A new technique for endoscopic submucosal dissection for early gastric cancer using an external grasping forceps.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) has improved the success rate of en-bloc resection. We report here on a new technique using an external grasping forceps. PATIENTS AND METHODS: A total of 25 patients with suitable EGCs over 10 mm in diameter located in the gastric body were enrolled. After submucosal injection followed by circumcision of the lesion with a needle-knife, an external grasping forceps was introduced with the help of a second grasping forceps and anchored at the distal margin of the lesion. With gentle oral traction applied with this forceps, the lesion was dissected endoscopically in retroversion from the aboral side. RESULTS: The mean lesion size was 15.0 mm (range 10 - 25 mm). Using the technique described, all lesions could be resected en bloc with free margins. The mean procedure time was 45 min (range 30 - 80 minutes). No significant bleeding requiring blood transfusion or perforation occurred. CONCLUSIONS: This technical modification may simplify and shorten the gastric ESD procedure, except for lesions in distal locations, without compromising the efficacy.

[Clinical evaluation of hepatopancreatoduodenectomy].

The clinical outcome of hepatopancreatoduodenectomy (HPD) carried out in 14 patients in our institute was evaluated retrospectively. In principle, HPD is performed in patients with far-advanced biliary carcinoma extending from the level of the liver to pancreas directly or via metastatic lymph nodes around the head of the pancreas. However, the survival periods after surgery did not improve, contrary to expectations. Curative surgery was not achieved in most patients who underwent HPD, even if resection of the portal vein or hepatoduodenal ligament was performed during surgery. Severe lymphatic, vascular, and neural involvement along the hepatoduodenal ligament existed in those patients. In addition, it is possible that they already had micrometastases to other organs based on a study of the pattern of recurrence after surgery. Quality of life did not appear to improve unless the patients survived more than one year. These findings suggest that HPD may be appropriate for patients in earlier disease stages than those in our series to achieve longer survival. However, HPD is associated with high rates of postoperative complications and operative mortality, especially after pancreatoduodenectomy with liver resection involving more than right hepatectomy. We need to establish the appropriate indications for HPD and improve the safety of the procedure.

Combined resection of the portal vein for pancreatic cancer: preoperative diagnosis of invasion by portography and prognosis.

BACKGROUND/AIMS: Pancreatic cancer often invades the portal vein because of the anatomical position. Pancreatic cancer with portal vein invasion was not considered operable, and thus the resectability rate was low. METHODOLOGY: Between March 1976 and February 1994, 140 of 243 patients underwent resection, a resectability rate of 58%. A total of 81 (58%) of these patients underwent portal vein resection. We assessed 56 patients in whom the depth of invasion had already been determined histopathologically and whose superior mesenteric arterial portograms were readable. The 56 patients were classified into 4 groups: normal (Type I), stricture on one side of the portal vein (Type II), stricture on both sides of the portal vein (Type III), complete obstruction (Type IV). The length of the longitudinal lesions on portograms was also measured. RESULTS: In 93% (27/29 cases) of portographic Type I or II lesions with longitudinal lesions of 2 cm or less, portal vein invasion was limited to the tunica media. No patients with cancer invasion into the lumen survived more than 1 year. CONCLUSIONS: For patients with pancreatic cancer Type I or II, preoperative portography findings and longitudinal lesions of 2 cm or less, portal vein resection is indicated, and long-term survival can be expected.

A new predictive factor for hepatocellular carcinoma based on two-dimensional electrophoresis of genomic DNA.

Molecular genetic analyses have clarified that accumulation of genomic changes provides important steps in carcinogenesis and have identified a number of valuable genetic markers for certain cancers. To date, however, no prognostic markers have been identified for hepatocellular carcinoma (HCC). In this study, we used restriction landmark genomic scanning (RLGS), a new high-speed screening method for multiple genomic changes, to detect unknown genetic alterations in HCC. Thirty-one HCC samples and their normal counterparts were examined by RLGS. Eight spot changes were common in several cases, and all were seen only on the HCC profile. Five of these spots were detected in more than 12 of 31 cases (38.7%). Viral infection had no influence on changes in the RLGS spots. The disease-free survival rate for patients with > or =16 changed RLGS spots was significantly lower than that for patients with fewer changed RLGS spots (< or =15 spots) (P<0.001). In multivariate analysis, the number of changed spots was proven to retain an independent prognostic value (relative risk 1.095: P = 0.0031). These results suggest that the number of changed RLGS spots may be a useful biological marker for recurrence of HCC.

Treatment strategy for pancreatic head cancer: pylorus-preserving pancreatoduodenectomy, intraoperative radiotherapy and portal catheterization.

Pancreatic cancer is the disease of gastrointestinal cancer with the poorest prognosis. At present, in addition to surgery, multimodality treatment combining a variety of therapeutic methods is used. We usually employ the following combination of surgery, radiotherapy and chemotherapy: D2 surgery with pylorus-preserving pancreatoduodenectomy (PPPD), intraoperative radiotherapy (IORT), and portal catheterization (PC) with fluorouracil as the chemotherapy. In this study, we made a historical comparison of PPPD and PD and obtained the following findings: (1) PPPD allows almost the same extent of D2 dissection as conventional PD, and achieves radical treatment without any problems; (2) suppression of local recurrence by IORT cannot be expected from the results of the comparison between the four approaches, i.e. surgery alone, surgery + IORT, surgery + PC and surgery + IORT + PC, and (3) the rate of liver metastasis in patients treated by PC was significantly low.

[A case of inoperable advanced gastric cancer remarkably responding to combined chemotherapy with UFT-E, MMC and PSK].

A 55-year-old male consulted a local doctor with the complaint of epigastralgia. Examination of the upper gastrointestinal tract revealed gastric cancer (Borrmann Type II) and he was referred to our hospital for operation. A few lymph nodes were palpable in the left supraclavicular fossa, and the biopsy of those lymph nodes revealed metastatic adenocarcinoma. The CT scan of the abdomen showed enlargement of paraaortic lymph nodes. Then, the patient was determined inoperable (T3, N4, H02 P01, M1 stage IVb). He was treated as an outpatient with UFT-E (300 mg/day, orally), Krestin (PSK 3.0 g/day, orally) and Mitomycin C (MMC 6 or 8 mg once a week, intravenously repeated interval of 4 weeks). The total dose of UFT-E, PSK and MMC was 219 g, 1,095 g and 136 mg, respectively. One month later, lymph nodes in the supraclavicular fossa disappeared, and the lesion in the stomach completely responded. We have followed the patient for more than one year. He visits our the outpatient department and has kept working until now.

[Surgical treatment for the upper and middle bile duct cancer].

A total of 45 patients with bile duct cancer, 13 patients predominantly with Bs bile duct cancer, 14 with Bm cancer, and 18 with Bim cancer, were chosen from 104 patients with bile duct cancer, not including gallbladder cancer or cancer of the papilla of Vater, who underwent surgical resection in our department between Sep 1974 and Nov 1996, and were evaluated with respect to surgical procedure, pathological findings, and outcome. The patients with Bs cancer were compared with 39 patients with cancer of the main hepatic duct junction who underwent hepatectomy, and the patients with Bim cancer were compared with another 20 patients with Bi bile duct cancer. The effect of combined resection of the vessels and hepatopancreatoduodectomy (HPD) on patients with advanced cancer was assessed. To attain a hw (-) margin, hepatectomy should be performed in patients with Bs bile duct cancer, unless localized. Bm and Bim bile duct cancer patients with negative margins had a relatively favorable outcome irrespective of surgical procedure. Resection of the vessels and HPD were useful in improving the resectability rate, but not in attaining longer survival.

Interaction with autologous platelets multiplies interleukin-1 and tumor necrosis factor production in mononuclear cells.

The effect of activated platelets on cytokine production by human peripheral blood mononuclear cells (PBMC) was investigated. When PBMC were coincubated with activated autologous platelets amid lipopolysaccharide (LPS, 50-100 pg/mL) for 8 h, the production of interleukin (IL)-1alpha increased 11- to 18-fold and tumor necrosis factor (TNF)-alpha 3- to 5-fold compared with PBMC without platelets. Activated platelets in a dual-chamber well that prevented platelet-PBMC contact but permitted passage of soluble factors enhanced IL-1alpha production (P < .01). Platelet-PBMC contact in the chamber resulted in a further enhancement of IL-1alpha production. These data suggest that platelet-PBMC interaction, both directly and with platelet-derived factors, enhances production of shock-producing IL-1alpha and TNF-alpha, albeit differently. The interaction of platelets with monocytes may play an important role in the pathophysiology of sepsis and disseminated intravascular coagulation.

Circulating concentrations and physiologic role of atrial natriuretic peptide during endotoxic shock in the rat.

OBJECTIVES: To determine if there are changes in circulating concentrations of endogenous atrial natriuretic peptide and the physiologic role of this peptide in endotoxic shock. DESIGN: A prospective, randomized, controlled animal trial. SETTING: University research laboratory. SUBJECTS: Anesthetized male Wistar rats, weighing 250 to 350 g. INTERVENTIONS: Six rats received 1.5 mg/kg body weight of lipopolysaccharide alone. Five rats received 1.5 mg/kg of lipopolysaccharide and 200 microL/100 g body weight of rabbit anti-atrial natriuretic peptide serum. Another five rats received 1.5 mg/kg of lipopolysaccharide and normal rabbit serum in the same volume as the antiserum. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of atrial natriuretic peptide, arginine vasopressin, and aldosterone were measured, and changes in hemodynamic parameters and renal function were monitored in rats with endotoxic shock after catheterization of the right jugular vein. Urine volume, urine sodium excretion, urinary potassium excretion, and urine 3', 5'-cyclic guanosine monophosphate (cGMP) excretion were measured at 12-hr intervals. The plasma atrial natriuretic peptide concentration was slightly but significantly lower 30 mins after the lipopolysaccharide injection (114.8 +/- 9.0 pg/mL at 0 hr, 75.6 +/- 6.2 pg/mL at 30 mins, p < .01) and then began to increase, peaking at 6 hrs (752.8 +/- 104.5 pg/mL, p < .01 vs. 0 time) and remaining at higher concentrations than before the preinjection value, up to 24 hrs. In contrast, acute spike-like increases of arginine vasopressin and aldosterone concentrations were observed 30 mins after the lipopolysaccharide injection, preceding the increase of the plasma atrial natriuretic peptide concentration. Measurements of urine volume and urine sodium excretion showed oliguria during the initial 12 hrs after the lipopolysaccharide injection, followed by diuresis and natriuresis during the subsequent 12 hrs. In addition, injection with anti-atrial natriuretic peptide serum in the diuretic phase 12 hrs after the lipopolysaccharide injection significantly inhibited the diuresis, natriuresis, and urine cGMP excretion in this model. Furthermore, the plasma aldosterone concentration 24 hrs after the lipopolysaccharide injection was significantly increased by the administration of the antisera. CONCLUSIONS: These findings suggest that endogenous atrial natriuretic peptide increases in the acute phase of endotoxic shock and plays an important role in water and electrolyte balance by regulating diuresis.

Altered interleukin-1 and tumor necrosis factor production and secretion during pyrogenic tolerance to LPS in rabbits.

Rabbits were injected intravenously with 10 micrograms/kg of endotoxin [lipopolysaccharide (LPS)] on days 0, 1, and 7, and rectal temperatures were monitored. The febrile responses were compared with circulating levels of interleukin-1 beta (IL-1 beta) and tumor necrosis factor (TNF) and in vitro synthesis of these cytokines by peripheral blood mononuclear cells (PBMC) isolated just before the injection of LPS. Fever after the first LPS injection was biphasic on day 0, attenuated and monophasic after the second LPS injection on day 1, and augmented after third injection of LPS on day 7. On day 1, circulating TNF and IL-1 beta levels were significantly (P < 0.05) decreased compared with those on days 0 and 7. Similarly, TNF and IL-1 beta synthesis by LPS-stimulated PBMC were significantly reduced on day 1. On day 7, cellular synthesis and secretion of IL-1 beta were significantly increased compared with that on day 0. A significant positive correlation was observed between fever index and total in vitro IL-1 beta synthesis by LPS-stimulated PBMC (r = 0.866, P = 0.001). These data demonstrate that pyrogenic tolerance in the rabbit after a single LPS injection is associated with decreased circulating IL-1 beta and TNF levels as well as decreased production of these cytokines in vitro. In addition, the pyrogenic hyperresponsiveness to LPS after 7 days is associated with increased synthesis and secretion of IL-1 beta from PBMC in vitro.

Pathophysiologic role of endothelin-1 in renal function in rats with endotoxin shock.

BACKGROUND: We hypothesized that endothelin-1 (ET-1) is an important mediator in renal dysfunction under septic conditions. This study clarified the pathophysiologic role of ET-1 in renal function under conditions of surgical stress, especially sepsis. METHODS: We investigated the correlation between ET-1 levels and renal function and the effect of anti-ET-1 antibody (AwET-1N40) on renal function in a septic shock rat model. RESULTS: The plasma ET-1 level increased significantly at 30 minutes and remained significantly elevated for 24 hours, reaching a peak (195 +/- 24.4 pg/ml) 3 hours after the endotoxin (lipopolysaccharide derived from Escherichia coli) injection. Increases in plasma creatinine concentration and blood urea nitrogen (BUN) level and decreases in urine volume and urinary sodium excretion were also observed in the early phase after endotoxin injection. The plasma creatinine concentration and the plasma ET-1 level increased significantly at 30 minutes, reached a peak at 3 hours, and then decreased. Anti-ET-1 antibody administration (5 nmol/kg body, four times intravenously) decreased plasma creatinine concentration and BUN level and increased urine volume and urinary sodium excretion 3 hours after endotoxin injection (creatinine, p = 0.07; BUN, p < 0.05; urine volume, p < 0.01; urinary sodium excretion, p < 0.01; anti-ET-1 vs shams). CONCLUSIONS: These results suggest that the increase in endogenous ET-1 induced by sepsis plays an important role in renal dysfunction in the septic state.

Interleukin-1 (IL-1) receptor antagonist prevents Staphylococcus epidermidis-induced hypotension and reduces circulating levels of tumor necrosis factor and IL-1 beta in rabbits.

Similar to shock in gram-negative sepsis, shock from gram-positive organisms is mediated, in part, by tumor necrosis factor (TNF) and interleukin-1 (IL-1). In the present study, rabbits were infused with IL-1 receptor antagonist (IL-1ra) prior to and during Staphylococcus epidermidis-induced hypotension. After injection of bacteria, a maximal fall in mean arterial pressure to -42% below baseline occurred at 200 min in vehicle-treated animals compared with a nonsignificant decrease of only 7% in the IL-1ra-treated group (P < 0.01, vehicle versus IL-1ra). A similar attenuation was observed in the fall in systemic vascular resistance (P < 0.05). After the injection of S. epidermidis, TNF levels rose to a peak elevation of 475 +/- 160 U/ml in vehicle-treated rabbits, but in rabbits receiving IL-1ra, maximal TNF levels rose only to 85 +/- 23 U/ml (P < 0.01). Plasma IL-1 beta reached maximal concentrations at 180 min of 364 +/- 71 pg/ml in vehicle-treated animals but only 145 +/- 12 pg/ml in rabbits given IL-1ra (P < 0.05). The reductions in TNF and IL-1 were not due to interference by IL-1ra in the respective assays. In vitro, IL-1ra inhibited S. epidermidis-induced TNF from mononuclear cells by 31% +/- 11%, from spleen cells by 17% +/- 4% (P < 0.05), and from whole blood by 42% +/- 17%. Despite the near reversal of the fall in mean arterial pressure and systemic vascular resistance in IL-1ra-treated rabbits, leukopenia and thrombocytopenia were unaffected. These results demonstrate that IL-1ra blocks shock-like hemodynamic parameters and reduces circulating IL-1 and TNF levels in a model of gram-positive sepsis.

Activated platelets induce endothelial secretion of interleukin-8 in vitro via an interleukin-1-mediated event.

Migration of neutrophils through endothelial cells (EC) and induction of cytokine secretion are two well-documented events during the inflammatory reaction. The inflammatory, chemotactic cytokine interleukin-8 (IL-8) is secreted by EC in response to IL-1 stimulation. In this study, we show that platelets activated with either adenosine-5'-diphosphate or epinephrine induce IL-8 secretion by EC. This stimulatory activity was found to be associated with sedimented platelets after activation. Blockade of IL-1 receptors on EC with IL-1 receptor antagonist (IL-1Ra) decreased the stimulatory effect of whole activated platelet preparations by 59% (P < .05). Similarly, IL-1Ra pretreatment of EC reduced the stimulatory effect of sedimented activated platelets by 60% (P < .01). In addition, we treated human blood donors with 750 mg of oral aspirin, and evaluated the stimulatory effect of epinephrine-activated platelets on IL-8 secretion by EC. IL-8 synthesis after aspirin ingestion was inhibited by 90% (P < .01) as compared with the preaspirin stimulation. These observations show that activated platelets induce IL-8 secretion via membrane-associated IL-1 activity, and provide a novel relationship between coagulation and inflammation that could be relevant to several diseases.