Hisahiro Hosogi

SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion.

Inactivation of TGF-β family signaling is implicated in colorectal tumor progression. Using cis-Apc+/Δ716 Smad4+/− mutant mice (referred to as cis-Apc/Smad4), a model of invasive colorectal cancer in which TGF-β family signaling is blocked, we show here that a new type of immature myeloid cell (iMC) is recruited from the bone marrow to the tumor invasion front. These CD34+ iMCs express the matrix metalloproteinases MMP9 and MMP2 and the CC-chemokine receptor 1 (CCR1) and migrate toward the CCR1 ligand CCL9. In adenocarcinomas, expression of CCL9 is increased in the tumor epithelium. By deleting Ccr1 in the background of the cis-Apc/Smad4 mutant, we further show that lack of CCR1 prevents accumulation of CD34+ iMCs at the invasion front and suppresses tumor invasion. These results indicate that loss of transforming growth factor-β family signaling in tumor epithelium causes accumulation of iMCs that promote tumor invasion.

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes.

Chemokines and their receptors are essential for leukocyte trafficking, and also implicated in cancer metastasis to specific organs. We have recently demonstrated that CXCR3 plays a critical role in metastasis of mouse melanoma cells to lymph nodes. Here, we show that some human colon cancer cell lines express CXCR3 constitutively. We constructed cells that expressed CXCR3 cDNA (‘DLD-1-CXCR3’), and compared with nonexpressing controls by rectal transplantation in nude mice. Although both cell lines disseminated to lymph nodes at similar frequencies at 2 weeks, DLD-1-CXCR3 expanded more rapidly than the control in 4 weeks. In 6 weeks, 59% of mice inoculated with DLD1-CXCR3 showed macroscopic metastasis in para-aortic lymph nodes, whereas only 14% of those with the control (P<0.05). In contrast, metastasis to the liver or lung was rare, and unaffected by CXCR3 expression. In clinical colon cancer samples, we found expression of CXCR3 in 34% cases, most of which had lymph node metastasis. Importantly, patients with CXCR3-positive cancer showed significantly poorer prognosis than those without CXCR3, or those expressing CXCR4 or CCR7. These results indicate that activation of CXCR3 with its ligands stimulates colon cancer metastasis preferentially to the draining lymph nodes with poorer prognosis.

Suppression of colon cancer metastasis by Aes through inhibition of Notch signaling

Metastasis is responsible for most cancer deaths. Here, we show that Aes (or Grg5) gene functions as an endogenous metastasis suppressor. Expression of Aes was decreased in liver metastases compared with primary colon tumors in both mice and humans. Aes inhibited Notch signaling by converting active Rbpj transcription complexes into repression complexes on insoluble nuclear matrix. In tumor cells, Notch signaling was triggered by ligands on adjoining blood vessels, and stimulated transendothelial migration. Genetic depletion of Aes in Apc(Δ716) intestinal polyposis mice caused marked tumor invasion and intravasation that were suppressed by Notch signaling inhibition. These results suggest that inhibition of Notch signaling can be a promising strategy for prevention and treatment of colon cancer metastasis.

Feasibility of laparoscopic gastrectomy with radical lymph node dissection for gastric cancer: from a viewpoint of pancreas-related complications.

BACKGROUND There is little evidence for the technical feasibility of laparoscopic gastrectomy (LG) with peripancreatic lymphadenectomy in terms of postoperative complications. To evaluate the technical feasibility of LG with radical lymphadenectomy, we focused on pancreas-related complications in LG and open gastrectomy (OG), and then investigated whether such complications increased in LG. METHODS We reviewed the surgical outcomes of 138 consecutive patients with gastric cancer who underwent LG with peripancreatic lymphadenectomy in our hospital between July 2005 and February 2009. As a control group, we used 95 consecutive OG cases with peripancreatic lymphadenectomy without splenectomy or para-aortic lymphadenectomy. LG and OG were compared for clinicopathologic characteristics, operative outcomes, postoperative morbidities and mortalities, and amylase concentration of drainage fluid (d-AMY). RESULTS The overall operative morbidity rates were 15% in the LG and 20% in the OG group. Rates of postoperative pancreatic fistula (POPF), Grade B and C in the International Study Group on Pancreatic Fistula definition, were 7% in the LG group and 2% in the OG group, indicating no statistical difference (P = .149). There were no in-hospital deaths. The median value of d-AMY in LG was 934.5 IU/L, while that in OG was 349 IU/L; d-AMY after LG was significantly higher than that after OG (P < .01). CONCLUSION Considering low morbidity and mortality rates, LG with peripancreatic lymphadenectomy is technically feasible. Although POPF after LG was infrequent, d-AMY level was higher than after OG. We should pay attention to the potential risk of pancreatic leakage when carrying out LG with peripancreatic lymphadenectomy.

Natural Orifice Specimen Extraction for Avoiding Laparotomy in Laparoscopic Left Colon Resections: A New Approach Using the McCartney Tube and the Tilt Top Anvil Technique

BACKGROUND Classical laparoscopic left colon resection requires a minilaparotomy. This wound can cause pain and morbidity. We describe our technique to avoid minilaparotomy by natural orifice specimen extraction. METHODS A four-port standard laparoscopic dissection for diverticular disease and small tumors of the left colon was performed. A silicon McCartney tube was transanally inserted into the rectum to remove the specimen and to pass the anvil of the circular stapler into the abdominal cavity. The head of the anvil was mechanically pretilted to facilitate introduction into the proximal colon. Double-stapled anastomosis was performed in the usual manner. RESULTS Eight patients with diverticular disease or small tumors were operated. There were no adverse events. Operating time ranged between 95 and 180 minutes. For malignancies, tissue margins and lymphadenectomy were oncologically adequate. Four week follow-up was uneventful. CONCLUSION The described natural orifice specimen extraction technique has the potential to avoid incision-related morbidity of the minilaparotomy in laparoscopic left colon resections.

Molecular mechanisms of liver metastasis

Colorectal cancer is the second most common cancer, and is the third leading cause of cancer-related death in Japan. The majority of these deaths is attributable to liver metastasis. Recent studies have provided increasing evidence that the chemokine–chemokine receptor system is a potential mechanism of tumor metastasis via multiple complementary actions: (a) by promoting cancer cell migration, invasion, survival and angiogenesis; and (b) by recruiting distal stromal cells (i.e., myeloid bone marrow-derived cells) to indirectly facilitate tumor invasion and metastasis. Here, we discuss recent preclinical and clinical data supporting the view that chemokine pathways are potential therapeutic targets for liver metastasis of colorectal cancer.

A case of ampullary carcinoma successfully managed with endoscopic snare resection.

Pancreaticoduodenectomy and transduodenal ampullectomy have been the procedures of choice for ampullary cancer in most patients. However, for patients with small ampullary neoplasms or who are unfit for laparotomy or refuse open surgical operations, endoscopic snare ampullectomy may be appropriate. We report here a case of ampullary carcinoma in which endoscopic snare ampullectomy was performed successfully, with long-term survival. The patient was a 77-year-old man with a 30-year history of ulcerative colitis, who presented with epigastric pain and fever. He had a history of four laparotomies. Laboratory studies showed a mild elevation in alkaline phosphatase, serum aspartate aminotransferase, gamma glutamyltransferase, and C-reactive protein values. At endoscopic retrograde cholangiopancreatography, the ampulla was prominent, with granulomatous proliferation. The common bile duct was dilated to approximately 25 mm in diameter. Biopsy specimens of the ampulla showed a well-differentiated adenocarcinoma. Because of extensive adhesions of the peritoneal cavity due to the prior four laparotomies and the patients refusal of surgery, endoscopic snare ampullectomy was performed. Ten days after the ampullectomy, the patient was discharged from the hospital without any complication. The patient has been well for the 4 years since then, without recurrence of the tumor or jaundice. Endoscopic snare ampullectomy may be considered as a viable alternative to surgery in patients with small ampullary tumors who are unfit for surgery or who prefer a nonsurgical approach.

Molecular insights into Peutz-Jeghers syndrome: two probands with a germline mutation of LKB1.

LKB1 encodes a serine/threonine protein kinase that is defective in patients with Peutz-Jeghers syndrome (PJS), a hereditary disorder characterized by gastrointestinal hamartomatous polyposis and an increased risk of cancer development. Although a tentative molecular classification of PJS patients was recently made according to their LKB1 mutation status, it is difficult to clarify the genotype-phenotype relationship because of the rarity and genetic heterogeneity of this disease. Here we report on two probands with PJS whose intestinal hamartomatous polyposis was treated by laparoscopyassisted polypectomy. Direct sequencing analyses revealed a nonsense mutation at codon 240 in exon 5 in one patient, and a mutation at a splicing donor site in intron 5 in the other patient. No additional somatic mutations were detected in the resected hamartomas in either case. Immunohistochemical analysis revealed an elevated expression of cyclooxygenase-2, and almost complete loss of LKB1 expression in the polyps, suggesting that a biallelic inactivation of the LKB1 gene was responsible for the hamartoma formation. Methylation-specific polymerase chain reaction analysis revealed no hypermethylation of the LKB1 promoter. Mutation analysis is useful in making a precise diagnosis of PJS in candidate probands, and may in the near future provide valuable information for predicting cancer risk based on genotype-phenotype correlations.

Right diaphragm injury: an unusual complication in single-port laparoscopic cholecystectomy.

Laparoscopic cholecystectomy (LC) is nowadays the standard method for cholecystectomy. Recently, surgeons attempt to introduce even less-invasive surgical procedures, such as single-port LC or LC through natural orifice transluminal endoscopic surgery (NOTES). The number of studies showing the feasibility of these techniques increased during the last years, but specific complications that correlated with these new techniques are still not apparent. Here, we report on a case with an unusual complication, iatrogenic right diaphragm injury in single-port LC. A 72-year-old man underwent single-port LC because of symptomatic cholecystolithiasis. During the operation, the long rigid straight forceps holding the fundus of the gallbladder slipped off toward the right diaphragm and caused a 1-cm full-thickness diaphragmatic tear. Laparoscopic suture repair was performed, and the patient recovered uneventfully. In using long forceps in single-port LC or transvaginal NOTES-LC, reticulating and bent instruments may avoid this unusual but possible complication in these operations.

Laparoscopic splenic hilar lymphadenectomy for advanced gastric cancer

Laparoscopic distal gastrectomy has recently become accepted as a surgical option for early gastric cancer in the distal stomach, but laparoscopic total gastrectomy (LTG) has not become widespread because of technical difficulties of esophagojejunal anastomosis and splenic hilar lymphadenectomy. Splenic hilar lymphadenectomy should be employed in the treatment of advanced proximal gastric cancer to complete D2 dissection, but laparoscopically it is technically difficult even for skilled surgeons. Based on the evidence that prophylactic combined resection of spleen in total gastrectomy increased the risk of postoperative morbidity with no survival impact, surgeons have preferred laparoscopic spleen-preserving splenic hilar lymphadenectomy (LSPL) for advanced tumors without metastasis to splenic hilar nodes or invasion to the greater curvature of the stomach, and reports with LSPL have been increasing rather than LTG with splenectomy. In this paper, recent reports with laparoscopic splenic hilar lymphadenectomy were reviewed.