北山 丈二

BACKGROUND: Primary sarcoma of the breast is rare. Surgery has been the only curative treatment available. Recently, neoadjuvant chemotherapy including anthracycline/ifosfamide has been reported effective for patients with high-risk sarcomas in a prospective trial. CASE PRESENTATION: A 52-year-old Japanese woman presented with a mass in her left breast. The 10 cm tumor was fixed to her chest wall on examination. A skin biopsy was performed which showed leiomyosarcoma. Neoadjuvant chemotherapy was given and the tumor became mobile. A mastectomy and axillary dissection were performed with surgically negative margins. After neoadjuvant chemotherapy, the amount of necrosis was profoundly influenced by chemotherapy, and the histological effect of neoadjuvant chemotherapy was assessed in reference to pre-neoadjuvant chemotherapy magnetic resonance imaging. CONCLUSION: In contrast to many other cancers, the evaluation of various treatments and of the histological effect of neoadjuvant chemotherapy for sarcoma has been difficult due to the rarity of these tumors. We report the case of a patient with a breast sarcoma, treated with neoadjuvant chemotherapy and discuss the appropriate pathological evaluation and therapeutic management.

Gastrointestinal stromal tumors (GIST) in patients under 18 years of age are classified as pediatric GIST. Pediatric GIST are extremely rare, and there are no reports of laparoscopic-endoscopic cooperative surgery for these lesions. We report the use of non-exposed endoscopic wall-inversion surgery as a laparoscopic-endoscopic cooperative surgery-related procedure for the treatment of a pediatric GIST. The case involved a 17-year-old male patient who presented with anemia and was found to have a bleeding gastric tumor. The tumor was resected transorally using the non-exposed endoscopic wall-inversion surgery technique. No gene mutation of c-Kit or Platelet-Derived Growth Factor Receptor α (PDGFRα) was found, and the final pathological diagnosis was epithelial-type GIST due to a succinate dehydrogenase abnormality. Follow-up included a CT scan every 4 months. No recurrence has occurred to date.

OBJECTIVE: Mucin1 (MUC1), a member of the mucin family, is a glycoprotein which is often expressed in malignant cells. However, the expression and function of MUC1 in human duodenal adenocarcinoma (DAC) has not yet been characterized because of its low frequency. Here, we examined the functional roles of core protein (MUC1-C) in DAC. MATERIALS AND METHODS: Using a human duodenal cancer cell line, HuTu80, proliferation, migration, invasion, ALDH activity was assessed by cell counting kit-8, scratch wound healing, matrigel invasion, and ALDEFUOR assays, respectively. The function of MUC1 protein was evaluated with knockdown using specific siRNA as well as anti-MUC1-C peptide, GO203. MUC1 expression in human DAC was evaluated immunohistochemically in surgically resected tumors. RESULTS: The positive expression of MUC1 in HuTu80 was confirmed by RT-PCR and flow cytometry. In vitro cell growth was inhibited by the addition of 50-100 μM GO203 as well as treatment with siRNA for MUC1-C. Silencing of MUC1-C also significantly reduced migration, invasion, ALDH activity. Local injection of GO-203 (14 mg/kg) significantly suppressed the growth of subcutaneous HuTu80 tumors in nude mice. Immunohistochemically, MUC1 was strongly detected in seven DAC cases, but not in 11 others. The outcome of patients with high MUC1 expression was significantly worse than those without MUC1 expression. CONCLUSIONS: These results suggest that MUC1 is functionally associated with the malignant potential of DAC and could be a novel therapeutic target for this rare tumor.

INTRODUCTION: Immune thrombocytopenic purpura is an acquired thrombocytopenia. Preoperative management of thrombocytopenia is important in patients with gastric cancer. Partial splenic embolization can be effective for patients with thrombocytopenia, but could lead to ischemic necrosis of the remnant stomach when performing subtotal gastrectomy with splenectomy. PRESENTATION OF CASE: The patient is an 84-year old woman evaluated for anemia. Endoscopy revealed an advanced gastric cancer with bleeding. The patient also had immune thrombocytopenic purpura with a platelet count <50,000/μL. Administration of platelets did not increase the platelet count. Partial splenic embolization was performed followed by administration of high-dose immunoglobulin. The platelet count was over 50,000/μL preoperatively. The patient underwent combined subtotal gastrectomy and splenectomy, followed by an uneventful course. DISCUSSION: Patients with immune thrombocytopenic purpura and advanced gastric cancer can have anemia. Partial splenic embolization has been used to treat patients with refractory immune thrombocytopenic purpura as an alternative to splenectomy. Preoperative partial splenic embolization and high-dose immunoglobulin therapy resulted an increased platelet count in this patient. Elderly patients with gastric cancer have a high risk of postoperative complications. Patients with gastric cancer undergoing total gastrectomy have an impaired postoperative quality of life compared to those who undergo subtotal gastrectomy. We performed a subtotal gastrectomy and splenectomy as a function-preserving operation, completed safely by maintaining blood flow to the remnant stomach. CONCLUSION: Partial splenic embolization is effective for patients with immune thrombocytopenic purpura and gastric cancer. Combined subtotal gastrectomy and splenectomy is achieved by preserving blood flow to the remnant stomach.

INTRODUCTION: Gastric hyperplastic polyps are common stomach lesion and these polyps are generally benign. However, they can undergo malignant transformation. Most reported cases of malignant transformation of gastric hyperplastic polyps have been to well or moderately differentiated adenocarcinoma, and those transformed into poorly differentiated adenocarcinoma are extremely rare. No case has been reported that has changed to diffuse type adenocarcinoma with lymphatic invasion. PRESENTATION OF CASE: A 48-year-old woman presented with worsening anemia. A polyp was seen in the gastric cardia seven years prior to presentation. Helicobacter pylori infection was also found at that time. She underwent upper gastrointestinal endoscopy and biopsy of the polyp revealed signet ring cell carcinoma. Total gastrectomy was performed due to concern about possible invasion into the submucosal layer and there was no evidence of distant metastases. Histologic examination revealed both poorly differentiated adenocarcinoma and signet ring cell carcinoma surrounded by hyperplastic epithelium at the head of the polyp. Lymphatic invasion was also found, and malignant cells were limited to the mucosa. DISCUSSION: Gastric hyperplastic polyps are commonly associated with chronic gastritis which is related to Helicobacter pylori infections. Gastric hyperplastic polyps are generally benign and rarely undergo malignant transformation to adenocarcinoma with differentiated histology. The gastric hyperplastic polyp in this patient transformed to poorly differentiated adenocarcinoma with lymphatic invasion. CONCLUSION: Even small polyps may become poorly differentiated adenocarcinoma with invasion, so close follow-up or endoscopic resection are recommended as well as eradication of Helico Pylori infection when appropriate.

Activated neutrophils release neutrophil extracellular traps (NETs), which can capture and destroy microbes. Recent studies suggest that NETs are involved in various disease processes, such as autoimmune disease, thrombosis, and tumor metastases. Here, we show a detailed in vitro technique to detect NET activity during the trapping of free tumor cells, which grow after attachment to NETs. First, we collected low density neutrophils (LDN) from postoperative peritoneal lavage fluid from patients who underwent laparotomies. Short-term culturing of LDN resulted in massive NET formation that was visualized with green fluorescent nuclear and chromosome counterstain. After co-incubation of human gastric cancer cell lines MKN45, OCUM-1, and NUGC-4 with the NETs, many tumor cells were trapped by the NETs. Subsequently, the attachment was completely abrogated by the degradation of NETs with DNase I. Time-lapse video revealed that tumor cells trapped by the NETs did not die but instead grew vigorously in a continuous culture. These methods may be applied to the detection of adhesive interactions between NETs and various types of cells and materials.

Purpose Intraperitoneal paclitaxel plus systemic chemotherapy demonstrated promising clinical effects in patients with gastric cancer with peritoneal metastasis. We aimed to verify its superiority over standard systemic chemotherapy in overall survival. Patients and Methods This randomized phase III trial enrolled patients with gastric cancer with peritoneal metastasis who had received no or short-term (< 2 months) chemotherapy. Patients were randomly assigned at a two-to-one ratio to receive intraperitoneal and intravenous paclitaxel plus S-1 (IP; intraperitoneal paclitaxel 20 mg/m2 and intravenous paclitaxel 50 mg/m2 on days 1 and 8 plus S-1 80 mg/m2 per day on days 1 to 14 for a 3-week cycle) or S-1 plus cisplatin (SP; S-1 80 mg/m2 per day on days 1 to 21 plus cisplatin 60 mg/m2 on day 8 for a 5-week cycle), stratified by center, previous chemotherapy, and extent of peritoneal metastasis. The primary end point was overall survival. Secondary end points were response rate, 3-year overall survival rate, and safety. Results We enrolled 183 patients and performed efficacy analyses in 164 eligible patients. Baseline characteristics were balanced between the arms, except that patients in the IP arm had significantly more ascites. The median survival times for the IP and SP arms were 17.7 and 15.2 months, respectively (hazard ratio, 0.72; 95% CI, 0.49 to 1.04; stratified log-rank P = .080). In the sensitivity analysis adjusted for baseline ascites, the hazard ratio was 0.59 (95% CI, 0.39 to 0.87; P = .008). The 3-year overall survival rate was 21.9% (95% CI, 14.9% to 29.9%) in the IP arm and 6.0% (95% CI, 1.6% to 14.9%) in the SP arm. Both regimens were well tolerated. Conclusion This trial failed to show statistical superiority of intraperitoneal paclitaxel plus systemic chemotherapy. However, the exploratory analyses suggested possible clinical benefits of intraperitoneal paclitaxel for gastric cancer.

Despite recent advances in chemotherapy, outcomes of patients with peritoneal metastases (PM) from gastric cancer are still very poor and standard treatment has not been established. Although oral S-1 appears to be effective for patients with PM, the effects of systemic chemotherapy are limited. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) yield fewer benefits in patients with PM from gastric cancer than in patients with PM from other malignancies. In comparison, repeated intraperitoneal chemotherapy (RIPEC) with taxanes using an implantable peritoneal access port has a pharmacokinetic advantage for the control of peritoneal lesions and in combination with systemic chemotherapy can result in surprisingly long-term survival in patients with PM from gastric cancer. Herein, we review the results of recent clinical studies specifically targeting PM from gastric cancer and discuss future prospects for an intraperitoneal approach to the ideal treatment of patients with gastric cancer with peritoneal involvement.

Background: Repeated intraperitoneal (IP) administration of paclitaxel (PTX) with concurrent systemic chemotherapy is clinically effective for the treatment of peritoneal metastases (PM) from gastric cancer. However, it is unclear how biochemical modifications may affect the pharmacokinetics and bioavailability of IP administered PTX. Methods: In a xenograft PM model using human gastric cancer cells, MKN45, fluorescein-conjugated PTX (OG-PTX) was given IP and the intra-tumor distribution of PTX examined with fluorescein microscopy. Results: After IP injection, PTX was seen to directly infiltrate up to several hundred micrometers from the surface of the PM. Co-injection with 5 % non-animal stabilized hyaluronic acid increased PTX infiltration and suppressed the development of PM more efficiently than PTX alone. PTX solubilized with amphiphilic polymer composed of 2-methacryloyloxyethyl phosphorylcholine (MPC) and n-butyl methacrylate (BMA) efficiently formed a micellar formation 50-100 nm in diameter. IP injection of the nanomicellar PTX (PTX-30W) also showed significantly enhanced tumor infiltration and further inhibition of the growth of PM compared with PTX solubilized with Cremophor-ethanol (PTX-Cre). Finally, IP administration of NK105, another nanomicellar PTX, inhibited the growth of subcutaneous tumors as well as PM, compared with conventional PTX-Cre in the same murine model. Conclusions: PTX administered IP directly infiltrates PM and are thus a useful strategy for the treatment of PM. Drug modification with nanotechnology may further enhance penetration of PM resulting in improved clinical efficacy.

Gastric cancer is a common malignancy and remains potentially lethal. The prognosis of patients with stage IV gastric cancer is thought to be poor, but new molecular targeted therapy may benefit patients with advanced gastric cancer. Currently, conversion surgery after chemotherapy with a trastuzumab-containing regimen is reported to be effective in these patients. We present 3 patients with human epidermal growth factor receptor 2 (HER2)–positive advanced gastric cancer who underwent conversion surgery after receiving a trastuzumab-containing chemotherapy regimen. Interestingly, the primary lesion acquired resistance to the trastuzumab-containing regimen, although the metastatic lesions maintained a complete response. The reason why the primary lesions became resistant to trastuzumab remains unclear. More studies are needed to clarify the mechanism of resistance. Conversion surgery, made possible by the use of molecular-targeted therapy, may improve the prognosis of patients with stage IV gastric cancer, particularly if metastatic lesions show a complete response to therapy.

BACKGROUND: CD133 is a transmembrane protein that is proposed to be a stem cell marker of colorectal cancer (CRC); however, the correlation between CD133 expression and survival of CRC patients with liver metastasis has not been fully examined. METHODS: CD133 expression was evaluated immunohistochemically, both in primary tumors and synchronous liver metastases of 88 consecutive CRC patients, as well as recurrent lesions in the remnant liver of 27 of these 88 patients. The relationship between CD133 expression and clinicopathological characteristics, recurrence-free survival, and overall survival (OS) was analyzed. RESULTS: CD133 expression in liver metastases (mCD133) was detected in 50 of 88 patients (56.8 %), and had significant correlation with CD133 expression in primary lesions (pCD133) (p < 0.001). CD133 expression in liver recurrent lesions (recCD133) also had a significant correlation with mCD133 (p < 0.001). mCD133+ patients had significantly longer disease-free survival (p = 0.043) and OS (p = 0.014) than mCD133- patients. In addition, mCD133+ patients had a significantly lower rate of extrahepatic recurrence (p < 0.001). CONCLUSIONS: Patients without CD133 expression in liver metastasis had significantly shorter survival, perhaps because mCD133- patients had a significantly higher rate of extrahepatic recurrence.