Yasuhiko Mohri

Sentinel Node Mapping for Gastric Cancer: A Prospective Multicenter Trial in Japan

PURPOSE Complicated gastric lymphatic drainage potentially undermines the utility of sentinel node (SN) biopsy in patients with gastric cancer. Encouraged by several favorable single-institution reports, we conducted a multicenter, single-arm, phase II study of SN mapping that used a standardized dual tracer endoscopic injection technique. PATIENTS AND METHODS Patients with previously untreated cT1 or cT2 gastric adenocarcinomas < 4 cm in gross diameter were eligible for inclusion in this study. SN mapping was performed by using a standardized dual tracer endoscopic injection technique. Following biopsy of the identified SNs, mandatory comprehensive D2 or modified D2 gastrectomy was performed according to current Japanese Gastric Cancer Association guidelines. RESULTS Among 433 patients who gave preoperative consent, 397 were deemed eligible on the basis of surgical findings. SN biopsy was performed in all patients, and the SN detection rate was 97.5% (387 of 397). Of 57 patients with lymph node metastasis by conventional hematoxylin and eosin staining, 93% (53 of 57) had positive SNs, and the accuracy of nodal evaluation for metastasis was 99% (383 of 387). Only four false-negative SN biopsies were observed, and pathologic analysis revealed that three of those biopsies were pT2 or tumors > 4 cm. We observed no serious adverse effects related to endoscopic tracer injection or the SN mapping procedure. CONCLUSION The endoscopic dual tracer method for SN biopsy was confirmed as safe and effective when applied to the superficial, relatively small gastric adenocarcinomas included in this study.

Metastasis-associated long non-coding RNA drives gastric cancer development and promotes peritoneal metastasis

The prognosis of gastric cancer (GC) patients with peritoneal dissemination remains poor, and a better understanding of the underlying mechanisms is critical for the development of new treatments that will improve survival in these patients. This study aimed to clarify the clinical and biological role of two key metastasis-associated long non-coding RNAs (lncRNAs) in GC. We analyzed the expression levels of two lncRNAs-Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) and HOX-Antisense Intergenic RNA (HOTAIR)-by real-time reverse transcription PCR in 300 gastric tissues (150 GC and 150 adjacent normal mucosa), and in seven GC cell lines. Functional characterization for the role of HOTAIR in GC was performed by small interfering RNA (siRNA) knockdown, followed by series of in-vitro and in-vivo experiments. Expression of both lncRNAs was significantly higher in cancerous tissues than in corresponding normal mucosa, and higher expression of these lncRNAs significantly correlated with peritoneal metastasis in GC patients. In addition, elevated HOTAIR expression emerged both as an independent prognostic and risk factor for peritoneal dissemination. SiRNA knockdown of HOTAIR in GC cells significantly inhibited cell proliferation, migration and invasion, but concurrently enhanced the anoikis rate in transfected cells. In an in vivo assay, HOTAIR siRNA-transfected MKN45 cells injected into nude mice inhibited the growth of xenograft tumors and peritoneal metastasis compared with controls. Our data provide novel evidence for the biological and clinical significance of HOTAIR expression as a potential biomarker for identifying patients with peritoneal metastasis, and as a novel therapeutic target in patients with gastric neoplasia.

Bioresorbable Hyaluronate-Carboxymethylcellulose Membrane (Seprafilm) in Surgery for Rectal Carcinoma: A Prospective Randomized Clinical Trial

PurposeTo evaluate the effectiveness of Seprafilm in preventing abdominal adhesions after radical resection of rectal carcinoma, and to observe whether Seprafilm had any adverse effects in patients treated with radiotherapy and chemotherapy.MethodsA total of 62 patients participated in this prospective randomized clinical study, which was conducted to compare the outcomes of patients operated on with Seprafilm (SEPRA+) with those operated on without Seprafilm (SEPRA−). All patients received preoperative radiotherapy, followed by a two-stage operation, and 5-fluorouracil (5-FU)-based systemic chemotherapy. The primary endpoint of severity and extent of adhesions were evaluated at the time of ileostomy closure. The secondary endpoint included the recurrence of tumors, late complications, and outcome.ResultsSeprafilm significantly reduced the adhesions in both the midline incision area and peristomal area. This in turn reduced the operation time, blood loss, and extent of the incision at ileostomy closure. Seprafilm was not associated with any postoperative complications or chemoradiation-related toxicity, nor did it affect recurrence or survival rates.ConclusionSeprafilm effectively reduced abdominal adhesions in chemoradiated patients, and had no adverse effects on the oncologic results of fully introduced adjuvant therapy. Thus, Seprafilm is a safe and effective tool for use in rectal carcinoma surgery.

Incidence and Risk Factors

Epidemiological data indicate that inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is the third highest risk condition for the development of colorectal cancer (CRC), namely, colitis-associated cancer (CAC). CD is also associated with an increased risk of small-bowel adenocarcinoma, in response to chronic inflammation of the small intestine. In studies published in the 1990s, the risk for CAC in IBD was approximately 7 % at 20 years after diagnosis. In recent studies, the overall incidence of CAC in IBD is lower, less than 5 % at 20 years. However, several factors, such as the longer duration of colitis, extensive or severer colitis, and coexistent primary sclerosing cholangitis, have continued to be important in the development of CRC in patients with IBD. Despite clinical and experimental investigations, the molecular mechanisms by which chronic inflammation promotes cancer progression are still unknown.

An intestinal fistula in a 3-year-old child caused by the ingestion of magnets: Report of a case

We describe herein the case of a 3-year-old child in whom a jejunoileal fistula was caused by the ingestion of magnets. This case report demonstrates that if more than one magnet is found as a foreign body in the intestine, they should not be left untreated even if there are no sharp edges and, it seems they could be evacuated spontaneously. This recommendation is made because the magnets will attract each other and hold the intestinal walls between them, causing necrosis and resulting in intestinal perforation or a fistula.

Operative Morbidity Associated with Groin Dissections

Purpose.Groin dissection remains the treatment of choice for malignant neoplasms of the skin in the lower extremities and perineum. We sought to quantify the hospital complications after groin dissection, and to identify the patient- and procedure-related factors affecting these complications.Methods.We reviewed 20 consecutive patients who underwent a collective 25 groin dissections for malignant neoplasms of the skin between 1996 and 2002 to determine the incidence and degree of morbidity, and to analyze the clinical factors associated with morbidity. An S-shaped incision was used for the first 8 procedures, whereas a straight incision was used for the next 17.Results.The overall incidences of complications were 24% for wound infection, 52% for skin flap problems, 32% for seromas, 40% for edema, and 4% for hemorrhage, whereas the incidences of moderate to severe complications were 16% for wound infection, 16% for skin flap problems, 12% for seromas, 4% for edema, and 4% for hemorrhage. The incidence of wound infection tended to be higher after S-shaped incisions than after straight incisions (P = 0.059), and the incidence of leg edema was significantly higher after S-shaped incisions than after straight incisions (P = 0.028).Conclusion.S-shaped incisions more often resulted in lymphatic collection and stagnation, with a higher incidence of wound infections and leg edema than straight incisions. Therefore, we now perform straight incisions to minimize the risk of wound infections and leg edema.

Co-expression of hepatocyte growth factor and c-Met predicts peritoneal dissemination established by autocrine hepatocyte growth factor/c-Met signaling in gastric cancer

Epithelial–mesenchymal transition (EMT) promotes and facilitates migration and invasion of epithelial tumor cells. EMT is induced by factors such as hepatocyte growth factor (HGF). This study aimed to establish whether the HGF/c‐Met pathway is associated with gastric cancer metastasis; especially peritoneal dissemination. HGF and c‐Met expression and EMT‐related molecules were evaluated using real‐time PCR and immunohistochemistry. The role of the HGF/c‐Met pathway in EMT and anoikis was determined, and kinase inhibitor SU11274 was tested for its ability to block HGF‐induced biological effects. In HGF−/c‐Met+ gastric cancer cells, recombinant HGF promoted an EMT phenotype that was characterized by morphology, impaired E‐cadherin and induction of vimentin. HGF promoted cell growth, invasiveness and migration and inhibition of anoikis. SU11274 blocked HGF‐induced EMT and biological effects in vitro. In HGF+/c‐Met+ gastric cancer cells, HGF did not affect the biological outcome of EMT and anoikis, but SU11274 exerted the same inhibitory effects as in HGF−/c‐Met+ cells. In vivo, HGF+/c‐Met+ gastric cancer cells only established peritoneal dissemination and SU11274 inhibited tumor growth. Clinically, HGF expression was significantly correlated with c‐Met expression in gastric cancer. Increased HGF and c‐Met had a significant association with poor prognosis and predicted peritoneal dissemination. We demonstrated that the HGF/c‐Met pathway induces EMT and inhibition of anoikis in gastric cancer cells. Co‐expression of HGF and c‐Met has the potential to promote peritoneal dissemination in gastric cancer. Blockade of the autocrine HGF/c‐Met pathway could be clinically useful for the treatment of peritoneal dissemination in gastric cancer.

CXCL5, a promoter of cell proliferation, migration and invasion, is a novel serum prognostic marker in patients with colorectal cancer

PURPOSE Serum CXCL5 levels in patients with colorectal cancer (CRC) were assessed to evaluate correlation with clinicopathologic features and prognosis. The effects of CXCL5 on CRC cells were also investigated in vitro. METHODS Based on cytokine array analysis, CXCL5 was identified as a novel prognostic serum marker. Serum levels of CXCL5 were assessed in 250 CRC patients and 33 normal volunteers by enzyme-linked immunosorbent assay (ELISA), and their relation to clinicopathologic findings and survival investigated. CXCL5 levels in CRC cell lines were also measured by ELISA, and CXCL5 and CXCR2 expression was evaluated by immunohistochemistry. To investigate the biological role of the CXCL5/CXCR2 axis, recombinant human CXCL5 and CXCR2 neutralisation antibodies were used for proliferation, migration and invasion assays. RESULTS Preoperative serum CXCL5 was significantly elevated in patients with CRC compared with healthy volunteers (p=0.013). High serum CXCL5 was significantly associated with female sex (p=0.0098) and liver metastasis (p=0.0040). Univariate analysis correlated elevated CXCL5 with poor overall survival (p=0.0002). Multivariate analysis showed that elevated CXCL5 was a significant and independent prognostic factor of survival in all CRC patients (p=0.038). CRC cells secreted CXCL5, and administration of recombinant human CXCL5 promoted proliferation, migration and partial invasion. These effects were generally inhibited by CXCR2 neutralisation antibody. CONCLUSIONS Preoperative serum CXCL5 could serve as a novel predictive marker for prognosis determination of CRC patients. CXCL5/CXCR2 axis might be associated with colorectal cancer progression.

PROGNOSTIC SIGNIFICANCE OF E-CADHERIN EXPRESSION IN HUMAN COLORECTAL CANCER TISSUE

The expression of E-cadherin was determined by immunohistochemical staining in tumor tissue and in adjacent normal mucosae taken from 100 resected specimens of colorectal carcinomas. The expression of E-cadherin was preserved in all normal mucosae, but in the tumor tissue specimens it was preserved in 43, heterogeneous in 32, and lost in 25 samples. The lost or heterogeneous expression of E-cadherin correlated closely to the following: an advanced clinical stage of colorectal cancer, advanced tumor penetration, undifferentiated tumor histology, widespread lymph node involvement, liver metastasis, and permeation into the lymphatic and venous channels. The lost or heterogeneous expression of E-cadherin in tumor tissue was also significantly associated with an increased incidence of tumor recurrence after apparently curative resection, a reduced overall survival rate, and a reduced disease-free patient survival rate. A multivariate analysis disclosed that the expression of E-cadherin in tumor tissue was a significant prognostic variable independent of other clinicopathological features.

Laparoscopic Lymphatic Mapping and Sentinel Node Biopsies for Early-stage Gastric Cancer: The Cause of False Negativity

Sentinel node (SN) biopsies might be useful for performing minimally invasive surgery without interrupting surgical curability. This study examined the cause of false negativity during laparoscopic lymphatic mapping and SN biopsies for early-stage gastric cancer. Thirty-seven patients with gastric cancer (preoperative stage T1-2 or N0) who underwent laparoscopic lymph node mapping and SN biopsies between March 2001 and June 2004 were enrolled in this study. The tracer, patent blue and technecium-99m-labeled tin colloid, was injected endoscopically. Blue-stained or radioactive nodes were defined as SNs. Gastrectomy with lymphadenectomy was performed then the results of the SN biopsies were compared with the final diagnosis of the removed lymph nodes in permanent sections. Sentinel nodes were successfully identified in 35 patients (94.6%), and they were positive in 3 of 4 patients with metastatic lymph nodes; sensitivity was 75% and specificity was 100%. Sentinel node status could therefore be used to diagnose lymph node status with 97.1% accuracy. Of 6 SNs with metastasis, 5 showed radioactivity, and only 2 were blue stained. In the false negative case, a radioactive SN with metastasis in the right paracardial region was missed during laparoscopic mapping. An error in laparoscopic intracorporeal detection of the radioactive node with metastasis occurred because we could not eliminate the shine-through effect. We found that during laparoscopic SN mapping there is a high risk of false negativity with SNs located in the right paracardial region. To apply laparoscopic SN mapping to early-stage gastric cancer patients, the shine-through effect must be eliminated because radiotracers are essential for this method.