Tumor-associated macrophages mediate gastrointestinal stromal tumor cell metastasis through CXCL2/CXCR2.

BACKGROUND: Tumor-associated macrophages (TAMs) are linked with the progression and poor prognosis of multifarious solid tumors, but the regulatory mechanisms involved in gastrointestinal stromal tumors (GIST) remain indistinct. This study intended to delve into the job of TAM-derived chemokines in promoting metastasis in GIST microenvironment. METHODS: Expression levels of M2-TAM markers and CXCL2 in primary and metastatic tissues of GIST were analyzed by bioinformatics methods, and we analyzed the correlation between CXCL2 and M2-TAM markers. Immunofluorescence was applied to assay CXCL2 and M2-TAM marker protein (CD68 and CD206) expression in tumor tissues. Serum CXCL2 concentration in metastatic and non-metastatic patients was assayed by ELISA. The differentiation of THP-1 cells was tested by flow cytometry. Cell function test was utilized to analyze the viability, invasion and migration of GIST cells. Western blot was used to examine the expression of epithelial-mesenchymal transition (EMT)-related proteins. The mouse liver metastasis model was established, and the effects of CXCL2 and EMT-related genes on metastasis were confirmed by hematoxylin-eosin staining and immunohistochemistry experiments. RESULTS: Bioinformatics analysis ascertained that M2-TAM marker proteins and chemokine CXCL2 were highly expressed in GIST metastatic tissues, and CXCL2 and TAM were co-located in tumor tissues. Results of in vitro cell function experiments displayed that CXCL2 secreted by M2-TAM promoted the invasion, migration and EMT of GIST tumor cells, and the anti-CXCL2 antibody could block the metastasis promoting effect of CXCL2. Additionally, the silencing of CXCR2 in GIST cells inhibited the metastasis promoting effect of CXCL2. Animal studies further confirmed that CXCL2 promoted liver metastasis of GIST in vivo. CONCLUSION: This study preliminarily revealed the mechanism of M2-TAM promoting tumor metastasis by secreting CXCL2 in GIST tumor microenvironment, and proffered theoretical reference for the development of immunotherapy strategies targeting M2-TAM.

Spontaneous intramural hematoma of the alimentary canal.

Spontaneous intramural hematoma of the alimentary canal has rarely been reported. We present two cases in which anticoagulation therapy brings spontaneous intramural hematoma of the alimentary canal. In one case, the lesion was located in the ileum, and the other was located in the ascending colon and distal ileum. Both patients were cured through conservative treatment. We suggest that increased attention should be paid if a patient has acute abdominal pain with a history of oral anticoagulant therapy, and the diagnosis of spontaneous intermural hematoma should be considered.

New clinical application of high-intensity focused ultrasound: local control of synovial sarcoma.

High-intensity focused ultrasound (HIFU) is playing an increasingly important role in cancer therapy. Primary synovial sarcomas of the chest wall are extremely rare. We report the first case of noninvasive HIFU therapy for the control of synovial sarcoma. A 51-year-old man was diagnosed with spindle cell sarcoma on the left chest wall through lumpectomy. After four cycles of chemotherapy, local recurrence of the sarcoma was detected. Subsequent extended resection confirmed synovial sarcoma. After five cycles of a new chemotherapy option, the sarcoma relapsed again. Then the patient received five courses of HIFU; this completely ablated the sarcoma without complications. No chemotherapy, radiotherapy, or biological therapy has been applied since. Now the patient is stable and has a high quality of life.

Solid-pseudopapillary neoplasms of the pancreas: clinical and pathological features of 33 cases.

PURPOSE: Solid-pseudopapillary neoplasms (SPNs) are rare pancreatic tumors, with a low potential for malignancy. The clinical and pathological features of 33 SPNs were reviewed. METHODS: This study conducted a retrospective analysis of 33 patients who underwent surgery for a pathologically confirmed SPN from 2000 to 2011. RESULTS: Thirty of the 33 patients (91 %) were female, and the median age at diagnosis was 29.2 years (range 12-59). The most common symptom was abdominal discomfort with dull pain (58 %). Others included asymptomatic lesions that were only detected incidentally during imaging (21 %), a palpable abdominal mass (15 %) and indigestion (6 %). All 33 patients underwent surgery with a curative intent and 3 (9 %) underwent laparoscopic surgery. The mean diameter of the tumors was 4.9 cm (range 2-15 cm), and they occurred in the head (9, 27 %), neck (5, 15 %), body or tail (19, 58 %) of the pancreas. One patient had lymph node metastases, one patient had portal venous invasion and 8 patients had perineural invasion. The patient follow-up ranged from 4 to 118 months, and 32 patients were alive and well without recurrence. One patient relapsed 10 months after distal pancreatectomy with splenectomy and underwent a second surgery via laparotomy. Unfortunately, the patient died of multiple organ failure 12 days after the second surgery. CONCLUSION: SPNs are rare neoplasms with malignant potential but excellent prognosis. Adequate surgical resection, including laparoscopic surgery, may therefore be performed safely and is associated with a long-term survival, even in invasive cases.

YAP/TAZ axis was involved in the effects of metformin on breast cancer.

Breast cancer is malignant tumours in women. A large amount of data analysis shows that Metformin has been shown to play a significance role in reducing the risk of breast cancer, but the mechanism remains unclear. The hippo signalling pathway can be involved in the formation, metastasis and recurrence of breast cancer. When YAP/TAZ is activated, cells can overcome contact inhibition and enter a state of uncontrolled proliferation. Therefore, YAP/TAZ is considered a potential therapeutic target for breast cancer. Eighty breast cancer patients, forty cases of triple-negative and forty cases of HER-2+, were included in this study. In vitro and in vivo experiments were used to confirm the YAP/TAZ axis was involved in the effects of metformin on breast cancer. EMT plays an important role in breast cancer, including chemoresistance and tumour metastasis. Our results confirmed that YAP could modulate the activity of EMT, which in turn altered tumour resistance. Therefore, MET can inhibit EMT by reducing the expression of YAP, and finally achieve the therapeutic effect of breast cancer. Our findings support metformin as a novel YAP inhibitor and potentially as a novel breast cancer drug.

Enhanced lymph node retrieval from colorectal cancer resections using a simple lymphatic staining method.

BACKGROUND/AIMS: This study evaluated the effect of lymphatic staining on the number of lymph nodes (LNs) examined and staging in patients with colorectal cancer. METHODOLOGY: Sixty-two consecutive specimens from patients with colorectal cancer resected between February 2009 and April 2010 were randomized to the stained group or the control unstained. Differences in the retrieval, number and size of nodes, and time for retrieval were measured. RESULTS: LN harvest differed significantly with 30±12 and 13±5 (p<0.01) nodes in the stained and the control groups, respectively. Insufficient LN harvest (less than 12 nodes) occurred in 14 cases of the control group and only in 1 case of the stained group (p<0.01). Metastases were confirmed in 57 LNs occurring in 17 cases of the stained group and in 39 nodes occurring in 15 cases of the control group. The mean time for LN retrieval in the stained and control groups were comparable, 27.6±6.9min and 24.7±6.0min (p>0.05), respectively, yet there was a significant difference in the number of LNs (<2mm) (294 vs. 59, respectively, p<0.01) as well as in the number of LNs 2-5mm in size (474 vs. 220, respectively, p<0.01). CONCLUSIONS: By lymphatic staining method, more and smaller LNs could be detected, which significantly improved the LN harvest of resected colorectal specimens and reduced cases of insufficient LN harvest.

[Research progress of protein tyrosine phosphatase SHP-2].

The Src homology-2 domain-containing phosphatase SHP-2 encoded by PTPN11 is an essential component in several signaling pathways.Different types of mutation in SHP-2 have been confirmed in several types of leukemia and solid tumors. Elucidation of the events underlying Shp2-evoked transformation may provide new insights into the novel targets for anti-cancer therapy.

[Corrigendum] Cyclophilin D modulates cell death transition from early apoptosis to programmed necrosis induced by honokiol.

Subsequently to the publication of the above article, the authors have realized that the printed version of Fig. 6 on p. 1661 contained some mistakes. Potential anomalies regarding this figure concerning the duplication of data both within Fig. 6 and comparing data between Figs. 5 and 6 were also drawn to our attention by an interested reader. Specifically, the authors realized that the bands of BCL­xl were erroneously selected from the GAPDH dataset during the process of compiling this figure. The authors subsequently found that the original photographs of these western blot bands had been lost during the time period that had elapsed since these experiments were completed. In order to corroborate the results, the authors repeated the contentious experiments shown in Fig. 6 and obtained similar results, thereby corroborating the results and conclusions reported in this study. A revised version of Fig. 6, containing the newly obtained data, is shown below. The errors made with the assembly of Fig. 6 originally did not have an adverse bearing on the overall conclusions reported in this study. The authors are grateful to the Editor of International Journal of Oncology for allowing them the opportunity to publish this Corrigendum, and all of the authors agree to the publication of this Corrigendum. The authors sincerely apologize for their errors, and apologize to the readership of the Journal for any inconvenience caused. [the original article was published in International Journal of Oncology 42: 1654­1663, 2013; DOI: 10.3892/ijo.2013.1863].

Clinical and epidemiologic profile of venomous snakebites in Chongqing Wuling mountainous area, western China.

BACKGROUND: In China, venomous snakebites are an important medical emergency and cause of hospital admission, but few studies have looked at the clinical and epidemiologic profile of human snakebite victims. METHODS: We conducted a retrospective study of 440 snakebite cases encountered at a single hospital in the Chongqing Wuling mountainous area of western China from July 2004 to August 2018. Data were collected from the electronic medical record system. RESULTS: The majority of bite victims were male (58.4%), 41-60 y of age (37.9%) and the bites occurred during the daytime (51.1%) in July-September (62.5%). The lower limbs were the most vulnerable sites to snakebites (73.9%). The most common local toxicity consisted of pain (86.1%), oedema (78.4%) and bleeding (35.9%). Of the systemic toxicities, haematuria (14.3%) and ophthalmoplegia (9.5%) were common. The majority (86.4%) of individuals presented to the hospital within 6 h. CONCLUSIONS: This study describes the clinical and epidemiologic profile of venomous snakebites in the Chongqing Wuling mountainous area of western China. Multicentre prospective studies were needed in the entire country of China.

An updated meta-analysis of transanal drainage tube for prevention of anastomotic leak in anterior resection for rectal cancer.

BACKGROUND: Anastomotic leakage (AL) is one of the most serious complications after anterior resection for rectal cancer. Transanal drainage tube (TDT) placement is widely used to reduce AL, but its efficacy remains controversial. We performed a meta-analysis to evaluate the effectiveness of TDT for prevention of AL, using updated evidence. METHODS: Randomized controlled trials (RCTs) and cohort studies evaluating the effectiveness of TDT for prevention of AL after anterior resection for rectal cancer were identified by using a predefined search strategy. Meta-analysis was performed to estimate the pooled rates of AL, reoperation, anastomotic bleeding and mortality separately. RESULTS: One RCT and ten cohort studies which including 1170 cases with TDT and 1262 cases without TDT were considered eligible for inclusion. Meta-analysis showed that the TDT group was associated with a significant lower rates of AL (RR: 0.42, 95% CI: 0.31-0.58, P < 0.00001) and reoperation (RR: 0.29, 95% CI: 0.19-0.45, P < 0.00001). There was no significant difference in anastomotic bleeding rate and mortality between the two groups. CONCLUSIONS: TDT placement is associated with significant lower rates of AL and reoperation, hence it is likely to be an effective method of preventing and reducing AL after rectal cancer surgery.

18ß-glycyrrhetinic acid inhibits migration and invasion of human gastric cancer cells via the ROS/PKC-α/ERK pathway.

18ß-glycyrrhetinic acid (18ß-GA) is a bioactive component of licorice root which exerts pharmacological activities including anti-inflammatory, antiviral, anti-oxidative and anti-cancer effects. The current study further investigated the molecular mechanisms associated with the inhibitory effects of 18ß-GA on tumor metastasis in human gastric cancer cells. The results indicated that 18ß-GA significantly reduced invasion and migration activities and suppressed MMP-2 and 9 activities on SGC-7901cells in a dose-dependent manner. Further study showed 18ß-GA upregulated E-cadherin expression but downregulated vimentin expression. The results also showed that 18ß-GA inhibited ROS formation, PKC-α expression and the phosphorylation of ERK in a dose-dependent manner. In conclusion, this study revealed that 18ß-GA inhibits migration and invasion via the ROS/PKC-α/ERK signaling pathway in gastric cancer cells. This suggests that 18ß-GA has the potential to be used as an effective chemopreventive agent for the prevention of gastric cancer metastasis.

MicroRNA-194 modulates epithelial-mesenchymal transition in human colorectal cancer metastasis.

MicroRNAs (miRNAs), as key regulators of gene expression, are closely related to tumor occurrence and progression. MiR-194 has been proved as a tumor regulatory factor in various cancers; however, the biological function and mechanism of action in colorectal cancer (CRC) have not been well explored. In the present study, we found that miR-194 expression is upregulated in CRC clinical specimens, while overexpression of miR-194 promotes cell migration and invasion in CRC cell lines. Besides, miR-194 significantly influenced the epithelial-mesenchymal transition (EMT) markers by downregulating E-cadherin expression (P<0.01) and upregulating vimentin and MMP-2 expression (P<0.001, P<0.05). Cell migration is the cell movement related to actin cytoskeleton. In this study, we found miR-194 increased cell polarization in SW480 cells. Moreover, zymography assay showed that miR-194 significantly upregulated the gelatin-degrading activity of MMP-2 (P<0.01). Collectively, our findings suggest that miR-194 functions as a tumor promoter in CRC, which may provide new insights for the study of CRC development and metastasis.

The Protective Effects of 18ß-Glycyrrhetinic Acid on Helicobacter pylori-Infected Gastric Mucosa in Mongolian Gerbils.

18ß-Glycyrrhetinic acid (GRA), a major component of Glycyrrhiza glabra, is widely used therapeutically in clinic. In this study, the effect of GRA on Helicobacter pylori- (H. pylori-) infected gastritis was investigated in Mongolian gerbils in vivo. The gerbils were randomly divided into groups: uninfected; H. pylori-infected; H. pylori + antibiotics (clarithromycin, amoxicillin, and esomeprazole); and H. pylori + GRA. The gastric intraluminal pH value, histopathological changes, and the expression levels of inflammation-related cytokines (IL-1ß, TNF-α, COX-2, and iNOS) were investigated. The results showed that, in the H. pylori + GRA group, the intraluminal gastric pH value was lower (2.14 ± 0.08 versus 3.17 ± 0.23, P < 0.05), erosion and hyperplasia were alleviated, the infiltration of neutrophils and mononuclear cells was attenuated (P < 0.05), and the expression levels of TNF-α, IL-1ß, COX-2, and iNOS were decreased (P < 0.05) compared with the H. pylori-infected group. There was no significant difference in results between the H. pylori + GRA group and the H. pylori + antibiotics group. This study indicated that GRA significantly attenuated H. pylori-infected gastritis in gerbils and has the potential to be developed as a new therapeutic drug.

Jejunal intussusception and polyps with different types of malignant transformation in Peutz-Jeghers syndrome: Report of a case.

Intussusception and malignant polyps are complications of Peutz-Jeghers syndrome. Very few cases of intussusception combined with polyps with different types of malignant transformation in Peutz-Jeghers syndrome have been reported to date. In the present study, we describe a case of Peutz-Jeghers syndrome with jejunal intussusception and malignant hamartoma in the jejunum and descending colon, combined with mucinous adenocarcinoma in the sigmoid colon.

Diaphragmatic perforation with colonic herniation due to hepatic radiofrequency ablation: A case report and review of the literature.

Radiofrequency ablation (RFA) has been widely accepted as an alternative treatment for unresectable primary and metastatic hepatic tumors, with satisfactory rates of local response and significant improvements in rates of overall survival. Numerous large series studies have shown that RFA is safe and effective, with a low mortality rate and a low major complication rate. Major complications, including diaphragmatic perforation and hernia, have rarely been previously reported. The current case report presents a case of diaphragmatic hernia with perforation of the incarcerated colon in the thoracic cavity 12 months following hepatic RFA, and reviews nine previously reported cases of diaphragmatic hernia. Comprehensive analysis of the nine cases demonstrated possibilities leading to diaphragmatic hernia following diaphragmatic thermal injury as a consequence of hepatic RFA. Clinicians and radiologists must consider diaphragmatic thermal damage following hepatic RFA for liver tumors adjacent to the diaphragm, particularly for patients with symptoms of ileus, dyspnea, chest pain, pleural effusion and right shoulder pain.

Cyclophilin D modulates cell death transition from early apoptosis to programmed necrosis induced by honokiol.

Honokiol is a pharmacologically active small molecule with multifunctional antitumor effects. Although plenty of literature is available on honokiol-triggered apoptosis and programmed necrosis, few studies have investigated the potential existence of death mode transition from apoptosis to programmed necrosis. In the current study, we demonstrated that the necrotic cell population (PI-positive) gradually increased and the early-stage apoptotic cell population (PI-negative and AV-positive) decreased in a dose- and time-dependent manner following honokiol treatment. Furthermore, we demonstrated that these PI-positive cells were under necrotic cell death, since no late-apoptosis characteristics including conspicuous chromatin condensation or DNA ladder patterns were detected. These results demonstrated that cells suffered death mode transition from early-stage apoptosis to programmed necrosis with the increase of honokiol dose or treatment time. The protein expression of RIP3 markedly increased in parallel with HNK-triggered death mode transition, while the expression of RIP1 decreased. Cyclophilin D expression increased during cell death mode transition, and inhibition of cyclophilin D by cyclosporin A clearly blocked HNK-triggered programmed necrosis. These data indicated that honokiol-induced programmed necrosis and death mode transition are potentially RIP3­dependent, cyclophilin D-regulated. Further results showed that blocked cyclophilin D by cyclosporin A inhibited HNK-induced necrosis, but did not affect HNK-induced RIP3 overexpression. This indicated that cyclophilin D was a potential modulator at downstream of RIP3. In conclusion, honokiol triggers a potential RIP3-dependent cell death mode transition from early-stage apoptosis to programmed necrosis, which is highly regulated by cyclophilin D.

Down-regulation of microRNA-200c is associated with drug resistance in human breast cancer.

Drug resistance remains a major clinical obstacle to successful treatment in breast cancer patients, and the evidence of microRNAs involvement in cancer drug resistance has been emerging recently. However, the role of microRNA-200c (miR-200c) in modulating chemoresistance of breast cancer remains largely unexplored. Here, we investigated the miR-200c expression in tumor specimens obtained from thirty-nine breast cancer patients who received neoadjuvent chemotherapy by quantitative real-time PCR. Down-regulated miR-200c was observed in non-responders as compared to responders. In addition, miR-200c expression was observed to be down-regulated over 800-fold in human breast cancer cells resistant to doxorubicin MCF-7/ADR as compared to the parental MCF-7 cells. Up-regulation of miR-200c with transfection of miR-200c mimics in breast cancer cells could enhance the chemosensitivity to epirubicin and reduce expression of multidrug resistance 1 mRNA and P-glycoprotein. Moreover, our study demonstrated that restoration of miR-200c in MCF-7/ADR cells could increase intracellular doxorubicin accumulation determined by flow cytometry. Taken together, our findings suggest that miR-200c may act as a promising therapeutic target for improvement of responsiveness to chemotherapy in breast cancer.

Colorectal cancer lymph node staining by activated carbon nanoparticles suspension in vivo or methylene blue in vitro.

AIM: To investigate whether activated carbon nanoparticles suspension (ACNS) or methylene blue (MB) can increase the detected number of lymph nodes in colorectal cancer. METHODS: Sixty-seven of 72 colorectal cancer patients treated at our hospital fulfilled the inclusion criteria of the study which was conducted from December 2010 to February 2012. Seven patients refused to participate. Eventually, 60 patients were included, and randomly assigned to three groups (20 in each group): ACNS group (group A), MB group (group B) and non-stained conventional surgical group (group C). In group A, patients received subserosal injection of 1 mL ACNS in a 4-quadrant region around the mass. In group B, the main artery of specimen was identified and isolated after the specimen was removed, and 2 mL MB was slowly injected into the isolated, stretched and fixed vessel. In group C, no ACNS and MB were injected. All the mesentery lymph nodes were isolated and removed systematically by visually inspecting and palpating the adipose tissue. RESULTS: No difference was observed among the three groups in age, gender, tumor location, tumor diameter, T-stage, degree of differentiation, postoperative complications and peritoneal drainage retention time. The total number of detected lymph nodes was 535, 476 and 223 in the three groups, respectively. The mean number of detected lymph nodes per patient was significantly higher in group A than in group C (26.8 ± 8.4 vs 12.2 ± 3.2, P < 0.001). Similarly, there were significantly more lymph nodes detected in group B than in group C (23.8 ± 6.9 vs 12.2 ± 3.2, P < 0.001). However, there was no significant difference between group A and group B. There were 50, 46 and 32 metastatic lymph nodes dissected in 13 patients of group A, 10 patients of group B and 11 patients of group C, without significant differences among the three groups. Eleven of the 60 patients had insufficient number of detected lymph nodes (< 12). Only one patient with T(4a) rectal cancer had 10 lymph nodes detected in group B, the other 10 patients were all from group C. Based on the different diameter categories, the number of detected lymph nodes in groups A and B was significantly higher than in group C. However, there was no statistically significant difference between group A and group B. The metastatic lymph nodes were not significant different among the three groups. Similarly, tumor location, T stage and tumor differentiation did not affect the staining results. Body mass index was a minor influencing factor in the two different staining methods. The stained lymph nodes can easily be identified from the mesenteric adipose tissues, and the staining time for lymph nodes was not significantly different compared with unstained group. None of the patients in groups A and B had drug-related complications. CONCLUSION: Both activated carbon nanoparticles suspension in vivo and methylene blue in vitro can be used as tracers to increase the detected number of lymph nodes in colorectal cancer.