Peritoneal carcinomatosis (PC) is the most frequent metastatic pattern of gastric cancer and its prognosis is extremely poor. PC is characterized by rich fibrosis and the development of obstructive disorders such as ileus, jaundice and hydronephrosis. Epithelial-mesenchymal transition (EMT) is one of the major causes of tissue fibrosis and transforming growth factor β (TGF-β) has a pivotal function in the progression of EMT. Protein-bound polysaccharide K (PSK) is a biological response modifier that can modulate the TGF-β/Smad signaling pathway in vitro. In the present study, we established a fibrotic tumor model using human peritoneal mesothelial cells (HPMCs) and a human gastric cancer cell line to evaluate whether PSK attenuates tumor fibrosis. HPMCs exposed to PSK did not undergo the morphological change from a cobblestone-like pattern to a spindle-shape pattern normally induced by treatment with TGF-β. Immunofluorescence further demonstrated that PSK suppressed TGF-β-induced overexpression of α-SMA in the HPMCs. We further showed that HPMCs contributed to the proliferation of tumor fibrosis by using a mouse xenograft model. Additionally, PSK treatment of these mice significantly reduced the area of observable tumor fibrosis. These results suggest that seeded cancer cells transformed HPMCs into myofibroblast-like cells through their release of TGF-β in the microenvironment, facilitating the development of fibrous tumors in organs covered with HPMCs. Therefore, our study indicates that PSK has potential utility as an anti-fibrotic agent in the treatment of gastric cancer patients with PC.
protein-bound polysaccharide; transforming growth factor β; gastric cancer; cancer-associated fibroblast
Intestinal malrotation is a rare congenital anomaly, and acute appendicitis associated with intestinal malrotation is extremely rare.
PRESENTATION OF CASE We report a rare case of a 47-year-old Japanese woman diagnosed with barium-related perforated appendicitis associated with intestinal malrotation. We used a transumbilical single-incision laparoscopic approach to resect the appendix, and the procedure was completed successfully without perioperative complications.
To our knowledge, single-incision laparoscopic surgery for appendicitis associated with intestinal malrotation has not been reported yet. In cases with mobile cecum such as this one, mobilization from inflammatory adhesion of the surrounding structures is easy.
We conclude that transumbilical single-incision laparoscopic appendectomy is a simple and less invasive method for treating appendicitis associated with intestinal malrotation.
Single-incision; Laparoscopy; Transumbilical; Appendectomy; Appendicitis; Malrotation; WBC, white blood cell; CT, computed tomography
Intraperitoneal (IP) chemotherapy is garnering attention as an effective treatment for gastric cancer with peritoneal metastasis. We report the case of a patient who developed colonic stenosis caused by infection of an IP access port system during IP chemotherapy. It was difficult to differentiate whether the extrinsic colonic stenosis arose from a catheter infection or peritoneal metastasis of the gastric cancer.
A 66-year-old Japanese man underwent total gastrectomy for gastric cancer. Because the intraoperative findings revealed peritoneal metastasis, a port system was implanted for subsequent IP chemotherapy. Two months after initiation of chemotherapy, he complained of vomiting and abdominal pain. A computed tomography scan revealed marked thickening of the sigmoid colon wall adjacent to the catheter of the IP access port system. A barium enema demonstrated extrinsic irregular stenosis of the sigmoid colon. Although it was difficult to distinguish whether infection or peritoneal metastasis had caused the colonic stenosis, we removed the port system to obtain a therapeutic diagnosis. Coagulase-negative staphylococci were detected by catheter culture. The wall thickening and stenosis of the sigmoid colon completely resolved after removal of the port system.
We report the case of a rare complication in association with an IP access port system. Infection of the port system should be considered as a differential diagnosis when colonic stenosis adjacent to the catheter is observed during IP chemotherapy.
Intraperitoneal chemotherapy; Gastric cancer; Peritoneal metastasis; Port complication
Methotrexate (MTX), a folic acid antagonist, is widely used in the treatment of neoplasms, psoriasis and rheumatoid arthritis. Despite its efficacy, MTX sometimes finds limited application because of its adverse effects, including renal or liver impairment, bone marrow toxicity and gastrointestinal mucosal injury. Intestinal mucositis, bleeding and peptic ulcers are well-known gastrointestinal adverse effects of MTX, although cases of fatal mucosal necrosis induced by MTX are extremely rare. Here, we report the case of an 82-year-old Japanese woman who developed severe gastrointestinal mucosal necrosis after 8 years of treatment with low-dose MTX (8 mg/week). In the drug lymphocyte stimulation test, MTX showed a strong positive reaction, with a stimulation index of 443% against normal controls. Physicians must be aware of potential drug-induced adverse effects in patients with chronic diseases who are on long-term medication.
Methotrexate; Adverse effect; Drug lymphocyte stimulation test; Type IV allergic reactions; Gastrointestinal tract; Mucosal injury; Necrosis; Rheumatoid arthritis
Epidermal-mesenchymal transition (EMT) confers an advantage to cancer cells by improving their invasive capacity and metastatic potential. This phenomenon by which epidermal cells change into mesenchymal cells and therefore acquire a higher ability to automaticity, is considered a key process in cancer development. Transforming growth factor-β (TGF-β) is a significant factor for accelerating EMT through the activation of proteins, including members of the Smad pathway. Furthermore, previous studies have shown that low-dose paclitaxel (PTX) inhibits EMT in certain cell lines, including those of cancer cells. The present study determined whether low-dose PTX was able to inhibit EMT in a human cholangiocarcinoma CCKS-1 cell line that had been treated with TGF-β1. First, the cytotoxic concentration of PTX for the CCKS-1 cells was identified to be ~5 nM by MTT assay and dead cell staining. Therefore, the concentrations of PTX were set as 1 nM, 2.5 nM and 5 nM for the subsequent experiments. In the morphological investigation, the CCKS-1 cells changed into a spindle morphology and became separated by the administration of TGF-β1. However, low-dose PTX inhibited these changes and the morphology resembled the control cells in a dose-dependent manner. Similarly, immunofluorescence and immunoblotting investigations revealed that the CCKS-1 cells expressed mesenchymal markers following the administration of TGF-β1. However, low-dose PTX inhibited the expression of the mesenchymal markers and the CCKS-1 cells expressed the epithelial marker, E-cadherin. In particular, a concentration-dependent effect was observed in the immunoblotting experiments. These results show that PTX may be able to inhibit EMT in cancer cells, depending on the dose concentration.
cholangiocarcinoma; paclitaxel; epidermal-mesenchymal transition
Hepatic metastasis is a common cause of treatment failure following resection of pancreatic cancer. In this study, we report our results of hepatic arterial infusion (HAI) chemotherapy with gemcitabine (GEM) plus 5-fluorouracil (5-FU) or oral S-1 treatment for postoperative liver metastases from pancreatic cancer. Seven patients with postoperative liver metastases from pancreatic cancer received HAI with GEM plus 5-FU or oral S-1 between October, 2008 and September, 2010 at Kanazawa University Hospital (Kanazawa, Japan). Three out of the 7 cases exhibited a partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) and stable disease (SD) was achieved in 3 out of the 7 cases (response rate, 85.7%). A decrease in serum tumor marker CA 19-9 levels was observed after 10 HAI treatment cycles in 5 out of the 7 cases. The median time to treatment failure was 8 months (range, 0–17 months). Adverse events included grade 3 leukocytopenia in 1 case and anemia in all 7 cases, although 5 out of the 7 patients were anemic prior to HAI therapy. Grade 2 thrombocytopenia was also observed in 2 cases. Non-hematological events, such as nausea, diarrhea, liver injury or neuropathy and life-threatening toxicities were not reported; however, 6 patients (85.7%) developed catheter-related complications and the HAI catheter and subcutaneous implantable port system had to be removed. These findings demonstrated that HAI may deliver high doses of chemotherapeutic agents directly into the tumor vessels, producing increased regional levels with greater efficacy and a lower incidence/severity of systemic side effects. In conclusion, HAI chemotherapy is a safe and effective treatment for liver metastases from pancreatic cancer.
pancreatic cancer; liver metastasis; hepatic arterial infusion; gemcitabine; 5-fluorouracil; S-1
The aim of this study was to determine the maximum-tolerated dose (MTD), the dose-limiting toxicity (DLT) and the recommended dose (RD) of neoadjuvant chemotherapy (NAC) with gemcitabine (GEM) plus oral S-1 in patients with resectable pancreatic cancer. Thirteen patients with radiologically proven resectable pancreatic cancer were included in this study. S-1 was administered orally for 14 consecutive days, and GEM was administered on days 8 and 15 for two pre-operative cycles. The dose of S-1 in this study was planned with fixed doses of GEM (1,000 mg/m2): 20, 30 and 40 mg/day for levels 0, 1 and 2, respectively. Treatment was initiated at level 1 in 3 patients, while adverse events occurred in 2 patients during the second course, leading to a dose reduction to level 0 for the 8 remaining patients. Two of the 10 patients enrolled at level 0 were excluded. Of the remaining 8 patients, GEM administration was terminated due to DLT on day 15, during the first course in 3 patients, while level 0 dosage reached MTD. Surgery was performed for the remaining 11 patients included in the study. Post-operative complications included pancreatic fistulas in 5 patients and Pseudomonas aeruginosa sepsis in 1 patient. Two of the 11 patients exhibited a partial response and 9 patients stable disease. Eight of the 11 tumor specimens showed histopathological evidence of tumor cell injury. In conclusion, NAC with GEM and S-1 was not well-tolerated in this study. However, pre-operative chemotherapy may be effective against pancreatic cancer. Therefore, it is necessary to reconsider NAC regimens for pancreatic cancer.
pancreatic cancer; gemcitabine; S-1; neoadjuvant chemotherapy; phase I
Various treatments have been used for peritoneal dissemination, which is the most common mode of metastasis in gastric cancer, but sufficiently good clinical outcomes have not yet been obtained because of the presence of rich fibrous components and acquired drug resistance. Epithelialmesenchymal transition (EMT) is one of the major causes of tissue fibrosis and transforming growth factor-β (TGF-β) has a pivotal function in the progression of EMT. Smad proteins play an important role in the TGF-β signalling pathway. The TGF-β/Smad signalling pathway can be modulated by stabilising microtubules with paclitaxel (PTX). Here, we investigated whether paclitaxel can modulate TGF-β/Smad signalling in human peritoneal methothelial cells (HPMCs). To determine the cytostatic concentrations of antineoplastic agents in HPMCs, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed using PTX, 5-fluorouracil and cisplatin. The minimum concentration that caused significant inhibition of TGF-β1-induced morphological changes in human peritoneal methothelial cells on pre-treatment with PTX was 5 nM at 48 h (cell viability: 87.1±1.5%, P<0.01). The TGF-β signalling cascade and the status of various fibrous components were evaluated by immunofluorescence staining, real-time quantitative PCR and western blotting. TGF-β signalling induced morphological changes, α-SMA expression and collagen I synthesis in HPMCs and PTX treatment suppressed these EMT-like changes. Moreover, PTX treatment markedly suppressed Smad2 phosphorylation. These data suggest that at a low-dose, PTX can significantly suppress the TGF-β/Smad signalling pathway by inhibiting Smad2 phosphorylation in the human peritoneum and that this can reduce stromal fibrosis.
gastric cancer; human peritoneal mesothelial cell; paclitaxel; epithelial-mesenchymal transitions; fibrosis
Chemotherapy and other systemic therapies are the primary treatments for patients with unresectable, locally advanced breast cancer. The clinical application of supportive care using Mohs paste has become widespread for the purpose of improving patients’ quality of life. Here, we report two cases of locally advanced breast cancer, for which the patients underwent radical surgery after a combination of systemic therapy and Mohs chemosurgery.
Patient 1 was a 90-year-old Japanese woman with right breast cancer diagnosed as stage IIIB (T4bN1M0). The treatment included Mohs paste application and hormonal therapies. Patient 2 was a 60-year-old Japanese woman with right breast cancer diagnosed as stage IIIB (T4cN2aM0). Her treatment included Mohs paste application, together with chemotherapy (four cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, and four cycles of docetaxel). In both cases, a reduction in the primary tumor volume was observed, and radical mastectomy and axillary lymph node dissection were possible without relaxation incision or skin flap.
We report patients with no distant metastases who were able to undergo radical resection after a combination of systemic therapy and Mohs chemosurgery. For locally advanced breast cancer, Mohs chemosurgery, in addition to multidisciplinary treatment, is useful.
Breast cancer; Modified radical mastectomy; Mohs surgery
A 56-year-old female with metastatic gallbladder cancer involving the liver and stenosis of the hilar bile duct was treated with gemcitabine (1,000 mg/m2) plus S-1 (60 mg/m2). After 9 cycles of therapy, CT showed evidence of stable disease; however, the serum CEA level was increased. Therefore, the chemotherapy regimen was changed to weekly low-dose paclitaxel (60 mg/m2). After 12 cycles of therapy, paclitaxel was reduced to 30 mg/m2 as the patient developed neutropenia. The patient completed 32 cycles of therapy, and the tumor was reduced in size and marked improvement in bile duct stenosis was noted without any impairment in quality of life. The patient succumbed to the disease 25 months after treatment was initiated. Thus, in this case paclitaxel was more effective than gemcitabine plus S-1. Palliative chemotherapy with paclitaxel after failure of gemcitabine and 5-FU was well-tolerated; therefore, it may be an effective treatment for biliary tract cancer (BTC). A phase I study of palliative chemotherapy with weekly low-dose paclitaxel following gemcitabine (plus cisplatin) and 5-FU is currently in progress in patients with unresectable or recurrent BTC.
gallbladder cancer; biliary tract cancer; paclitaxel; palliative chemotherapy
Ischemic colitis is the most common type of intestinal ischemia. The etiology of this condition is multifactorial, and the diagnosis is based on a combination of clinical symptoms, as well as endoscopic and histological findings. Although conservative therapy is effective in most cases, surgery still plays a key role in the treatment of ischemic colitis. Here, we describe a case of a 73-year-old man in whom laparoscopy-assisted left colectomy was performed 80 d after the onset of ischemic colitis. He recovered completely after surgery, and the pathological findings were consistent with ischemic colitis. To the best of our knowledge, there are no detailed reports of laparoscopic surgery for chronic segmental stenotic ischemic colitis. We discussed the usefulness of laparoscopic surgery, comparing it with endoscopic treatment, and we propose an optimal treatment strategy from a viewpoint of stenosis length and duration of disease.
Ischemic colitis; Laparoscopic surgery; Stenosis; Chronic; Endoscopy
We evaluated the safety and validity of cholecystomucoclasis (CM) and compared its intraoperative characteristics with those of standard cholecystectomy (SC).
We enrolled 174 patients who underwent cholecystectomy and retrospectively evaluated the outcomes of patients in the SC and CM groups.
Significant differences in age (71.1 vs. 61.9 years), American Society of Anesthesiologists physical status (ASA-PS), and serum C-reactive protein levels (CRP) (18.1 vs. 4.7 mg/dL) were observed between the CM and SC groups. Conversely, no significant differences were observed in the operation time (129 vs. 108 min), amount of blood loss (147 vs. 80 mL), intraoperative complications (0% vs. 5.7%), or duration of hospital stay (13.2 vs. 8.9 days) between the 2 groups. A high conversion rate (35.3%), postoperative complications (33%), and frequent drain insertions (94%) were observed in the CM group.
CM is a safe and valid surgical procedure and surgeons should not hesitate to transition to CM for patients who are of advanced age, in poor general condition (high ASA classification), or have high levels of serum CRP.
Cholecystitis; Cholecystomucoclasis; Deroofing; Subtotal cholecystectomy
Peritoneal dissemination is the most frequent metastatic pattern of scirrhous gastric cancer. However, despite extensive research effort, disease outcomes have not improved sufficiently. Tumor progression and metastasis result from interactions between cancer and various cells in the stroma, including endothelial cells, immune cells and fibroblasts. Fibroblasts have been particularly well studied; they are known to change into carcinoma-associated fibroblasts (CAFs) and produce transforming growth factor β (TGF-β), which mediates cancer-stroma interactions. Here, we investigated whether TGF-β derived from cancer cells in the peritoneal microenvironment activates human peritoneal mesothelial cells (HPMCs), leading to the progression and fibrosis of gastric cancer. We found that activated HPMCs (a-HPMCs) took on a spindle shape formation, decreased the expression of E-cadherin and increased that of α-SMA. Furthermore, a-HPMCs became more invasive and upregulated proliferation of human gastric cancer-derived MKN45 cells following direct cell-cell contact. Notably, MKN45 cells co-cultured with a-HPMCs also acquired anchorage-independent cell growth and decreased expression of E-cadherin in vitro. To measure the effects of the co-culture in vivo, we developed a mouse xenograft model into which different culture products were subcutaneously injected. The largest tumors were observed in mice that had been given MKN45 cells co-cultured with a-HPMCs. Furthermore, these tumors contained HPMC-derived fibrous tissue. Thus, the epithelial-mesenchymal transition (EMT) of HPMCs appears to drive peritoneal dissemination and tumor fibrosis.
gastric cancer; human peritoneal mesothelial cell; fibrosis; epithelial-mesenchymal transition; cell-cell interaction
18F-fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (integrated FDG PET/CT) has been used to diagnose recurrence and differentiate postoperative changes from lymph node metastasis in colorectal cancer, although its accuracy is questionable. We report a prone thoracoscopic surgery for a rectal cancer patient in which false-positive mediastinal lymph nodes were found on FDG-PET/CT. A 60-year-old man underwent a laparoscopic high anterior resection and D3 lymph node dissection for rectal cancer. The histopathological diagnosis was moderately differentiated adenocarcinoma of the rectum, stage IIIB (pT3N1M0), necessitating oral fluoropyrimidine agent S-1. After the primary surgery, a solitary mediastinal lymph node measuring 30 mm in diameter was detected, and abnormal accumulation was confirmed by FDG-PET/CT (SUVmax, 11.7). Thoracoscopic resection was performed in the prone position, but histopathological results showed no metastasis. He was subsequently diagnosed with reactive lymphadenitis. The patient was discharged on postoperative day 4 in good condition and is alive without recurrence 12 months after surgery. PET/CT is useful for the detection of colorectal cancer recurrence; however, it does have a high false-positive rate for mediastinal lymph nodes. There is a limit to its diagnostic accuracy, and one must determine the indication for surgical treatment carefully. Surgery in the prone position is a useful and minimally invasive approach to the mediastinum and allows aggressive resection to be performed.
False-positive; FDG-PET/CT; Mediastinal lymph node; Thoracoscopic surgery; Prone position
Adiponectin is inversely related to BMI, positively correlates with insulin sensitivity, and has anti-atherogenic effects. In recent years, adiponectin has been well studied in the field of oncology. Adiponectin has been shown to have antiproliferative effects on gastric cancer, and adiponectin expression is inversely correlated with clinical staging of the disease. However, no studies have reported the correlation between serum adiponectin and receptor expression with disease progression.
In this study, we evaluated expression levels of 2 adiponectin receptors--AdipoR1 and AdipoR2--and attempted to correlate their expression with prognosis in gastric cancer patients. AdipoR1 and AdipoR2 expression in gastric cancer cell lines (MKN45, TMK-1, NUGC3, and NUGC4) was evaluated by western blotting analysis, and the antiproliferative potential of adiponectin was examined in vitro. Serum adiponectin levels were evaluated in 100 gastric cancer patients, and the expression of AdipoR1 and AdipoR2 was assessed by immunohistochemical staining.
MKN45 and NUGC3 expressed higher levels of AdipoR1 compared to NUGC4, even though there was no significance in AdipoR2 expression. The antiproliferative effect of adiponectin was confirmed in MKN45 and NUGC3 at 10 μg/ml. No significant associations were observed between serum adiponectin levels and clinicopathological characteristics, but lymphatic metastasis and peritoneal dissemination were significantly higher in the negative AdipoR1 immunostaining group (24/32, p = 0.013 and 9/32, p = 0.042, respectively) compared to the positive AdipoR1 group (lymphatic metastasis, 33/68; peritoneal dissemination, 8/68). On the other hand, AdipoR2 expression was only associated with histopathological type (p = 0.001). In survival analysis, the AdipoR1 positive staining group had significantly longer survival rates than the negative staining group (p = 0.01). However, multivariate analysis indicated that AdipoR1 was not an independent prognostic factor on patient's survival on gastric cancer.
In gastric cancer, adiponectin has the possibility to be involved in cell growth suppression via AdipoR1. The presence of AdipoR1 could be a novel anticancer therapeutic target in gastric cancer.
Adiponectin; AdipoR1; AdipoR2; gastric cancer; survival