Expression profiling stratifies mesothelioma tumors and signifies deregulation of spindle checkpoint pathway and microtubule network with therapeutic implications

PURPOSE To investigate the antitumor activity and mechanism of chloroquine (CQ) in combination with cisplatin (DDP) in nude mice xenografted with gastric cancer SGC7901 cells. MATERIALS AND METHODS 35 cases of gastric cancer patients with malignant ascites were enrolled and intraperitoneal cisplatin injection was performed. Ascites were collected before and 5 days after perfusion for assessment of autophagy levels in cancer cells. In addition, 24 tumor-bearing mice were randomly divided into control, DDP, CQ and CQ + DDP groups. RESULTS In 54.3% (19/35) of patients the treatment was therapeutically effective (OR), 5 days after peritoneal chemotherapy, 13 patients had the decreased ascites Beclin-1 mRNA levels. In 16 patients who had NR, only 2 cases had decreased Beclin-1 (P=0.001). Compared with the control group, the xenograft growth in nude mice in the DDP group was low, and the inhibition rate was 47.6%. In combination with chloroquine, the inhibition rate increased to 84.7% (P<0.01). The LC3-II/I ratio, and Beclin1 and MDR1/P-gp expression were decreased, while caspase 3 protein levels increased (P<0.05). CONCLUSIONS Antitumor ability of cisplatin was associated with autophagy activity and chloroquine can enhance chemosensitivity to cisplatin in gastric cancer xenografts nude mice.

http://koreascience.or.kr:80/article/JAKO201528551640876.pdf

Antitumor activity of chloroquine in combination with Cisplatin in human gastric cancer xenografts.

Lymph node metastasis (LNM) is the prominent route of gastric cancer dissemination, and usually leads to tumor progression and a dismal prognosis of gastric cancer. Although exosomal lncRNAs have been reported to be involved in tumor development, whether secreted lncRNAs can encode peptides in recipient cells remains unknown. Here, we identified an exosomal lncRNA (lncAKR1C2) that was clinically correlated with lymph node metastasis in gastric cancer in a VEGFC-independent manner. Exo-lncAKR1C2 secreted from gastric cancer cells was demonstrated to enhance tube formation and migration of lymphatic endothelial cells, and facilitate lymphangiogenesis and lymphatic metastasis in vivo. By comparing the metabolic characteristics of LN metastases and primary focuses, we found that LN metastases of gastric cancer displayed higher lipid metabolic activity. Moreover, exo-lncAKR1C2 encodes a microprotein (pep-AKR1C2) in lymphatic endothelial cells and promotes CPT1A expression by regulating YAP phosphorylation, leading to enhanced fatty acid oxidation (FAO) and ATP production. These findings highlight a novel mechanism of LNM and suggest that the microprotein encoded by exosomal lncAKR1C2 serves as a therapeutic target for advanced gastric cancer. 

The microprotein encoded by exosomal lncAKR1C2 promotes gastric cancer lymph node metastasis by regulating fatty acid metabolism

Background
Microsatellite instability (MSI) is one of the new groups of molecular divisions of gastric cancer (GC). The aim of this study was to investigate the pattern of lymph node metastasis according to MSI status.
Methods
MSI analysis of 361 GC patients with information about lymph node stations was performed using 5 quasimonomorphic mononucleotide repeats. The metastasis rates for each lymphatic station was analyzed, combined with clinicopathologic characteristics. Stations were divided into compartments 1-3 on the basis of Japanese Classification. A median number (interquartile range, IQR) of 33(18-50) lymph nodes were removed and analyzed.
Results
N0 status was observed in 53.7% MSI patients, and in 29.7% microsatellite stable (MSS) (p<0.001).

The median value of involved nodes was 1 in MSI vs. 5 in MSS (p<0.001).

Furthermore, the number of involved node stations was significantly lower in the MSI group (p<0.001).

MSS tumors showed a higher propensity to spread to second and third compartment nodes.

In absence of lymphovascular invasion only 3.2% cases demonstrated positive nodes beyond the first compartment.

Skip metastases were seen in 6.1% MSS patients and 0% MSI (p=0.011).

No difference in the 10-year cancer related survival among MSI and MSS patients was found, for both those with 1st compartment (p=0.223) and with 2nd compartment involvement (p=0.814).
Conclusions
MSI GC shows a high rate of N0 stage, a lower number of lymph node metastases, and a less extensive spread to lymph node stations than MSS tumors. These data indicate that tailored lymphadenectomy may be investigated for these patients.

The pattern of lymph node metastases in microsatellite unstable gastric cancer.

Lymph node metastasis (LNM) status is an important prognostic factor that strongly influences the treatment decision of early gastric cancer (EGC). This study aimed to evaluate the pattern and clinical significance of LNM in EGC. A total of 354 patients with carcinoma in situ (n = 42), EGC (n = 312) who underwent radical gastrectomy were enrolled. Their clinicopathological features, pathological reports, and prognostic data were collected and analyzed. The incidence of LNM in all patients was 18.36% (65/354). The rates of D1 and D2 station metastases were 12.10% (43/354) and 6.21% (22/354), respectively. The rates of LNM in absolute indication of endoscopic resection and expanded indication were 3.27% (2/61) and 28.55% (4/14), respectively. Skip LNM was observed in 3.67% (13/354) of patients. For those with middle-third tumor, the metastasis rate of the No. 5 lymph node was 3.05% (5/164). The independent risk factors for LNM were tumors measuring > 30 mm, poorly differentiated tumors, and lymphovascular invasion (all P   20 mm and LNM were independent predictive factors for poor survival outcome in all patients. Patients with EGC conforming to expanded indications have a relatively high risk of LNM and may not be suitable for endoscopic submucosal dissection. Pylorus-preserving gastrectomy for patients with middle-third EGC remains controversial due to the high metastasis rate of the No. 5 lymph node.

/pdf/the-risk-of-lymph-node-metastasis-in-gastric-cancer-l46n5hqz4i.pdf

The risk of lymph node metastasis in gastric cancer conforming to indications of endoscopic resection and pylorus-preserving gastrectomy: a single-center retrospective study.

Background
Current rates of survival for gastric cancer patients are much improved compared with those of the past. The purpose of our study was to analyze the survival of gastric cancer patients according to time period and to examine how different prognostic factors are related to changing survival rates.

/pdf/changes-in-postoperative-recurrence-and-prognostic-risk-4588i2c4or.pdf

Changes in Postoperative Recurrence and Prognostic Risk Factors for Patients with Gastric Cancer who Underwent Curative Gastric Resection during Different Time Periods

Purpose Given the recent increase in the incidence of early gastric cancer, there is greater interest in identifying a minimally invasive therapy. The purpose of this study was to analyze the patterns of lymph node metastasis in patients with gastric cancer and to elucidate the clinical significance of skip metastasis. Methods We retrospectively analyzed patterns of lymph node metastasis (LNM) and clinicopathologic factors related to skip metastasis. Results Among 2963 patients with gastric cancer, 997 patients (33.6%) were detected as having LNM, and 27 patients (2.7%) with skip metastasis were detected among 997 patients with LNM. Skip metastasis were detected more frequently in the elderly. Compared with the N1 group, the skip metastasis group showed lower frequency of vascular invasion, and compared with the stepwise N2 group, the skip metastasis group showed smaller tumor size and a significantly higher incidence of negative lymphatic, vascular, and perineural invasion. Conclusions Currently there is no way to predict N2 station LNM including skip metastasis, D2 LN dissection for gastric cancer is thought to be the appropriate treatment, even during early stage disease. Minimally invasive therapy should be performed cautiously in consideration of possible skip metastasis.

Clinical significance of skip lymph node metastasis in gastric cancer patients

PURPOSE This study aimed to investigate the correlation between multiple early gastric cancer (MEGC) and multiple primary malignancies during the follow-up of patients with gastrectomy. MATERIALS AND METHODS The number of primary tumors detected in other organs after gastrectomy for early gastric cancer (EGC) has been increasing because of improved survival and surveillance programs. A total of 3,129 patients underwent radical gastrectomy for treatment of EGC at Samsung Medical Center from January 2000 to December 2005. Of these, 3,057 patients were selected and their medical records were retrospectively analyzed. RESULTS Among the 3,057 patients, 148 (4.8%) had MEGC, 84.5% were male, 57.4% were over 60 years old, 42.6% had a macroscopic type EGC IIb main lesion, and 68.9% had well-differentiated tumors with a significantly high incidence of MEGC. There were no differences between patients with solitary early gastric cancer (SEGC) and those with MEGC with regard to overall survival or recurrence-free survival, but MEGC was an independent risk factor for metachronous primary malignancies in other organs (P=0.004, hazard ratio [HR]=2.444). CONCLUSIONS MEGC is not a risk factor for poor prognosis after curative gastrectomy, but it is a risk factor for metachronous primary malignancies in other organs during postoperative follow-up; therefore, careful surveillance is needed.

/pdf/multiple-primary-malignancies-in-patients-with-multiple-2rlvuclthj.pdf

Multiple Primary Malignancies in Patients with Multiple Early Gastric Cancer

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Papers

Changes in Postoperative Recurrence and Prognostic Risk Factors for Patients with Gastric Cancer who Underwent Curative Gastric Resection during Different Time Periods

Clinical significance of skip lymph node metastasis in gastric cancer patients

Multiple Primary Malignancies in Patients with Multiple Early Gastric Cancer