[A Case of Gastric Cancer Invading the Pancreas with Pathological Complete Response Treated by Preoperative S-1 plus Oxaliplatin Therapy].

A 66-year-old man with severe anemia was diagnosed with gastric cancer. CT examination revealed primary gastric tumor, which involved the pancreas body, with regional lymph nodes that were enlarged(T4b[panc], cN2, cM0, cStage ⅣA). He received three courses of preoperative S-1 plus oxaliplatin therapy. Primary tumor and metastatic lymph nodes were reduced remarkably. We performed a curative distal gastrectomy(D2)without pancreas resection. Histopathological examination revealed Grade 3 pathological complete response in both primary tumor and metastatic lymph nodes.

[A Case of Cystoid Macular Edema Secondary to Albumin-Bound Paclitaxel Therapy].

A 73-year-old woman diagnosed with unresectable pancreatic cancer received weekly gemcitabine(GEM)plus albuminbound paclitaxel(nab-PTX)therapy. Four months after nab-PTX therapy was initiated, she presented with a rapidly decreasing vision in her left eye at an ophthalmology clinic. On admission, her visual acuity was decreased, and optical coherence tomography(OCT)revealed a cystoid macular edema(CME)only in her left eye. She discontinued the nab-PTX therapy immediately. Her visual acuity improved on follow-up 6 months later. The CME finding on OCT was reduced but not completely resolved. CME is a rare adverse event induced by nab-PTX therapy, with only 14 cases reported since 2008. In most of the reported cases, the patients had breast cancer, and this is the first reported case of CME in a patient with pancreatic cancer. The time to CME onset from starting nab-PTX therapy was reported to range from3 to 30months, but the predilection time has not been clarified. Many reports indicated that symptoms improved in a short period after discontinuation of nab-PTX therapy, but effective treatment was not established, except discontinuation of nab-PTX therapy. In daily medical treatment, the incongruity of the ophthalmologic domain should be confirmed for early detection of CME.

[STI571 for gastrointestinal stromal tumors].

Since the effectiveness of STI571 for GIST was reported, therapy for GIST has changed markedly, and the disease has attracted attention. We have treated 19 patients with GIST since 2000 by 19 resections (local resection in 14 patients, total gastrectomy in 2 patients, distal gastrectomy in 2 patients, and hepatectomy in 1 patient), and administered STI571 to 5 patients with unresectable or recurrent GIST. Of these 5 patients, 2, 1, 1, and 1 had PR, SD, PD, and inevaluable disease, respectively, with a response rate of 50%. The disease was controllable in 80% of the patients. All patients had palpebral and crural edema as side effects, which were not severe, suggesting the safety of the drug. It is important to tailor therapy (STI571 or surgery) to the patient.

Dextran sulfate suppresses cell adhesion and cell cycle progression of melanoma cells.

We have reported that dextran sulfate is a possible candidate for an antimetastatic drug because it inhibits cell adhesion. It has been demonstrated that dextran sulfate can detach cancer cells adhering to the bottom of plastic flasks, and that the detached cells do not readhere or proliferate. In this study, we investigated the effects of dextran sulfate on cancer cells, focusing on cell cycle regulators as well as cell adhesion molecules. The effects of dextran sulfate on the cell cycle were examined by flow cytometry, and changes in gene expression caused by dextran sulfate were analyzed by cDNA microarray to identify changes in adhesion and cell cycle genes. By flow cytometry, treatment with dextran sulfate increased the percentage of cells in the G1/G0-phase, and decreased those in the S- and G2/M-phases. Analysis by cDNA microarray revealed decreased expression of several genes essential for progression of the G1- and S-phases. The expression of the adhesion factors involved in metastases was also suppressed. Furthermore, we confirmed these changes in the gene expression by Northern and Western blotting. Our results indicate that dextran sulfate suppresses cell adhesion and cell cycle progression, both of which are essential for metastasis, suggesting that dextran sulfate could be used as an antimetastatic agent.

Local administration of methotrexate bound to activated carbon particles (MTX-CH) for treating cancers in mice.

PURPOSE: A new dosage formulation of methotrexate (MTX-CH) was developed to control cancer growth by local administration. MATERIALS AND METHODS: BALB/c mice received a subcutaneous inoculation with transplantable Colon 26 cancer cells on the back. When cancerous tumor became 7 mm in diameter, MTX-CH or MTX aqueous solution (MTX-sol) was injected into the tumor. The MTX concentration in the tumor was compared between the MTX-CH group and the MTX-sol group. The tumor growth was assessed in single or repeated local administration experiments. RESULTS: The MTX concentrations were significantly higher for longer periods in the MTX-CH group than those in the MTX-sol group. Repeated MTX-CH administration was significantly more effective for suppressing the tumor growth compared with repeated MTX-sol administration. CONCLUSION: MTX-CH is superior to MTX-sol in controlling the tumor growth by local administration because of its long-acting effect.

Biodegradation of polyglycolic acid-collagen composite tubes for nerve guide in the peritoneal cavity.

The rate of biodegradation of new types of polyglycolic acid (PGA)-collagen composite tubes for nerve regeneration was evaluated in the peritoneal cavity. PGA mesh tubes with a diameter of 2 or 4 mm were coated with collagen solution and dried at room temperature. The tubes were then subjected to dehydrothermal treatment (composite tube). A 2 mm PGA-collagen composite tube filled with collagen sponge was also investigated in this study (sponge tube). Tubes with a length of 15 mm were fixed at the parietal peritoneum of BALB/c mice and excised 2 weeks and 1, 2, and 3 months after the operation. The inner areas of the excised tubes were measured microscopically. Statistical analysis was performed by one way ANOVA and Fisher's PLSD test. Although the inner areas of the 2 and 4 mm composite tubes were not maintained 1 month after the operation (62 +/- 6.8% and 21 +/- 3.8%, respectively), they were well maintained in the sponge tubes (83 +/- 6.4%). The inner areas of the sponge tubes were significantly larger than those of the composite tubes until 2 months after surgery. These results suggest that sponge tubes are more suitable than composite tubes for nerve regeneration in the peritoneal cavity.

[Detection of sentinel lymphatic region with activated carbon particles in lymph node dissection for colorectal cancer].

Sentinel node navigation surgery (SNNS) for gastrointestinal cancer has been examined using various methods, but the SN concept has not been established. For 18 patients who had colorectal cancer without macroscopic nodal metastases, we had attempted to detect sentinel lymph nodes (SNs) with activated carbon particles and investigate the existence of nodal metastases histologically. SNs were detected in 17 of 18 patients. Thus activated carbon particles are a useful tracer for SN detection. Three patients had microscopic nodal metastases, and two had nodal metastases in SNs. Although the remaining patient was a false negative case which had nodal metastases in non-SNs only, the nodal metastases were within the sentinel lymphatic region (SLR) which includes SNs. It is considered possible to safely perform minimally invasive lymphadenectomy for colorectal cancer without macroscopic nodal metastases, by means of SLR dissection using activated carbon particles.

[Analysis of effect of dextran sulfate on cancer cells].

Peritoneal recurrence is one of the critical problems that occurs after surgery for gastrointestinal cancers. Since no curative treatment has been established for peritoneal recurrence, many efforts have been made to develop an effective method for preventing such recurrence. We focused on dextran sulfate, an anti-cell-adherence agent, to prevent peritoneal metastasis. Our previous studies in vitro and in vivo clarified that dextran sulfate prevents cancer cells from adhering to plastic flasks and the abdominal wall. In this study, we investigated the effects of dextran sulfate on cancer cells from the viewpoint of the cell cycle. Changes in gene expression caused by dextran sulfate were analyzed by cDNA microarrays. Analysis by cDNA microarray revealed the decreased expression of the genes essential to the progression of G1 and S phases. Our results indicate that dextran sulfate suppresses progression of the cell cycle as well as cell adhesion, suggesting that dextran sulfate could be used as an antimetastatic agent. Anti-cell-adherence agents with such mechanisms of action could be effective drugs for treatment during and after operation to prevent peritoneal metastases induced by surgical operation.

[Intratumoral administration of methotrexate bound to activated carbon particles (MTX-CH) inducing antitumor effect in vivo].

Methotrexate is one of the anticancer drugs that can be safely administered subcutaneously, but locally injected MTX in aqueous solution form does not function in the administration site for very long. We developed a new dosage formulation: methotrexate bound to activated carbon particles (MTX-CH), and can report that it controlled tumor growth through its long-acting effect at the administration site. In this study, we investigated the effect of local administration of MTX-CH compared with MTX aqueous solution in tumors from transplanted human colon cancer cells (LoVo) into the back of nude mice. MTX-CH is superior to MTX aqueous solution in terms of its long-acting effect at the administration site and antitumor effect. We suggest that intratumoral injection therapy of MTX-CH is useful for patients in poor condition and with high surgical risk due to cardiac disease or old age, and patients who are diagnosed positive for cancer after endoscopic mucosal resection of early colorectal cancer.

[Endoscopic local injection of anticancer drugs bound to carbon particles for treatment of advanced rectal cancer, when surgical treatment was contraindicated].

Generally, patients with advanced rectal cancer in whom surgical treatment is contraindicated receive radiation or chemotherapy. In such patients, we have administered local injection of methotrexate and mitomycin C bound to activated carbon particles. Four patients received intratumoral injection of the dosage formulation (total dose 100-400 mg of methotrexate or 8-32 mg of mitomycin C) under colonofiberscope. After the treatment, bleeding and pain were lessened in all 4 patients. In two patients, the tumor markedly decreased in size and there was no regrowth prior to death 12-14 months after the treatment. In another patient, bleeding and pain disappeared until the patient died of pulmonary and liver metastases. The fourth patient is alive without regrowth 5 months after treatment. Side effects were not severe.

[A case of hepatocellular carcinoma with multiple lymph node metastases detected by FDG-PET].

We report a case of hepatocellular carcinoma (HCC) with multiple lymph node (LN) metastases. A 68-year-old man underwent hepatectomy at our hospital. Intrahepatic recurrence and swelling of multiple LNs were detected by enhanced CT 21 months later. FDG-PET was positive for multiple swollen LNs, but all were negative for the intrahepatic recurrences. Biopsy of para-aortic LNs was revealed LN metastases from HCC. Immunohistochemically, the LN metastases were composed of poorly differentiated HCC. The sensitivity of FDG-PET in patients with HCC varies in relation to degree of differentiation and decreased FDG uptake must be noted.

Histologic and electrophysiological study of nerve regeneration using a polyglycolic acid-collagen nerve conduit filled with collagen sponge in canine model.

OBJECTIVES: To determine the rate of achieving electrophysiologically proved functional recovery by autonomic nerve regeneration, with the aid of an artificial nerve conduit. METHODS: A polyglycolic acid (PGA) collagen nerve conduit filled with collagen sponge was interposed in a 10-mm-long gap of the right hypogastric nerve (HGN) in 16 dogs. Histologic evaluation of nerve regeneration and electrophysiological analysis at 2 weeks and 2, 3, 4, 5, 6, 7, and 8 months (n = 2, each) after surgery was performed, measuring the responses for the spermatic ducts (SD), bladder neck (BN), and prostate contraction, by stimulating the right lumbar splanchnic nerves (LSNs) from L2 to L4, after transection of the left HGN to eliminate substitutive pathways. RESULTS: Two months after implantation, the regenerated neurofilaments were successfully extended through the graft from the proximal-to-distal direction. In 2 control dogs, electrostimulation of the right LSNs induced elevation of the intraluminal pressure of the SD, elevation of the BN pressure, and prostate contraction. No responses were observed in all dogs up to 6 months of follow-up after implantation. In 1 dog with a 7-month follow-up, electrostimulation elicited elevation of BN pressure alone. In both dogs with an 8-month follow-up, electrostimulation induced similar responses to control in all SD, BN, and prostate; however, after excision of the area of the interposed right HGN, no response was observed. CONCLUSIONS: These results proved that regeneration of a 10-mm gap of the HGN, using a novel PGA-collagen nerve conduit could be achieved within 8 months.

Results of total gastrectomy with extended lymphadenectomy for gastric cancer in elderly patients.

BACKGROUND AND OBJECTIVES: The incidence of gastric cancer, in people over 70 years of age, has increased remarkably. Aggressive lymphadenectomy with gastrectomy has been reported to improve survival in patients with gastric cancer. Because complication rates following gastrectomy increase with advancing age, we sought to determine whether this procedure was merited in elderly patients with gastric cancer. METHODS: We performed a retrospective analysis of 202 patients who underwent total gastrectomy with extended lymphadenectomy for gastric carcinoma. Postoperative complication rates were compared between patients over and under 70 years of age. RESULTS: The 10-year survival rates of patients under and over 70 years of age following total gastrectomy with extended lymphadenectomy were not significantly different. Although medical comorbidities in each group were similar, pulmonary dysfunction was significantly more common following total gastrectomy in patients over 70 years than in patients under 70 years. Moreover, logistic regression analysis revealed that patient's age was the only variable that independently correlated with the presence of postoperative complications. CONCLUSIONS: The prognosis of the gastric cancer patients over 70 years of age was similar to that of younger patients after total gastrectomy with extensive lymphadenectomy. However, pulmonary dysfunction was significantly more common in patients over 70 years old.

Transanal excision of a large rectal polyp assisted by transsacral manipulation of the rectum.

Standard transanal excision of the rectal polyps is curative and is less invasive than transsacral resection or low anterior resction, but it is difficult to resect tumors that are distant from the anal verge. Moreover, in the case of large polyps, the risks of complications, such as hemorrhage or perforation, increase because exposure on the oral side of the tumor is poor. If exposure can be improved, transanal excision can be performed safely and completely when the polyp is large and distant from the anal verge. We used transsacral manual assistance to achieve transanal resection of a large tubulovillous adenoma of the rectum that was hard to be resected using the traditional transanal approach.

Intratumoral administration of methotrexate bound to activated carbon particles: antitumor effectiveness against human colon carcinoma xenografts and acute toxicity in mice.

We previously developed a new formulation of methotrexate (MTX) that is adsorbed onto a suspension of activated carbon particles (MTX-CH) and reported the usefulness of local administration in murine tumors. The present study examines the effects of human colon carcinoma (LoVo) xenografts and the acute toxicity of MTX-CH compared with MTX aqueous solution (MTX-AQ) in mice. In therapeutic experiments, LoVo cells were implanted into the backs of BALB/c nude mice. When the cells had developed into tumors, we performed an intratumoral administration of a weekly dose of 30 mg/kg. The MTX concentration in the tumor was compared between the MTX-CH group and MTX-AQ group. In experiments on acute toxicity, MTX-CH and MTX-AQ were injected subcutaneously in BDF1 mice, and intoxication symptoms, changes in body weight, and date of death were recorded. In the therapeutic experiments, intratumoral administration of MTX-CH was much more effective in suppressing the tumor growth compared with MTX-AQ. In experiments of acute toxicity, the death time of the MTX-CH group was delayed to a greater extent, and the 50% lethal dose (LD(50)) values of MTX-CH were lower than those of MTX-AQ. The LD(50) values of MTX-CH are 75 times higher than the efficacious dose of 30 mg/kg. The present results suggest that intratumoral administration of MTX-CH is useful for local therapy and the therapeutic dose of MTX-CH can be safely injected subcutaneously.