Phase I/II study of adding intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis.

BACKGROUND: Intraperitoneal chemotherapy using paclitaxel is considered an experimental approach for treating peritoneal carcinomatosis. This study aimed to determine the recommended dose, and to evaluate the clinical efficacy and safety, of the combination of intravenous gemcitabine, intravenous nab-paclitaxel and intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis. METHODS: The frequencies of dose-limiting toxicities were evaluated, and the recommended dose was determined in phase I. The primary endpoint of the phase II analysis was overall survival rate at 1 year. Secondary endpoints were antitumour effects, symptom-relieving effects, safety and overall survival. RESULTS: The recommended doses of intravenous gemcitabine, intravenous nab-paclitaxel and intraperitoneal paclitaxel were 800, 75 and 20 mg/m2 respectively. Among 46 patients enrolled in phase II, the median time to treatment failure was 6·0 (range 0-22·6) months. The response and disease control rates were 21 of 43 and 41 of 43 respectively. Ascites disappeared in 12 of 30 patients, and cytology became negative in 18 of 46. The median survival time was 14·5 months, and the 1-year overall survival rate was 61 per cent. Conversion surgery was performed in eight of 46 patients, and those who underwent resection survived significantly longer than those who were not treated surgically (median survival not reached versus 12·4 months). Grade 3-4 haematological toxicities developed in 35 of 46 patients, whereas non-haematological adverse events occurred in seven patients. CONCLUSION: Adding intraperitoneal paclitaxel had clinical efficacy with acceptable tolerability.

ANTECEDENTES: La quimioterapia intraperitoneal con paclitaxel se considera una terapia experimental para el tratamiento de la carcinomatosis peritoneal. Este estudio tuvo como objetivo determinar la dosis recomendada y evaluar la eficacia clínica y la seguridad de la combinación de gemcitabina intravenosa, nab-paclitaxel intravenoso y paclitaxel intraperitoneal en pacientes con cáncer de páncreas y metástasis peritoneales. MÉTODOS: Se evaluaron las frecuencias de las toxicidades limitantes de la dosis, y la dosis recomendada se determinó en la fase I. El objetivo principal de la fase II fue la tasa de supervivencia global a 1 año. Los objetivos secundarios fueron los efectos antitumorales, los efectos de alivio de los síntomas, la seguridad y la supervivencia global. RESULTADOS: Las dosis recomendadas de gemcitabina intravenosa, nab-paclitaxel intravenoso y paclitaxel intraperitoneal fueron de 800, 75 y 20 mg/m2 , respectivamente. De los 46 pacientes incluidos en la fase II del estudio, la mediana de tiempo hasta el fracaso del tratamiento fue de 6,0 meses (rango, 0-22,6). Las tasas de respuesta y de control de la enfermedad fueron del 45% y 95%, respectivamente. La ascitis desapareció en el 40% de los pacientes, y la citología se negativizó en el 39% de los pacientes. La mediana del tiempo de supervivencia fue de 14,5 meses y la tasa de supervivencia global a 1 año del 60,9%. La cirugía de rescate se realizó en ocho (17%) pacientes, y los que se sometieron a cirugía sobrevivieron significativamente más tiempo que los que no fueron tratados quirúrgicamente (mediana de supervivencia no alcanzada versus 12,4 meses). Las toxicidades hematológicas de grado 3/4 ocurrieron en el 76% de los pacientes, mientras que los eventos adversos no hematológicos se presentaron en el 15% de los pacientes. CONCLUSIÓN: Agregar paclitaxel intraperitoneal tuvo eficacia clínica con una tolerabilidad aceptable. (UMIN000018878).

Clinical pattern and progression of ulcerative proctitis in the Japanese population: a retrospective study of incidence and risk factors influencing progression.

AIM: The rate of extension of proctitis in Western countries has been reported, but no data regarding long-term follow-up have been described for the Japanese population. Additionally, patients with long-standing or extensive ulcerative colitis have an increased risk for developing colorectal cancer. This study evaluated both the rate of extension of the disease and the development of neoplasia among patients with an initial diagnosis of ulcerative proctitis. METHOD: We retrospectively investigated the medical charts of patients with proctitis from 1979 to 2014. The primary focus of this research was the extension of the inflammatory area. The secondary focus included risk factors for disease extension and the development of neoplasia. RESULTS: Sixty-six patients satisfied the inclusion criteria. Proximal extension of the disease occurred in 34 patients: 19 patients had left-sided colitis and 15 had pancolitis. According to a multivariate analysis, disease extension was significantly higher in patients with disease onset before 25 years of age (P-value = 0.043). The cumulative rates of disease extension at 10 and 20 years were 33.8% and 52.2%, respectively. Three patients were diagnosed with dysplasia during follow-up, all of whom experienced disease extension before the development of dysplasia. CONCLUSION: The rate of extension of ulcerative colitis in the Japanese population was comparable to that in Western countries. A younger age of disease onset was associated with disease extension. Extension of proctitis may be associated with an increased risk of colorectal cancer.

Cell-free and concentrated ascites reinfusion therapy (CART) for management of massive malignant ascites in gastric cancer patients with peritoneal metastasis treated with intravenous and intraperitoneal paclitaxel with oral S-1.

BACKGROUND: Massive malignant ascites originating from peritoneal metastasis of gastric cancer is difficult to control and resistant to chemotherapy. Cell-free and Concentrated Ascites Reinfusion Therapy (CART) is one of the types of apheresis therapy, by which filtered and concentrated ascites containing albumin and globulin is reinfused intravenously to patients. We retrospectively studied the feasibility of intraperitoneal (IP) chemotherapy combined with CART in gastric cancer patients with massive malignant ascites. METHODS: Paclitaxel (PTX) was administered via an IP access port implanted in the subcutaneous space. If patient had massive ascites at the start of treatment, paracentesis was performed through a percutaneous IP catheter and then CART was performed. PTX was administered through the catheter until the ascites diminished. RESULTS: A total of 127 CART procedures in 30 patients were analyzed. The average volume of processed ascites was 3.1 L, which was concentrated to 0.33 L containing 85.5 g protein on average. Significant increases in urine volume, serum total protein and albumin level were found after the CART. Increase in body temperature (0.3°C), decrease in platelet count (3.8 × 10(4)/µl), and changes in blood pressure (2 mm Hg) were found after the CART procedure, but no clinically significant adverse event was experienced. The median survival time and 1-year survival of 30 patients who received IP chemotherapy combined with the CART procedure was 10.2 months and 43.3% respectively. CONCLUSIONS: IP chemotherapy combined with CART might be a promising strategy for patients with massive malignant ascites originating from peritoneal metastasis of gastric cancer.

Surgical stress response after colorectal resection: a comparison of robotic, laparoscopic, and open surgery.

BACKGROUND: The perioperative immune status of colorectal robotic surgery (RS), laparoscopic surgery (LS), and open surgery (OS) patients has not been compared. Our aim was to evaluate perioperative stress and immune response after RS, LS and OS. METHODS: This prospective study included 46 colorectal surgery patients from the Department of Surgical Oncology of the University of Tokyo Hospital. Peripheral venous blood samples were obtained preoperatively and on postoperative days 1, 3, and 6. We evaluated expression of HLA-DR (marker of immune competence), C-reactive protein (CRP) levels, and lymphocyte subset counts (natural killers, cytotoxic T cells and helper T cells). RESULTS: Fifteen, 23, and 8 patients underwent RS, LS and OS, respectively. HLA-DR expression was the lowest on day 1 and gradually increased on days 3 and 6 in all the groups. There was no significant difference in postoperative HLA-DR expression between the RS and LS group. However, on day 3, HLA-DR expression in the RS group was significantly higher than in the OS group (p = 0.04). On day 1, CRP levels in the LS group were significantly lower than in the RS group (p = 0.038). There were no significant perioperative changes in the lymphocyte subset cell count between the three groups. CONCLUSIONS: Perioperative surgical stress, as evaluated by immunological parameters, was comparable between robotic and laparoscopic surgery and higher with open surgery. Robotic surgery may be an alternative to laparoscopic surgery, as a minimally invasive surgery option for colorectal cancer.

Nomograms for predicting the prognosis of stage IV colorectal cancer after curative resection: a multicenter retrospective study.

PURPOSE: Although stage IV colorectal cancer (CRC) encompasses a wide variety of clinical conditions with diverse prognoses, no statistical model for predicting the postoperative prognosis of stage IV CRC has been established. Thus, we here aimed to construct a predictive model for disease-free survival (DFS) and overall survival (OS) after curative surgery for stage IV CRC using nomograms. METHODS: The study included 1133 stage IV CRC patients who underwent curative surgical resection in 19 institutions. Patients were divided into derivation (n = 586) and validation (n = 547) groups. Nomograms to predict the 1- and 3-year DFS rates and the 3- and 5-year OS rates were constructed using the derivation set. Calibration plots were constructed, and concordance indices (c-indices) were calculated. The predictive utility of the nomogram was validated in the validation set. RESULTS: The postoperative carcinoembryonic antigen (CEA) level, depth of tumor invasion (T factor), lymph node metastasis (N factor), and number of metastatic organs were adopted as variables for the DFS-predicting nomogram, whereas the postoperative CEA level, T factor, N factor, and peritoneal dissemination were adopted for the nomogram to predict OS. The nomograms showed moderate calibration, with c-indices of 0.629 and 0.640 in the derivation set and 0.604 and 0.637 in the validation set for DFS and OS, respectively. CONCLUSIONS: The nomograms developed were capable of estimating the probability of DFS and OS on the basis of only 4 variables, and may represent useful tools for postoperative surveillance of stage IV CRC patients in routine practice.

Proteinuria and clinical outcomes after ischemic stroke.

OBJECTIVES: The impact of chronic kidney disease (CKD) on clinical outcomes after acute ischemic stroke is still not fully understood. The aim of the present study was to elucidate how CKD and its components, proteinuria and low estimated glomerular filtration rate (eGFR), affect the clinical outcomes after ischemic stroke. METHODS: The study subjects consisted of 3,778 patients with first-ever ischemic stroke within 24 hours of onset from the Fukuoka Stroke Registry. CKD was defined as proteinuria or low eGFR (<60 mL/min/m(2)) or both. The study outcomes were neurologic deterioration (≥2-point increase in the NIH Stroke Scale during hospitalization), in-hospital mortality, and poor functional outcome (modified Rankin Scale score at discharge of 2 to 6). The effects of CKD, proteinuria, and eGFR on these outcomes were evaluated using a multiple logistic regression analysis. RESULTS: CKD was diagnosed in 1,320 patients (34.9%). In the multivariate analyses after adjusting for confounding factors, patients with CKD had significantly higher risks of neurologic deterioration, in-hospital mortality, and poor functional outcome (p <0.001 for all). Among the CKD components, a higher urinary protein level was associated with an elevated risk of each outcome (p for trend < 0.001 for all), but no clear relationship between the eGFR level and each outcome was found. CONCLUSIONS: CKD is an important predictor of poor clinical outcomes after acute ischemic stroke. Proteinuria independently contributes to the increased risks of neurologic deterioration, mortality, and poor functional outcome, but the eGFR may not be relevant to these outcomes.

A case of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease) with multiple polyps arising in the cecum and appendix.

We present the case of a 32-year-old female with cecal and appendiceal polyps that were removed by laparoscopy-assisted surgery. She also had recurrent nosebleeds due to telangiectases in the nasal mucosa and arteriovenous malformations in the lung, all of which contributed to the diagnosis of hereditary hemorrhagic telangiectasia.

Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis.

BACKGROUND: A phase II study to evaluate the efficacy and tolerability of weekly i.v. and i.p. paclitaxel (PTX) combined with S-1 was carried out in gastric cancer patients with peritoneal metastasis. PATIENTS AND METHODS: Gastric cancer patients with peritoneal dissemination and/or cancer cells on peritoneal cytology were enrolled. PTX was administered i.v. at 50 mg/m(2) and i.p. at 20 mg/m(2) on days 1 and 8. S-1 was administered at 80 mg/m(2)/day for 14 consecutive days, followed by 7 days rest. The primary end point was the 1-year overall survival (OS) rate. Secondary end points were the response rate, efficacy against malignant ascites and safety. RESULTS: Forty patients were enrolled, including 21 with primary tumors with peritoneal dissemination, 13 with peritoneal recurrence and six with positive peritoneal cytology only. The median number of courses was 7 (range 1-23). The 1-year OS rate was 78% (95% confidence interval 65% to 90%). The overall response rate was 56% in 18 patients with target lesions. Malignant ascites disappeared or decreased in 13 of 21 (62%) patients. The frequent grade 3/4 toxic effects included neutropenia (38%), leukopenia (18%) and anemia (10%). CONCLUSION: Combination chemotherapy of i.v. and i.p. PTX with S-1 is well tolerated and active in gastric cancer patients with peritoneal metastasis.

Preoperative evaluation of enterovesical fistula using magnetic resonance imaging: case report.

We report a case of sigmoido-vesical fistula due to sigmoid diverticulitis. Magnetic resonance imaging enabled us to visualize the fistula itself in the bladder wall. Magnetic resonance imaging was highly effective in making a precise diagnosis and also provided important additional information for the preoperative work-up of the patient.

Angleplasty in gastric tube reconstruction after esophagectomy.

Anastomotic leakage after radical esophagectomy is mostly caused by the hypoxia and high tension at the esophagogastric anastomotic site. Here, we introduce a new surgical technique, 'Angleplasty,' to enable the tensionless anastomosis at a highly oxygenic site of gastric conduit. In short, the seromuscular layer is cut for a perpendicular direction against a lesser curvature at a gastric angle and the gastric wall is carefully divided between the muscular and submucosal layers for longitudinal direction for 4-5 cm in length. Then, the wound is closed with seromuscular sutures for longitudinal direction. With this maneuver, the lesser curvature of the gastric roll is significantly elongated and the anastomosis site of the gastric conduit can be moved more distal on the greater curvature of the stomach where it is expected to receive more oxygen supply. This technique takes only several minutes, but provides highly favorable conditions for esophagogastric anastomosis and thus is clinically useful to reduce the risk of anastomotic leakage after esophagectomy.

The suppressive effect of sphingosine 1-phosphate on monocyte-endothelium adhesion may be mediated by the rearrangement of the endothelial integrins alpha(5)beta(1) and alpha(v)beta(3).

BACKGROUND: Sphingosine 1-phosphate (S1P), known to play important roles in vascular biology, is a bioactive lysophospholipid mediator that maintains endothelial integrity via its cell-surface receptors (S1Ps). In this in vitro study, we aimed to examine the role of S1P in monocyte-endothelium adhesion, which is an important event in the pathophysiology of atherosclerosis. METHODS AND RESULTS: S1P pretreatment of human umbilical vein endothelial cells (ECs), but not U937 cells, effectively suppressed U937-EC adhesion independently from the expression of adhesion molecules, namely ICAM-1, VCAM-1, and E-selectin. This S1P-induced suppressive effect was inhibited by the blockage of S1P(1) and S1P(3) receptors and the specific inhibitors of G(i) protein, Src family proteins, phosphatidylinositol 3-kinase, and Rac1, indicating involvement of these key downstream pathways. Moreover, the RGD peptide and antibodies, which neutralize adhesion via alpha(5)beta(1) and alpha(v)beta(3), effectively inhibited U937-EC adhesion with a degree similar to S1P pretreatment. Both an adhesion assay and flow-cytometric analysis demonstrated that U937 cells adhered through integrins alpha(5)beta(1) and alpha(v)beta(3) expressed on the apical surface of monolayer ECs, and S1P shifted the localization of these integrins from the apical surface to the basal surface. CONCLUSIONS: From the present results, we propose that S1P may contribute to the maintenance of vascular integrity and the regulation of atherogenesis through the rearrangement of endothelial integrins.

A study of dendritic and endothelial cell interactions in colon cancer in a cell line and small mammal model.

AIM: Historically, cancer therapy directly targeting tumor cells have yielded suboptimal clinical results, and therefore anti-angiogenic therapy that targets tumor cells indirectly through impairing tumor vasculature is now considered to be one of the novel approaches potentially effective against various types of cancer. In this study, we evaluated whether lysates of endothelium could be effectively pulsed in dendritic cells (DCs), to enhance their anti-tumor effects. METHODS: For this purpose, we prepared DCs of BALB/c mouse, incubated them with lysates of autologous or xenogeneic endothelium, and tested their anti-tumor effects in two syngeneic models of colon cancer. RESULTS: DCs pulsed with the respective endothelium lysates significantly inhibited the growth of subcutaneous tumors as well as pulmonary metastases in mice, and their anti-tumor effect was superior to that of unpulsed DCs. Immunohistopathological analysis showed significant decrease in the mean vascular density of tumors, correlating well with the extent of tumor inhibition. In vitro analysis of splenocytes isolated from immunized mice revealed an induction of cytotoxic T lymphocytes and activation of natural killer cells, with a lytic activity against activated endothelium but not tumor cells. In addition, antibodies reacting with activated endothelium, but not tumor cells, were detected in murine sera by ELISA, and their function was confirmed by complement-dependent cytotoxicity assay. CONCLUSIONS: Our present results suggest that lysates of endothelium can be effectively pulsed in DCs and enhance their anti-tumor effects through induction of anti-angiogenesis, and therefore should have important clinical implications for adjuvant cancer therapy.

Overexpression of hRFI inhibits 5-fluorouracil-induced apoptosis in colorectal cancer cells via activation of NF-kappaB and upregulation of BCL-2 and BCL-XL.

Resistance to apoptosis is one of the important determinants of resistance to 5-fluorouracil (5-FU) in colorectal cancer cells. Human Ring-Finger homologous to Inhibitor of apoptosis protein type (hRFI) is a newly discovered gene that has been shown to inhibit death receptor-mediated apoptosis in colorectal cancer cells. However, the molecular mechanism of the inhibition of apoptosis is presently unknown. In order to investigate the molecular function of hRFI in the regulation of 5-FU-induced apoptosis in colorectal cancer cells, HCT116 cells were stably transfected with hRFI or LacZ as a control. hRFI overexpression resulted in cellular resistance to 5-FU through an inhibition of the mitochondrial apoptotic pathway and specific upregulation of Bcl-2 and Bcl-XL. Futhermore, hRFI overexpression resulted in the activation of nuclear factor-kappaB (NF-kappaB). Inhibition of NF-kappaB effectively reversed the resistance to apoptosis as well as the upregulation of Bcl-2 and Bcl-XL in the hRFI transfectant, indicating that the activation of NF-kappaB is the key mechanism for all these findings. Overexpression of hRFI in SW480 and COLO320 colorectal cancer cells similarly resulted in resistance to 5-FU with the activation of NF-kappaB and upregulation of Bcl-2 and Bcl-XL. hRFI might be a novel therapeutic target for gene therapy in colorectal cancer.

High hRFI expression correlates with resistance to fluoropyrimidines in human colon cancer cell lines and in xenografts.

We previously reported that the over-expression of hRFI, a protein preferentially expressed in the digestive tract regions of several cancers, exhibited a tendency to inhibit TNF-alpha induced apoptosis. In this study, we sought to determine the potential effect of hRFI expression on the sensitivity to 5-fluorouracil (5-FU) and/or other fluoropyrimidines. For the whole lysates of 8 colon cancer cell lines, we performed Western blotting with anti-hRFI antibody and analyzed the correlations between the expression level of hRFI and the cell lines' sensitivity to 5-FU induced apoptosis. Furthermore, for a tissue microarray consisting of 32 xenograft derived human cancer cell lines, we examined the expression levels of hRFI and survivin by immunohistochemical staining, and analyzed the correlations between the expression of each protein and the sensitivity to several chemotherapeutic agents in the xenografts examined. Both in colon cancer cell lines and in xenografts, the expression level of hRFI was correlated with resistance to 5-FU and its derivatives. This evidence suggests that hRFI may be a marker predicting the response to fluorouracil derived chemotherapeutic agents and that the reduction of the expression level of hRFI might improve the outcome of chemotherapy.

Effects of expression of hRFI on adenoma formation and tumor progression in colorectal adenoma-carcinoma sequence.

For colorectal carcinomas as well as colonic polyps we investigated the expression of a newly discovered gene, hRFI, which is isolated by the yeast two-hybrid screening using hTid as a bait and expressed highly in esophageal carcinomas. Immunohistochemical staining was performed on 48 colorectal carcinomas and 77 colorectal polyps consisting of 70 adenomas and 7 hyperplastic polyps using the antibody of hRFI. We analyzed the expression of hRFI and the correlation between the percentage of staining of each and their clinico-pathological characteristics. Protein coding by hRFI was specifically and diffusely expressed in most of the cancerous regions of the colorectum. Also, in the early stage of colorectal adenomas, staining of hRFI was focal, and the percentage area of diffuse staining increased as the degree of dysplasia progressed. Although all normal colorectal glands and most hyperplastic polyps (71.4%) showed no staining of hRFI, most colorectal adenomas and carcinomas (93.2%) showed a focal or diffuse staining (P<0.001). Furthermore, the percentage of diffuse staining in carcinomas (81.3%) was significantly higher than in adenomas (5.7%) (P<0.001). hRFI is highly expressed in colorectal carcinomas. In the adenoma-carcinoma sequence, hRFI is involved at the initial tumor formation and its diffuse expression is associated with colorectal carcinogenesis. This evidence suggests that hRFI may act as an oncogenic molecule affecting the apoptotic pathway.

Hyperlipidaemia is positively correlated with lymph node metastasis in men with early gastric cancer.

BACKGROUND: Although increased dietary fat or cholesterol has been reported to be a risk factor for the development of certain cancers, the effect of serum lipid levels on tumour metastasis is not clearly understood. METHODS: The association between lymph node metastasis and preoperative serum levels of total cholesterol (TC) and triglyceride (TG) as well as various pathological findings for tumours was examined in 353 patients with early gastric cancer who underwent gastrectomy with classical lymphadenectomy. RESULTS: The rate of lymph node metastasis was significantly higher in patients with early gastric cancer who had hypercholesterolaemia (TC 220 mg/dl or greater) or hypertriglyceridaemia (TG 150 mg/dl or greater). The tendency was more prominent in men, and multivariate analysis showed that hypertriglyceridaemia was an independent risk factor for nodal metastasis in men, in addition to pathological invasion to the submucosal layer or to lymphatic vessels. In contrast, neither hypercholesterolaemia nor hypertriglyceridaemia showed a significant association with nodal status in women with early gastric cancer. CONCLUSION: Raised serum lipid levels might favour the development of lymph node metastasis in men with early-stage gastric cancer. In patients with early gastric cancer serum lipid levels should be checked before operation, and the use of minimal local treatments must be considered carefully in male patients with hyperlipidaemia.

Beta-chemokine, macrophage inflammatory protein-1beta (MIP-1beta), is highly expressed in diffuse type human gastric cancers.

Chemokines have been shown to be expressed in some malignant or precancerous tissues. However, the role of these chemokines on tumor development or progression is not clear. The expression patterns of chemokines in gastric cancer tissues were examined in 86 surgically resected samples using immunohistochemistry. Macrophage inflammatory protein-1beta (MIP-1beta) was clearly detected in many gastric carcinoma cells. In most of the differentiated carcinomas, intracellular localization of MIP-1beta was detected in more than 5% of cancer cells, although the percentages of MIP-1beta-positive cells differed among each sample. Undifferentiated carcinomas showed contrasted staining pattern between solid type and non-solid (diffuse) type. MIP-1beta was totally absent in all the poorly differentiated carcinomas with solid type growth pattern (por1). In contrast, MIP-1beta was highly expressed in all of the non-solid type of poorly differentiated carcinoma (por2) and signet-ring cell carcinoma samples. In particular, MIP-1beta was strongly stained in carcinoma cells at the front of invasive lesions. In 43 diffuse type undifferentiated cancers, tumors with high expression of MIP-1beta exhibited significantly more lymph node metastasis. Our results suggest a possibility that MIP-1beta may be related to the scattering and invasion step of gastric carcinoma cells with undifferentiated phenotype.