Naomi Konishi

C-Reactive Protein as a Prognostic Variable That Reflects Uncontrolled Up-Regulation of the IL-1-IL-6 Network System in Colorectal Carcinoma

Up-regulation of the IL-1-IL-6 network stimulates systemic expression of C-reactive protein (CRP).This cytokine network system plays a pivotal role in inducing angiogenic growth factors in in-testinalmucosa. Serum CRP level and tissue concentrations of cytokines in colorectal cancerpatients were determined and an in vitro model was employed to determine the time course ofinduction of IL-6 in Caco-2 cells. Increased serum CRP was associated with recurrent diseaseand shorter survival time. Intense surgical stress and the presence of an acute phase reactantwere independently associated with overexpression of IL-6 in the tumor. Enhanced IL-6 pro-teinexpression in Caco-2 cells induced by the initial treatment with IL-1β or lipopolysaccha-ridecould be abrogated by additional presupplementation of IL-1ra. The presence of an acutephase reactant reflects uncontrolled up-regulation of the local IL-1-IL-6 network system in thetumor, which may enhance the survival and proliferation of remnant cancer cells after tumorresection.

Operative Morbidity Associated with Groin Dissections

Purpose.Groin dissection remains the treatment of choice for malignant neoplasms of the skin in the lower extremities and perineum. We sought to quantify the hospital complications after groin dissection, and to identify the patient- and procedure-related factors affecting these complications.Methods.We reviewed 20 consecutive patients who underwent a collective 25 groin dissections for malignant neoplasms of the skin between 1996 and 2002 to determine the incidence and degree of morbidity, and to analyze the clinical factors associated with morbidity. An S-shaped incision was used for the first 8 procedures, whereas a straight incision was used for the next 17.Results.The overall incidences of complications were 24% for wound infection, 52% for skin flap problems, 32% for seromas, 40% for edema, and 4% for hemorrhage, whereas the incidences of moderate to severe complications were 16% for wound infection, 16% for skin flap problems, 12% for seromas, 4% for edema, and 4% for hemorrhage. The incidence of wound infection tended to be higher after S-shaped incisions than after straight incisions (P = 0.059), and the incidence of leg edema was significantly higher after S-shaped incisions than after straight incisions (P = 0.028).Conclusion.S-shaped incisions more often resulted in lymphatic collection and stagnation, with a higher incidence of wound infections and leg edema than straight incisions. Therefore, we now perform straight incisions to minimize the risk of wound infections and leg edema.

Interleukin-1 Receptor Antagonist Inhibits the Expression of Vascular Endothelial Growth Factor in Colorectal Carcinoma

Objective: Interleukin (IL)-1 is known to act as a tumor growth factor by inducing angiogenic factors. We examined the significance of IL-1β and IL-1 receptor antagonist (RA) for inducing the expression of vascular endothelial growth factor (VEGF) in colorectal cancers. Methods: We investigated the expression of VEGF induced by IL-1β in five colon cancer cell lines and the possible involvement of IL-1 RA. We also measured the tissue concentrations of IL-1β, IL-1 RA and VEGF by ELISA in 65 colorectal cancer patients. Results: IL-1β induced VEGF secretion with a 19-fold increase in Caco-2 cells. A significant increase in VEGF secretion was also observed in SW480 and WiDr cells. IL-1 RA inhibited IL-1β-induced VEGF secretion by 87%. Our data from the clinically obtained specimens showed that the IL-1 RA/IL-1β ratio is significantly lower in cancer tissue. Regarding the clinicopathological parameters, the IL-1 RA/IL-1β ratio was significantly lower in patients with vessel involvement than in those without involvement, and IL-1 RA/IL-1β ratio was negatively correlated with the VEGF protein level in colorectal tumors. Conclusions: Our data suggest that IL-1β induces VEGF expression and IL-1 RA acts as the competitive inhibitor, and that the IL-1 RA/IL-1β ratio is significant for VEGF expression in the microenvironment of colorectal cancer tissue. We conclude that IL-1β induces VEGF secretion in a certain population of colorectal cancer patients, and that IL-1 RA is the potential therapeutic agent for antiangiogenic therapy in colorectal cancer patients.

Lymphatic Mapping and Sentinel Node Biopsy during Laparoscopic Gastrectomy for Early Cancer

Background/Aims: Intraoperative lymphatic mapping and sentinel node (SN) biopsy can potentially be combined with minimally invasive surgery, but there are few reports of laparoscopic lymphatic mapping for gastrointestinal cancer. We examined the feasibility and accuracy of laparoscopic lymphatic mapping in predicting lymph node status in patients with gastric cancer. Methods: Seventeen patients with gastric cancer invading the mucosal or submucosal layers (T1) underwent laparoscopic gastrectomy with lymphatic mapping between March 2001 and May 2002. The day before surgery, a technetium-99m-labelled tin colloid solution was injected endoscopically around the tumor. Immediately after the pneumoperitoneum, patent blue was injected. Gastrectomy was performed in all patients, and blue-stained or radioactive nodes were defined as SNs. Fresh SNs were immediately processed for frozen-section examination by hematoxylin-eosin (H&E) and immunohistochemical (IHC) staining. All non-SNs harvested from resected specimens were subjected to histological examination with H&E. Results: SNs were detected in all patients by combination of the two kinds of tracers. Three patients had lymph node metastases in their final examination, and SNs in these 3 were operatively diagnosed as positive by H&E or IHC staining. Lymphatic mapping and SN biopsy under laparoscopic surgery were performed with 100% accuracy. Conclusion: Our preliminary study shows the feasibility of intraoperative lymphatic mapping in laparoscopic gastrectomy for T1 gastric cancer.

Clinical significance of serum soluble E-cadherin in colorectal carcinoma.

BACKGROUND E-cadherin expression has been associated with an outcome in patients with colorectal cancer, and serum levels of soluble E-cadherin (sE-cadherin) are significantly elevated in patients with malignant disease. However, the prognostic value of serum sE-cadherin level has not been demonstrated in colorectal cancer. METHODS Serum samples were collected from 186 patients with colorectal cancer and 21 normal volunteers. Serum sE-cadherin levels were measured using an enzyme-linked immunosorbent assay kit. We investigated the relationship between serum sE-cadherin level and clinicopathologic findings. RESULTS Mean serum sE-cadherin levels were significantly higher in CRC patients than in controls. Mean sE-cadherin levels were significantly correlated with hepatic metastasis, UICC classification, and poor prognosis. Elevated serum sE-cadherin level was an independent risk factor for predicting poor prognosis, and was an independent marker for predicting hepatic metastasis. Among patients with synchronous hepatic metastases, the prognosis was significantly worse in patients with elevated serum sE-cadherin levels than in those with lower levels. CONCLUSIONS Preoperative elevated sE-cadherin level is associated with poor prognosis in colorectal cancer. Measuring serum sE-cadherin may provide valuable information for predicting prognosis in patients with hepatic metastasis.

Serum Immunosuppressive Acidic Protein as an Interleukin-6 Related Index of Deteriorating Condition in Gastric Cancer Patients

Background/Aims: Immunosuppressive acidic protein (IAP) is an acute-phase reactant which has a close correlation with the impairment of the host’s immunity. The present study aims to investigate the significance of serum IAP as an index of cytokine-related disease status in gastric cancer patients. Methods: Serum IAP levels were determined in 76 gastric cancer patients and 20 healthy subjects. In a subgroup of 39 patients, tissue interleukin-6 (IL-6) concentrations and expression of IL-6 protein in tumor tissues were also examined. Results: The mean serum IAP level in the patients was significantly higher than that in the normal controls. The serum IAP level in the patients was associated with clinicopathological features, such as tumor size and serosal invasion. The prognosis of patients with high IAP levels was significantly worse than that of those with low IAP levels. Moreover, the serum IAP level was closely correlated with various parameters reflecting the host’s nutritional and immunological conditions. Immunohistochemically, IL-6 was overexpressed in the cytoplasm of tumor cells. The IL-6 concentration and immunoreactivity of IL-6 protein in tumor tissue was significantly correlated with the serum IAP level. Conclusions: Elevated serum IAP, which may be upregulated by an activated IL-6 network in tumor tissue, may reflect not only tumor progression, but also a deteriorated condition that is associated with malnutrition and immunosuppression in gastric cancer patients.

Administration sequence-dependent antitumor effects of paclitaxel and 5-fluorouracil in the human gastric cancer cell line MKN45

Background: The clinical outcome of gastric cancer patients has been improved by combination of 5-fluorouracil (5-FU) and paclitaxel (PXL). However, the optimal schedule of this combination has not been determined. Methods: The efficacies of sequential administrations of 5-FU and PXL on the gastric cancer cell line MKN45 were investigated using a WST-8 colorimetric assay. The cell cycle distribution of each drug was evaluated by flow-cytometry. Furthermore, the mechanism of antitumor activity enhancement by the administration sequence was investigated by western blotting. Results: MKN45 cell growth was significantly inhibited by each drug in a dose- and time-dependent manner. The cytotoxicities of PXL followed by 5-FU were significantly greater than those of 5-FU followed by PXL. The flow-cytometric analysis revealed that PXL exposure caused viable cell accumulation in G2/M phase in a dose-dependent manner. Western blotting showed that PXL exposure followed by 5-FU up-regulated Chk1 and Wee1 protein expressions until PXL removal and 5-FU exposure, when these expressions gradually decreased to their basal levels. 14-3-3σ protein expression was significantly up-regulated upon PXL treatment followed by 5-FU. Interestingly, Mad2 protein expression with PXL treatment followed by 5-FU gradually increased after the PXL removal and 5-FU exposure. Conclusions: PXL followed by 5-FU administration may be the optimal sequence for treatment of gastric cancer. The enhanced viable cell accumulation after PXL pretreatment may be related to G2 arrest. After PXL removal and 5-FU exposure, the cells progressing to M phase may undergo cell death by mitotic catastrophe due to DNA damage caused by 5-FU exposure.

Serum monocyte chemoattractant protein-1 in patients with postoperative infectious complications from gastrointestinal surgery for cancer

We examined the kinetics of serum monocyte chemoattractant protein-1 (MCP-1) perioperatively and clarified its significance regarding the development of infectious complications. We studied 94 patients who underwent gastrointestinal surgery for gastric or colorectal cancer at Mie University Hospital from 1996 to 2000. Serum concentrations of MCP-1 and interleukin-6 (IL-6) were measured perioperatively. The number of circulating lymphocytes and neutrophils were counted to assess the apoptotic rate of neutrophils. Patients were divided into two groups at the median preoperative MCP-1 level obtained from 40 gender-and agematched healthy volunteers. The rate of developing infectious complications was significantly higher and tumor size was significantly larger in the low MCP-1 group than in the high MCP-1 group. The increasing IL-6 ratio (postoperative/preoperative IL-6 level) in the low MCP-1 group was about twofold greater than that in the high MCP-1 group. The neutrophil level calculated for the low MCP-1 group was significantly higher than that in the high MCP-1 group on postoperative day 3. We concluded that a decreased level of serum MCP-1 reflected tumorrelated immunosuppression. Low MCP-1 levels were associated with an exaggerated postoperative IL-6 response and delayed neutrophil apoptosis, which affected the incidence of postoperative infectious complications developing in patients with gastrointestinal malignancies.RésuméNous avons examiné la cinétique périopératoire de la protéine monocytaire chimiosensible 1 (MCP-1) et avons clarifié sa signification dans le développement de complications infectieuses. Quatrevingt quatorze patients opérés entre 1996 et 2000 pour cancer gastrique ou colorectal à l’hôpital universitaire Mie ont été étudiés. Les concentrations sériques de MCP-1 et de l’interleukine (IL)-6 ont été dosées en périopératoire. Pour l’évaluation du taux de l’apoptose des neutrophiles, le nombre de lymphocytes circulants et de neutrophiles a été compté. Les patients ont été divisés en deux groupes selon la value médiane des taux de MCP-1, obtenue à partir de 40 volontaires appariés pour le sexe et pour l’âge. Le taux de complications infectieuses a été significativement plus élevé, et la taille tumorale significativement plus importante dans le groupe de MCP-1 en dessous de la valeur médiane (MCP-1 inf) par rapport au groupe de MCP-1 au-dessus (MCP-1 sup). Le rapport (taux d’IL-6 postopératoire/taux d’IL-6 préopératoire) dans le groupe de MCP-1 inf était approximativement deux fois ceux du groupe MCP-1 sup. Le taux de neutrophiles calculé dans le groupe MCP-1 inf a été significativement plus élevé que le group MCP-1 sup au troisième jour postopératoire. En conclusion, nous considérons que le taux diminué de MCP-1 sérique témoigne d’une immunodépression tumorale. Un taux de CP-1 plus bas était associé à une réponse IL-6 postopératoire exagérée et un retard de l’apoptose neutrophile, ce qui a influencé l’incidence des complications postopératoires infectieuses chez le patient porteur de maladie maligne gastro-intestinale.ResumenCon objeto de aclarar la trascendencia que tiene en el desarrollo de complicaciones infecciosas estudiamos, la cinética durante el perioperatorio del factor quimiotáctico proteina-1 monocitario (MCP-1). Se estudiaron 94 pacientes sometidos a cirugía gastrointestinal por cáncer gástrico o colorrectal entre los años 1996–2000 en el Hospital Universitario de Mie. Se determinaron en el perioperatorio las concentraciones séricas de MCP-1 e interleucina (IL-6). Se realizó un recuento del número de linfocitos y neutrófilos circulantes con objeto de averiguar la tasa de apoptosis de los neutrófilos. En concordancia con los niveles preoperatorios de MCP-1 y tomando como referenda los valores medios obtenidos en 40 voluntaries sanos comparables tanto por lo que al sexo como por lo que a la edad se refiere, los pacientes se dividieron en 2 grupos. En el grupo con bajos niveles de MCP-1 el porcentaje de complicaciones infecciosas fue significativamente mayor al igual que el tamaño de los tumores, que en el grupo con niveles de MCP-1 elevados. En el grupo con niveles bajos de MCP-1 el incremento del cociente IL-6 (nivel de IL-6 postoperatorio/nivel de IL-6 preoperatorio) duplicó al del grupo con niveles de MCP-1 elevados. En POD3, el valor de los neutrófilos, calculado para el grupo con niveles bajos de MCP-1 fue significativamente mayor que en el grupo con niveles de MCP-1 elevados. En conclusión, consideramos que el descenso del nivel sérico de MCP-1 refleja un estado de inmunosupresión propiciado por el tumor. Niveles bajos de MCP-1 se acompañaron de una hiperrespuesta postoperatoria de la IL-6 así como de un retraso en la apoptosis de los neutrófilos, lo que se relaciona con la incidencia de las complicaciones infecciosas desarrolladas en pacientes con neoplasias malignos gastrointestinales.

Successful treatment of ileal pouch desmoids using multimodal chemotherapy with low-dose vinblastine and methotrexate in a patient with familial adenomatous polyposis

We describe a case of multiple desmoid tumors (DT) that developed in an ileal J pouch, which were successfully treated by low-dose combination chemotherapy using vinblastine (VBL) and methotrexate (MTX). Serial changes in the serum d-dimer levels reflected the treatment response. DT involving both the abdominal wall and the ileal pouch developed after total proctocolectomy with ileoanal anastomosis for familial adenomatous polyposis in a 26-year-old female who was treated in an outpatient unit with low-dose VBL and MTX biweekly for 12 months. The treatment response was assessed at routine intervals by physical examination and abdominal computer tomography (CT) imaging. We assessed serial changes in plasma d-dimers, a potential marker for angiogenic activity, during the low-dose VBL and MTX treatment. DT were successfully treated with low-dose VBL and MTX chemotherapy without any significant side effects or pouch sacrifice. Abdominal CT imaging revealed a decrease in tumor size, and the plasma d-dimer levels decreased in association with tumor regression. This case report shows the efficacy of a low-dose combination chemotherapeutic regimen of VBL and MTX for the treatment of ileoanal pouch mesenteric DT in an outpatient setting. In addition, plasma d-dimers may be a marker for desmoid tumor treatment efficacy.

Laparoscopic sigmoidectomy using a hemi-double-stapling technique.

Background: The double-stapling technique (DST) is frequently used in laparoscopic sigmoidectomy. Unfortunately, anastomotic leakage after laparoscopic intracorporeal colorectal anastomosis with DST is seen with some frequency. Methods: We performed DST on 40 patients (June 2007 to August 2008) and hemi-DST on 50 patients (September 2008 to December 2011) undergoing laparoscopic sigmoidectomy. Results: There were no occurrences of anastomotic leakage in the hemi-DST group, and 2 instances of anastomotic leakage in the DST group were observed. In these patients, the leakage appeared at the lateral intersecting anastomotic margins. Conclusions: Using the hemi-DST for laparoscopic intracorporeal colorectal anastomosis will make laparoscopic sigmoidectomy a safer procedure.