[A Case of Pathological Complete Response of Advanced Rectal Cancer with Direct Invasion of the Prostate and Extra-Regional Lymph Node Metastasis after Chemotherapy].

A 62-year-old man was diagnosed as having advanced rectal cancer with an invasive carcinoma of the prostate and the right inguinal lymph node metastasis. He received chemotherapy consisting of combination of 5-FU, oxaliplatin, Leucovorin (mFOLFOX6)and bevacizumab. After 5 courses of the chemotherapy, CT and MRI findings revealed the tumor shrinkage. After 6 courses of the chemotherapy, a laparoscopic abdominoperineal resection, bilateral lymph node dissection and a resection of right inguinal lymph node were performed. The pathological findings showed a pCR. NAC with mFOLFOX6 and bevacizumab may contribute to the reduction of the surgical stress for the patients and be an effective treatment for advanced rectal cancer with distant lymph node metastasis.

[The Usefulness of Preoperative Modified Glasgow Prognostic Score Evaluation in Elderly Colorectal Cancer Cases].

BACKGROUND: In cancer treatment of the elderly, it is important to grasp the"degree of inflammation"and"nutritional status"in advance. OBJECTIVE: This study aims to investigate the usefulness of preoperative modified Glasgow Prognostic score(mGPS)evaluation in elderly patients with colorectal cancer. PATIENT: 89 cases of primary resection of colorectal cancer over 80 years old were enrolled. METHODS: In the preoperative mGPS score normal group(score 0)and abnormal group (scores 1 or 2)were divided. Clinicopathological factors(patient-related 13 factors, treatment-related 6 factors, and tumor-related 4 factors)were compared, and the long-term results were also investigated. RESULTS: Between 42 cases in the normal group and 47 cases in the abnormal group, there were significant differences(p<0.05)in 6 factors: BMI, total protein, cholinesterase, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and Onodera prognostic nutritional index. The long-term results(5-year survival rate)were also significantly different in the normal group(76.8%)and the abnormal group(51.6%)(p=0.007). CONCLUSION: Even in elderly patients with colorectal cancer, preoperative suppression of inflammatory conditions and improvement of nutritional status may contribute to the improvement of long-term prognosis, so mGPS evaluation is useful.

Early administration of amatuximab, a chimeric high-affinity anti-mesothelin monoclonal antibody, suppresses liver metastasis of mesothelin-expressing pancreatic cancer cells and enhances gemcitabine sensitivity in a xenograft mouse model.

Amatuximab is a promising therapeutic antibody targeting mesothelin, a 40-kDa glycoprotein that is highly expressed in pancreatic cancer. We investigated the effectiveness of early amatuximab treatment, imitating an adjuvant chemotherapy setting, and combination therapy with amatuximab and gemcitabine in liver metastasis of pancreatic cancer. Liver metastasis mouse models were established in 8-week-old male BALB/c nu/nu mice using the hemisplenic injection method. Tridaily amatuximab monotherapy or combination with gemcitabine was administered to the liver metastasis mouse model before metastatic lesions had formed huge masses. Gaussia luciferase-transfected AsPC-1 was used as a mesothelin-overexpressing pancreatic cancer cell line. The amount of liver metastases and the serum luciferase activity were significantly lower in the treatment groups than those in the control IgG group. Notably, the anti-tumor activity of gemcitabine was synergically enhanced by combination therapy with amatuximab. Furthermore, western blotting revealed that the high expression of phosphorylated c-Met and AKT in liver metastatic lesions treated with gemcitabine monotherapy was canceled by its combination with amatuximab. This result indicated that the observed synergic therapeutic effect may have occurred as a result of the inhibitory effect of amatuximab on the phosphorylation of c-Met and AKT, which were promoted by exposure to GEM. In conclusion, our study revealed that early administration of amatuximab alone or in combination with GEM significantly suppressed the liver metastases of mesothelin-expressing pancreatic cancer cells. A phase II clinical trial of amatuximab as part of an adjuvant chemotherapy regimen for resected pancreatic cancer is expected.

Mesothelin blockage by Amatuximab suppresses cell invasiveness, enhances gemcitabine sensitivity and regulates cancer cell stemness in mesothelin-positive pancreatic cancer cells.

BACKGROUND: Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known. Amatuximab is a chimeric monoclonal IgG1/k antibody targeting mesothelin. We recently demonstrated that the combine therapy of Amatuximab and gemcitabine was effective for peritonitis of pancreatic cancer in mouse model. METHODS: We discover the role and potential mechanism of mesothelin blockage by Amatuximab in human pancreatic cells both expressing high or low level of mesothelin in vitro experiment and peritonitis mouse model of pancreatic cancer. RESULTS: Mesothelin blockage by Amatuximab lead to suppression of invasiveness and migration capacity in AsPC-1 and Capan-2 (high mesothelin expression) and reduce levels of pMET expression. The combination of Amatuximab and gemcitabine suppressed proliferation of AsPC-1 and Capan-2 more strongly than gemcitabine alone. These phenomena were not observed in Panc-1 and MIA Paca-2 (Mesothelin low expression). We previously demonstrated that Amatuximab reduced the peritoneal mass in mouse AsPC-1 peritonitis model and induced sherbet-like cancer cell aggregates, which were vanished by gemcitabine. In this study, we showed that the cancer stem cell related molecule such as ALDH1, CD44, c-MET, as well as proliferation related molecules, were suppressed in sherbet-like aggregates, but once sherbet-like aggregates attached to peritoneum, they expressed these molecules strongly without the morphological changes. CONCLUSIONS: Our work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine.

Rare case of idiopathic sclerosing cholangitis, which was difficult to distinguish from cholangiocarcinoma: A case report.

It is often difficult to correctly diagnose patients who present with dilation of the bile duct. Cholangiocarcinoma, primary sclerosing cholangitis (PSC) and immunoglobulin (Ig)G4-related sclerosing cholangitis must be considered as potential diagnoses for these cases. The current study presents a 73-year-old female patient who presented with a high fever and abdominal pain. Contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography revealed stenosis and dilation of the intrahepatic bile duct without solid components. It was suspected that the patient had intrahepatic cholangiocarcinoma. A left liver lobectomy, cholecystectomy and distal gastrectomy combined with a D2 lymph node dissection were performed. A pathological examination of the liver revealed increased fibrosis in the stroma, irregular bile duct dilation and clusters of inflamed lymph cells. No carcinoma or IgG4-positive plasma cells were observed and the typical findings of PSC were not detected. Based on these clinical and pathological results, the diagnosis was idiopathic sclerosing cholangitis, which is particularly rare. It is often difficult to preoperatively differentiate between cholangiocarcinoma and benign bile duct stenosis.

The anti-mesothelin monoclonal antibody amatuximab enhances the anti-tumor effect of gemcitabine against mesothelin-high expressing pancreatic cancer cells in a peritoneal metastasis mouse model.

Pancreatic cancer often has a very poor prognosis, even after complete resection. The recurrence of hepatic and peritoneal metastases is an important prognostic factor; therefore, the development of improved adjuvant therapy is urgently required. Mesothelin is a cell surface glycoprotein whose expression is restricted to a variety of cancer types, including pancreatic cancer. This expression pattern makes mesothelin an attractive target for cancer therapy, and several agents targeting mesothelin are currently in clinical trials. Here, we used the chimerized high-affinity anti-mesothelin monoclonal antibody amatuximab to investigate its effect on peritoneal metastasis. We used the AsPC-1 pancreatic cancer cell line engineered to express Gaussia luciferase (Gluc), (AsPC-1-Gluc) for in vivo experiments. Results showed that while amatuximab was not directly cytotoxic on an AsPC-1-Gluc tumor cells in a peritoneal metastasis model, it prevented the formation of tumor growth. In combination therapy with gemcitabine, amatuximab exhibited synergistic killing. Our results suggest that blockade of mesothelin by amatuximab may be a useful strategy for preventing the peritoneal dissemination of pancreatic cancer under an adjuvant setting.

Mutant p53-Expressing Cells Undergo Necroptosis via Cell Competition with the Neighboring Normal Epithelial Cells.

p53 is a tumor suppressor protein, and its missense mutations are frequently found in human cancers. During the multi-step progression of cancer, p53 mutations generally accumulate at the mid or late stage, but not in the early stage, and the underlying mechanism is still unclear. In this study, using mammalian cell culture and mouse ex vivo systems, we demonstrate that when p53R273H- or p53R175H-expressing cells are surrounded by normal epithelial cells, mutant p53 cells undergo necroptosis and are basally extruded from the epithelial monolayer. When mutant p53 cells alone are present, cell death does not occur, indicating that necroptosis results from cell competition with the surrounding normal cells. Furthermore, when p53R273H mutation occurs within RasV12-transformed epithelia, cell death is strongly suppressed and most of the p53R273H-expressing cells remain intact. These results suggest that the order of oncogenic mutations in cancer development could be dictated by cell competition.

L-Carnitine supplementation reduces the general fatigue of cancer patients during chemotherapy.

L-Carnitine (LC) plays an important role in the metabolism of fatty acids, and LC deficiency is associated with a feeling of weakness or general fatigue. Cancer patients receiving chemotherapy often develop LC deficiency, which is considered to be a factor contributing to general fatigue. The aim of the present study was to evaluate the efficacy of LC supplementation as a treatment for general fatigue in cancer patients during chemotherapy. A total of 11 cancer patients who were suffering from general fatigue during chemotherapy in our hospital between September 2014 and December 2015 were examined (6 cases involved adjuvant chemotherapy and 5 cases involved chemotherapy for unresectable or recurrent disease). The patients were administered 1,500 mg/day of levocarnitine per os, and the change in mean daily fatigue from the baseline to 8 weeks was assessed using the Brief Fatigue Inventory. The change in the plasma levels of albumin and the lymphocyte counts from the baseline to 8 weeks were also assessed. LC supplementation reduced general fatigue in all cases. Moreover, LC supplementation maintained the plasma levels of albumin and lymphocyte counts during chemotherapy, and enabled patients to continue chemotherapy sequentially without dose reduction. Therefore, LC supplementation improved general fatigue in all the examined cancer patients during chemotherapy. This treatment may make improve the tolerability of chemotherapy in cancer patients by reducing general fatigue and improving the nutritional status.

Serosal Laceration During Firing of Powered Linear Stapler Is a Predictor of Staple Malformation.

BACKGROUND: Although several types of staplers have been developed, staple-line leaks have been a great problem in gastrointestinal surgery. Powered linear staplers were recently developed to further reduce the risk of tissue trauma during laparoscopic surgery. The aim of this study was to identify the factors that predict staple malformation and determine the effect of precompression and slow firing on the staple formation of this novel powered stapling method. METHODS: Porcine stomachs were divided using an endoscopic powered linear stapler with gold reloads. We divided the specimens into 9 groups according to the precompression time (0/60/180 seconds) and firing time (0/60/180 seconds). The occurrence and length of laceration and the shape of the staples were evaluated. We examined the factors influencing successful stapling and investigated the key factors for staple malformation. RESULTS: Precompression significantly decreased the occurrence and length of serosal laceration. Precompression and slow firing significantly improved the optimal stapling formation rate. Univariate analysis showed that the precompression time (0 seconds), firing time (0 seconds), and presence of serosal laceration were significantly associated with a low optimal formation rate. Multivariate analysis showed that these three factors were associated independently with low optimal formation rate and that the presence of serosal laceration was the only factor that could be detected during the stapling procedure. CONCLUSIONS: We have shown that serosal laceration is a predictor of staple malformation and demonstrated the importance of precompression and slow stapling when using the powered stapling method.

Long-term survival and prognosis associated with conversion surgery in patients with metastatic gastric cancer.

In gastric cancer, primary systemic chemotherapy is the standard approach for the management of patients with initially unresectable metastasis, and it occasionally leads to a reduction in the size of the lesion, which facilitates surgical resection. The aim of this study was to examine the prognosis of patients who were able to undergo complete resection following chemotherapy. A total of 10 patients who underwent radical surgery for stage IV primary gastric cancer after chemotherapy between 2009 and 2015 at the Department of Surgery of Hokkaido Social Work Association Obihiro Hospital (Obihiro, Japan) were retrospectively investigated. Three regimens were used (S-1, n=1; S-1 + cisplatin, n=8; and S-1 + docetaxel, n=1). The mean time from chemotherapy to surgery was 210 days. One total gastrectomy + splenectomy + colectomy, one total gastrectomy + splenectomy, four total gastrectomies and three distal gastrectomies were performed. There were two cases of pancreatic fistula formation postoperatively. All the patients survived for >1 year. Of the 10 patients, 5 survived without recurrence. The median survival time was 871.1 days after diagnosis. Therefore, curative resection after chemotherapy is associated with a better prognosis in stage IV gastric cancer patients.

Successful treatment of rectovaginal fistula and rectal stenosis due to perianal Crohn's disease by dual-port laparoscopic abdominoperineal resection: a report of two cases.

BACKGROUND: The incidence of rectovaginal fistula in women with Crohn's disease has been reported to be 3-10 %. Although rectovaginal fistulas can be managed medically and surgically, they have high rates of recurrence and complications. Rectal stenosis is another condition that occurs due to perianal Crohn's disease. A novel, minimally invasive procedure, dual-port laparoscopic abdominoperineal resection using a multichannel port, has been shown effective in patients with lower rectal cancer and patients with medically uncontrolled ulcerative colitis. This report describes the use of the same method for two patients with Crohn's disease-related rectovaginal fistula and rectal stenosis. CASE PRESENTATION: The first patient, a 22-year-old woman, was diagnosed with rectovaginal fistula and rectal stenosis due to perianal Crohn's disease 2 years earlier. Induction therapy with infliximab and endoscopic balloon dilatation did not improve her symptoms. The second patient, a 33-year-old woman, was also diagnosed with rectovaginal fistula and rectal stenosis due to perianal Crohn's disease, and medical treatment was also unsuccessful. Both patients underwent dual-port laparoscopic abdominoperineal resection using a multichannel port, with no perioperative and postoperative complications. CONCLUSION: These findings show that this reduced port method can be used to successfully treat patients with Crohn's disease-associated rectovaginal fistula and rectal stenosis.

Clinical impacts of mesothelin expression in gastrointestinal carcinomas.

Mesothelin, C-ERC/mesothelin is a 40-kDa cell surface glycoprotein that is normally present on normal mesothelial cells lining the pleura, peritoneum, and pericardium. Moreover, mesothelin has been shown to be overexpressed in several human cancers, including virtually all mesothelioma and pancreatic cancer, approximately 70% of ovarian cancer and extra bile duct cancer, and 50% of lung adenocarcinomas and gastric cancer. The full-length human mesothelin gene encodes the primary product, a 71-kDa precursor protein. The 71-kDa mesothelin precursor is cleaved into two products, 40-kDa C-terminal fragment that remains membrane-bound via glycosylphosphatidylinositol anchor, and a 31-kDa N-terminal fragment, megakaryocyte potentiating factor, which is secreted into the blood. The biological functions of mesothelin remain largely unknown. However, results of recent studies have suggested that the mesothelin may play a role of cell proliferation and migration. In pancreatic cancer, mesothelin expression was immunohistochemically observed in all cases, but absent in normal pancreas and in chronic pancreatitis. Furthermore, the expression of mesothelin was correlated with an poorer patient outcome in several human cancers. The limited mesothelin expression in normal tissues and high expression in many cancers makes it an attractive candidate for cancer therapy. The present review discusses the expression and function of mesothelin in cancer cells and the utility of mesothelin as a target of cancer therapy.

Accurate evaluation of axillary sentinel lymph node metastasis using contrast-enhanced ultrasonography with Sonazoid in breast cancer: a preliminary clinical trial.

Breast cancer is the most common type of cancer in women. The 5-year survival rate in patients with breast cancer ranges from 74 to 82 %. Sentinel lymph node biopsy has become an alternative to axillary lymph node dissection for nodal staging. We evaluated the detection of the sentinel lymph node and metastasis of the lymph node using contrast enhanced ultrasonography with Sonazoid. Between December 2013 and May 2014, 32 patients with operable breast cancer were enrolled in this study. We evaluated the detection of axillary sentinel lymph nodes and the evaluation of axillary lymph nodes metastasis using contrast enhanced computed tomography, color Doppler ultrasonography and contrast enhanced ultrasonography with Sonazoid. All the sentinel lymph nodes were identified, and the sentinel lymph nodes detected by contrast enhanced ultrasonography with Sonazoid corresponded with those detected by computed tomography lymphography and indigo carmine method. The detection of metastasis based on contrast enhanced computed tomography were sensitivity 20.0 %, specificity 88.2 %, PPV 60.0 %, NPV 55.6 %, accuracy 56.3 %. Based on color Doppler ultrasonography, the results were sensitivity 36.4 %, specificity 95.2 %, PPV 80.0 %, NPV 74.1 %, accuracy 75.0 %. Based on contrast enhanced ultrasonography with Sonazoid, the results were sensitivity 81.8 %, specificity 95.2 %, PPV 90.0 %, NPV 90.9 %, accuracy 90.6 %. The results suggested that contrast enhanced ultrasonography with Sonazoid was the most accurate among the evaluations of these modalities. In the future, we believe that our method would take the place of conventional sentinel lymph node biopsy for an axillary staging method.

Accurate diagnosis of axillary lymph node metastasis using contrast-enhanced ultrasonography with Sonazoid.

Axillary lymph node enlargement following sentinel lymph node biopsy (SLNB) is often difficult to accurately diagnose. In keeping with the characteristically tortuous and aberrant pattern of tumor neovasculature, metastatic lymph nodes exhibit peripheral and mixed vascularity, resulting in a microvasculature that is often difficult to visualize. Contrast-enhanced ultrasonography (CEUS) with Sonazoid, a new generation contrast agent for ultrasonography, allows for the visualization of lymph node microvessels and may enable a more accurate evaluation of lymph node metastasis. This is a case report of axillary lymph node enlargement following SLNB, in which CEUS with Sonazoid resulted in an accurate diagnosis. On the basis of our experience with this case, we have initiated a clinical trial to evaluate the detection of lymph node metastasis through the use of CEUS in breast cancer patients.