67 expression but promoted TUNEL expression.ConclusionsMetformin may potentially enhance the effect of sorafenib to inhibit HCC recurrence and metastasis after liver resection by regulating the expression of HIF-2α and TIP30.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0253-6) contains supplementary material, which is available to authorized users.

Anatomic resection of liver segments 6-8 for hepatocellular carcinoma

To report the devised anatomic liver resection of segments 6, 7 and 8 to improve the resection rate for patients with right liver tumors. We performed anatomic liver resection of segments 6, 7 and 8 to guarantee the maximum preservation of the remaining normal liver tissue. Segment 5 was determined by two steps of Glissonean pedicle occlusion. And a "┏┛" shaped broken resection line was marked upon the diaphragmatic surface of the liver. Selective right hemihepatic inflow occlusion was used to reduce blood loss during parenchymal transection between segments 6 and 5 and between segments 8 and 5. If needed, total hepatic Glissonean pedicle occlusion was used during parenchymal transection between segment 8 and the left liver. Compared to right hemihepatectomy, the percentage of future liver remnant volume was increased by an average of 13.9% if resection of segments 6, 7 and 8 was performed. Resection of segments 6, 7 and 8 was completed uneventfully. After hepatectomy, the inflow and outflow of segment 5 were maintained. There was no perioperative mortality, postoperative abdominal bleeding or bile leakage in this group. Alpha-fetoprotein (AFP) returned to the normal range within 2 mo after the operation in all the patients. One patient died 383 d postoperatively due to obstructive suppurative cholangitis. One patient suffered from severe liver dysfunction shortly after surgery and had intrahepatic recurrence 4 mo postoperatively. Postoperative lung metastasis was found in one patient. No tumor recurrence was found in the other patients and the parameters including liver function and AFP level were in the normal range. Anatomic liver resection of segments 6, 7 and 8 can be a conventional operation to improve the overall resection rate for hepatocellular carcinoma.