Ten-year follow-up results of a randomized clinical trial comparing left thoracoabdominal and abdominal transhiatal approaches to total gastrectomy for adenocarcinoma of the oesophagogastric junction or gastric cardia.

BACKGROUND: The optimal surgical approach for treatment of oesophagogastric junction (OGJ) cancer is controversial. A randomized clinical trial (JCOG9502) comparing transhiatal (TH) and left thoracoabdominal (LTA) approaches was stopped after the first interim analysis owing to limited efficacy for LTA resections. Complete 10-year follow-up data are now available. METHODS: Patients with histologically proven adenocarcinoma of the OGJ or gastric cardia with oesophageal invasion of 3 cm or less were randomized to a TH or LTA approach. Both groups underwent total gastrectomy and splenectomy with D2 nodal dissection plus para-aortic lymphadenectomy above the left renal vein. For LTA, a thorough mediastinal lymphadenectomy below the left inferior pulmonary vein was also mandatory. The primary endpoint was overall survival. RESULTS: A total of 167 patients (82 TH, 85 LTA) were enrolled. The 10-year overall survival rate was 37 (95 per cent c.i. 26 to 47) per cent for the TH approach and 24 (15 to 34) per cent for the LTA technique (P = 0·060). The hazard ratio for death was 1·42 (0·98 to 2·05) for the LTA technique. Subgroup analysis based on the Siewert classification indicated non-significant survival advantages in favour of the TH approach. CONCLUSION: LTA resections should be avoided in the treatment of adenocarcinoma of the OGJ or gastric cardia. REGISTRATION NUMBER: NCT00149266 (https://www.clinicaltrials.gov).

Functional outcomes after extended surgery for gastric cancer.

BACKGROUND: Extended gastrectomy with para-aortic nodal dissection (PAND) or thorough dissection of mediastinal nodes using a left thoracoabdominal (LTA) approach is an alternative to D2 lymphadenectomy, with variable postoperative results. METHODS: Two randomized controlled trials have been conducted to compare D2 lymphadenectomy alone (263 patients) versus D2 lymphadenectomy plus PAND (260), and the abdominal-transhiatal (TH) approach (82) versus the LTA approach (85), in patients with gastric cancer. Prospectively registered secondary endpoints bodyweight, symptom scores and respiratory function were evaluated in the present study. RESULTS: Bodyweight was comparable after D2 and D2 plus PAND, but higher after TH than after LTA procedures at 1 and 3 years. At 1- and 3-year follow-up symptom scores were comparable between D2 and D2 plus PAND. A LTA approach resulted in significantly worse scores than a TH approach in terms of meal volume, return to work, incisional pain and dyspnoea up to 1 year. The decrease in vital capacity was significantly greater after LTA than TH procedures up to 6 months. CONCLUSION: Bodyweight and postoperative symptoms were not affected by adding PAND to a D2 procedure. A LTA approach aggravated weight loss, symptoms and respiratory functions compared with a TH approach.

Effect of carbohydrates on the ability of bull sperm to bind to bovine oviduct epithelial cells.

In the present study, we investigated the effect of various carbohydrates on the ability of bovine spermatozoa to bind to the bovine oviduct epithelial cells (OECs). We also examined the fertilization competence and motility of spermatozoa that bind to OECs in the presence of carbohydrates. Frozen-thawed spermatozoa were incubated with OECs, with and without various carbohydrates. The sperms were then divided into two fractions: OEC-binding sperms (B-sperm) and non-OEC binding sperms (NB-sperm). The fertilization rate, ability to bind the zona pellucida, and membrane integrity of the spermatozoa as determined using a hypo-osmotic-swelling test (HOST) were lower in NB-sperm than in the unseparated spermatozoa (control). The motility of the B-sperm was maintained for a longer time than that of the control spermatozoa. The addition of N-acetyl-d-glucosamine (GlcNAc, 5 mm) to the sperm-OEC mixture increased the number of B-sperm. D-mannose (5 mm) and D-fucose (5 mm) had no effect on the number of B-sperm. The motility of B-sperm, which bound to OECs in the presence of GlcNAc, however, was not maintained. When either OECs or the spermatozoa were treated with GlcNAc prior to sperm-OEC co-incubation, only sperm-side treatment enhanced sperm-OEC binding, but B-sperm motility was not maintained. The motility of spermatozoa incubated with GlcNAc was lower than that of controls. These results indicate that GlcNAc enhances sperm binding to OECs, probably via sperm surface modification, but does not promote increased sperm survival.

[Large cell neuroendocrine carcinoma of the lung].

Large cell neuroendocrine carcinoma (LCNEC) is a neuroendocrine tumor comprising a subgroup of large cell carcinoma and is a type of lung cancer showing a neuroendocrine characteristic similar to that of small cell lung carcinoma In our institution, we started to diagnose LCNEC by immunostaining in 2002, and we herein report 9 patients diagnosed with LCNEC from January 2002 to May 2008. The average patient age was 74.9, male/female ratio was 8/1, and all 9 patients had a smoking history. Pathological stages IA/IB/IIB/IIIA comprised 4/1/2/2, respectively. Peripherally located and lobulated tumors were noted on preoperative computed tomography (CT), and moderate uptake of fluoro-2-deoxy-D-glucose (FDG), which balanced with the size, was recognized on positron emission tomography (PET). All 9 patients underwent surgery and 7 underwent radical surgery. Postoperative adjuvant chemotherapy was performed for 4 patients. Three showed recurrence, and 2 of these 3 died of the primary disease. The remaining 7 patients have survived to date. The possibility of LCNEC must be considered when peripherally located lung cancer with lobulation is noted on CT and shows moderate uptake of FDG for its size on PET, and multimodal treatment is needed if the diagnosis is determined postoperatively.

Evaluation of sentinel node identification with isosulfan blue in gastric cancer.

AIMS: The aim of this study was to clarify whether the metastasis of gastric cancer can be detected by identifying the sentinel lymph nodes (SNs) using only lymphatic dye. METHOD: The study was based on 101 patients clinically diagnosed with T1 and T2 gastric cancer. Isosulfan blue was intraoperatively injected within the submucosal layer around the lesion through an endoscope and blue stained nodes (BNs) were identified as SNs and harvested. Standard radical gastrectomy with D2 lymphadenectomy was performed on all patients and SNs and other nodes were evaluated. RESULTS: Out of 101 patients, 21 had lymph-node metastases. The accuracy of SN identification was 97.0% (98/101) and the metastasis detection rate was 85.7% (18/21). With improvement of the manoeuvre in the latter 84 cases, the detection rate was elevated up to 100.0% (18/18), as was the accuracy (84/84). CONCLUSION: The sentinel concept using lymphatic dye is applicable to gastric cancer, but the identification of SNs with lymphatic dye requires some practice. Furthermore, the issue of intraoperative metastasis detection remains to be resolved.

Intravenous administration of irinotecan elevates the blood beta-glucuronidase activity in rats.

7-Ethyl-10-hydroxycamptothecin (SN-38) is the active metabolite of an anticancer drug, irinotecan (CPT-11). Severe late diarrhea is the dose-limiting toxic effect of CPT-11. This diarrhea has been examined regarding biliary excretion and deconjugation of SN-38 glucuronide by the enzyme beta-glucuronidase (beta-GL) in intestinal microflora. Prompted by the enzymological and structural similarity of CPT-11 to organophosphorus and carbamate insecticides, we studied the effect of CPT-11 on blood beta-GL activity in rats. The i.v. injection of CPT-11 in rats significantly elevated their plasma beta-GL activity (with phenolphthalein glucuronide as a substrate) at doses of 10 and 40 mg/kg, with peak activity observed 2-3 h after administration. SN-38 lactone and carboxylate had no effect on the plasma beta-GL level. The enhancement of the activity was also observed in serum using SN-38 glucuronide as a substrate. The serum beta-GL levels showed a close correlation between these substrates. The enhancement of plasma (serum) beta-GL activity is suggested to be a result of the release of beta-GL from liver microsomes. Serum and microsomal carboxylesterase were not significantly affected by CPT-11 administration.

Role of coronary collateral vessels during transient coronary occlusion during angioplasty assessed by hemodynamic, electrocardiographic and metabolic changes.

The clinical role of collateral vessels was evaluated during transient coronary occlusion by percutaneous transluminal coronary angioplasty in 22 patients with (8) and without (14) collateral vessels. Coronary occlusion pressure, the ratio of mean coronary occlusion pressure to mean aortic pressure and myocardial perfusion pressure at 40 s of balloon inflation were significantly higher in patients with than in patients without collateral vessels. The changes in left ventricular systolic and end-diastolic pressure, maximal rate of rise of left ventricular pressure (peak dP/dt) and maximal rate of fall of left ventricular pressure (negative peak dP/dt) during balloon inflation were less in patients with than in patients without collateral vessels. Myocardial lactate was produced in patients without collateral vessels but not in those with such vessels. Marked ST segment elevation in the electrocardiogram occurred in patients without collateral vessels but either ST segment depression or mild ST segment elevation was observed in patients with collateral vessels. This study indicates that collateral vessels limit myocardial ischemia during coronary occlusion, probably as a result of increased myocardial perfusion pressure.

Angioscopic identification of coronary thrombus in patients with postinfarction angina.

OBJECTIVES: The purpose of this study was to determine the prevalence of intracoronary thrombus and associated anatomic abnormalities in patients with postinfarction angina using coronary angioscopy and angiography. BACKGROUND: Postinfarction angina, previously studied by angiographic methods only, identifies patients at high risk for sudden death, recurrent angina and refractory angina. The recent development of coronary angioscopy, which permits direct observation of a thrombus or atheroma and is especially used for the detection of intraluminal changes, encourages a reexamination of the pathogenesis of postinfarction angina. METHODS: Fifty-one consecutive patients with a diagnosis of acute myocardial infarction underwent cardiac catheterization. Coronary angiography followed immediately by coronary angioscopy was performed in 17 patients with and 34 without postinfarction angina during the same period of time (10.2 +/- 3.7 or 15.7 +/- 5.5 days [mean +/- SD]) after the onset of acute myocardial infarction. RESULTS: The frequency of thrombus, as observed by angioscopy, was significantly higher in patients with than without postinfarction angina (17 of 17 vs. 5 of 34, respectively, p < 0.01). There were no significant differences between groups with respect to degree of stenosis in the infarct-related artery, number of vessels with significant stenosis, presence of collateral flow, type of therapy and risk factors. CONCLUSIONS: Infarct-related artery thrombus is universally present in postinfarction angina and may be the primary pathogenic factor. Angioscopy is much more sensitive than coronary angiography for the detection of coronary thrombus.

New percutaneous transluminal coronary angioscope.

A new percutaneous transluminal coronary angioscopic catheter has been developed for visualization of the coronary artery. A specially made balloon, fixed at the catheter tip, and an angulation mechanism made a precise coaxial alignment possible in the coronary lumen. This angioscopic catheter, 1.22 mm in outer diameter, has four channels, one for irrigation in which a 0.36 mm (0.014 in.) angioplasty guide wire can be used. With the use of this angioscope, coronary lumens in 8 dogs, thrombi that were produced with copper coils in the left anterior descending coronary artery in 11 dogs, atherosclerotic coronary arteries in 20 patients during cardiac catheterization and the sequence of transluminal coronary angioplasty in 1 patient were observed. The angioscopic catheter was introduced into the coronary artery by an 8F guide catheter. The steerable guide wire enabled the angioscopic catheter to be accurately and safely inserted into the target lesion in all cases. The inflated balloon and angulation mechanism allowed a curved coronary lumen and atheroma to be seen with a limited volume of irrigation fluid. Visualization was good (complete visualization of the inner lumen) in 46% (10 of 22 lesions), moderate (visualization of greater than 50% of the inner lumen) in 36% (8 of 22 lesions) and poor (visualization of less than 50% of the inner lumen) in 18% (4 of 22 lesions) in humans. There were no major complications. These preliminary experiences in closed chest cardiac catheterization in dogs and in humans indicate the feasibility of this angioscope. The information yielded by angioscopy may be clinically useful in the study of the pathophysiologic changes in coronary disease that are not detected by coronary arteriography.

Effect of betaxolol hydrochloride on heart rate variability indices during exercise stress testing in patients with hypertension.

Betaxolol hydrochloride is a beta1-selective antagonist that produces vasodilation in patients with hypertension and ischemic heart disease. The goal of the present study was to characterize the effect of betaxolol on heart rate variability indices (HRV), a well-established prognostic marker. Symptom limited-treadmill exercise testing was performed in 17 hypertensive patients (60.9 +/- 14.8 years-old) before and immediately a 3 weeks course of betaxolol hydrochloride (5 mg daily). Frequency domain HRV (high frequency spectra, HF; 0.15-0.40 Hz: low frequency spectra, LF; 0.04-0.15 Hz) was measured during exercise treadmill testing using MemCalc software. Betaxolol hydrochloride significantly decreased the maximal systolic blood pressure and heart rate (184 +/- 29 vs. 156 +/- 26 mmHg, P < 0.01; 132 +/- 21 vs. 113 +/- 15 bpm, P < 0.01) and significantly increased HF and LF during exercise treadmill testing (HF, 32 +/- 36 vs. 56 +/- 55 men/Hz, P < 0.01; LF, 64 +/- 58 vs. 95 +/- 86 men/Hz, P < 0.01). Thus, treatment with betaxolol hydrochloride resulted in a decrease in blood pressure during exercise treadmill testing and in an increase in HRV. This suggests that this agent could have beneficial effects on long-term prognosis in patients with hypertension.

Risk factors for myocardial injury during off-pump coronary artery bypass grafting.

BACKGROUND: Although off-pump coronary artery bypass grafting (CABG) is now used worldwide for coronary revascularization, the pre- and intraoperative risk factors for myocardial injury associated with the surgical procedure remain to be elucidated. We performed a multivariate analysis to investigate factors that contribute to myocardial injury during off-pump CABG. METHODS: The study population consisted of 22 patients who underwent off-pump CABG without apparent intraoperative complications. Blood samples were obtained before surgery and at 3 and 12 hours after the last anastomosis and serum Troponin T (cTnT) levels were measured to assess myocardial injury. Patient characteristics and factors related to preoperative cardiac function and the intraoperative process were analyzed to determine their correlation with serum cTnT levels, and the Spearman's correlation coefficient (r(s)) was computed. RESULTS: Neither age, preoperative cardiac function, time required for anastomosis, the number of grafts, nor the total amount of bleeding were associated with serum cTnT levels. Serum cTnT at 3 and 12 hours after completed anastomosis correlated with the product of mean systolic blood pressure and mean heart rate (double product) during anastomosis. The r(s) values at 3 and 12 hours were 0.62 (P = .002) and 0.58 (P = .004), respectively. With respect to the serum cTnT level at 12 hours, creatinine clearance (Ccr) had a slight effect on the serum cTnT values. CONCLUSIONS: High blood pressure and an increased heart rate during anastomosis are unfavorable factors for off-pump CABG. However, strict control of the blood pressure and heart rate makes it possible to subject even patients at high-risk to off-pump CABG from the viewpoints of myocardial injury.

A new method to detect systemic inflammatory response syndrome by continuous monitoring system: an experimental study in rats.

A continuous monitoring system was designed for detection of systemic inflammatory response syndrome (SIRS) using spectrum analyser and local temperature mapping system with deep body thermometer. This method demonstrated significant increases of heart and respiratory rates and deep body temperature from normal levels within 120 minutes after lipopolysaccharide administration in rats. Our monitoring system appears promising for clinical detection of SIRS in the early stages to prevent multiple organ failure.

Neurophysiological evidence for altered higher brain functions in NIDDM.

OBJECTIVE: To investigate neurophysiological alterations of higher brain function in patients with NIDDM. RESEARCH DESIGN AND METHODS: Auditory P300 event-related potentials were recorded in 60 NIDDM patients who had no evidence of stroke, dementia, or any other neurological illnesses. The P300 wave latencies in diabetic patients were compared with those in neurologically healthy control subjects, with consideration of clinical parameters and diabetic complications. RESULTS: Diabetic patients had significantly longer P300 latencies than control subjects. Seven diabetic patients had pathologically prolonged P300 values. There was a trend toward longer P300 latencies in diabetic patients with retinopathy and in those with HbA1 of > or = 10%; the differences between these diabetic subgroups and control subjects were both statistically significant. However, three of seven diabetic patients with abnormal P300 latencies had no retinal lesions, and no significant correlation was observed among diabetic patients between P300 latencies and HbA1 levels. Peripheral neuropathy, nephropathy, blood glucose levels, and disease duration appeared not to correlate with P300 alterations. CONCLUSIONS: These findings suggest the presence of central nervous pathological processes in NIDDM that affect higher brain functions, as assessed by P300 latencies. Our findings also suggest that microangiopathy and metabolic derangement during the preceding 4- to 8-week period may contribute in small part to the pathophysiology of this central nervous involvement.

A phase I study of S-1 combined with weekly cisplatin for metastatic gastric cancer in an outpatient setting.

A dose-escalation study was conducted for patients with metastatic gastric cancer to determine the recommended dose of weekly intravenous (i.v.) cisplatin combined with a fixed dose of a new oral dihydropyrimidine dehydrogenase-inhibitory fluoropyrimidine, S-1, on an outpatient basis. Secondary endpoints were to define the toxicity profile and to determine tumour responses. S-1 was fixed at a dose of 70 mg/m(2)/day and was administered for 2 weeks followed by a 1-week rest. Three dose levels of cisplatin (10, 15 and 20 mg/m(2)) were studied. Cisplatin was infused over 30 min on days 1 and 8. 20 patients were enrolled. No dose-limiting toxicities (DLTs) were recorded during the administration of cisplatin up to 20 mg/m(2), except for grade 3 diarrhoea and stomatitis in one patient at dose level 3. No grade 4 adverse events occurred. However, grade 2 gastrointestinal adverse reactions, such as nausea and anorexia, were seen in 7 of 13 patients at dose level 3 within the first two treatment cycles. This was determined to be the maximum acceptable level that would not negate the advantages observed with use of an oral drug such as S-1. An objective tumour response was seen at all dose levels, and the overall response rate in the 18 patients evaluated was 61%. A higher response rate of 78% was observed in 9 patients who had received no prior chemotherapy. Oral S-1 with weekly cisplatin is a feasible and promising combination regimen that is appropriate for an outpatient setting. A randomised phase II study comparing this combination with S-1 alone in chemo-nai;ve patients is warranted.

Significance of exercise-induced junctional S-T depression in evaluation of coronary artery disease.

Isolated junctional S-T depression induced during treadmill exercise testing was correlated with coronary arteriographic findings in 230 patients. Of 75 patients with junctional depression of less than 1.5 mm, 10 had 50% or greater stenosis of at least one major coronary artery and 2 patients (3%) had multivessel disease. Of 42 with junctional depression of 1.5 mm or more and a rapid upsloping S-T segment, 23 had 50% or greater coronary stenosis and 12 of these had multivessel disease. Of 35 with an upsloping pattern (junctional depression of more than 2 mm, upsloping S-T segment depressed 2 mm or more, 0.08 second after the J point), 33 (94%) had 50% or greater coronary stenosis compared with 46 (96%) and 30 (97%) with 2 mm or more junctional depression ahd a horizontal or downsloping S-T segment. In conclusion, multivessel disease is rare with isolated exercise-induced junctional depression of less than 1.5 mm but common when the J point is depressed 1.5 mm or more. Junctional depression of more than 2 mm is associated with the same incidence of coronary disease when the S-T segment is slowly ascending (upsloping pattern) as when it is horizontal.

Impaired endothelium-dependent vasodilation in the brachial artery in variant angina pectoris and the effect of intravenous administration of vitamin C.

UNLABELLED: Endothelial dysfunction in the coronary artery contributes to the pathogenesis of variant angina, and endothelial dysfunction in variant angina may be associated with increased oxidant stress in the systemic arteries. We investigated whether endothelial dysfunction exists in the peripheral artery in patients with variant angina, and also examined the effect of vitamin C, an antioxidant, on endothelium-dependent vasodilation. Using high-resolution ultrasound, both the flow-mediated vasodilation (FMD, endothelium-dependent vasodilation) and sublingual nitroglycerin-induced vasodilation (NTG-D, endothelium-independent vasodilation) in the brachial artery were measured in 28 patients with variant angina and 24 control subjects who had normal coronary arteries. FMD was significantly impaired in patients with variant angina compared with control subjects (1.8 +/- 2.2% vs 6.4 +/- 4.9%, p <0.001). FMD and NTG-D before and after intravenous administration of either vitamin C or placebo were measured in 17 patients with variant angina. FMD significantly improved after the administration of vitamin C (from 2.2 +/- 2.4% to 4.5 +/- 1.6%, p <0.01), but not after administration of the placebo (from 2.0 +/- 2.6% to 1.7 +/- 1.9%). The improved FMD due to vitamin C in patients with variant angina, however, was not significantly different from that in the control subjects. NTG-D was not significantly different between patients with variant angina and control subjects (14.0 +/- 7.8% vs 13.6 +/- 5.0%) and it was also not affected by vitamin C. IN CONCLUSION: (1) FMD in the brachial artery is impaired in patients with variant angina, and (2) the acute administration of the antioxidant, vitamin C, was observed to reverse this endothelial dysfunction. These findings support the theory that the systemic inactivation of nitric oxide due to oxidative stress might exist in patients with variant angina.

Usefulness of plasma beta-endorphin level, pain threshold and autonomic function in assessing silent myocardial ischemia in patients with and without diabetes mellitus.

The differences between diabetic and nondiabetic patients with silent myocardial ischemia were investigated. Based on the results of previous exercise testing, a total of 110 patients (15 diabetic and 95 nondiabetic) with exercise-induced myocardial ischemia were divided into the following 3 groups: 15 diabetics with silent myocardial ischemia, 49 nondiabetics with silent myocardial ischemia, and 46 nondiabetics with anginal symptoms. All patients underwent treadmill exercise testing and 24-hour ambulatory electrocardiographic recording. Before and during exercise, blood samples from the antecubital vein were obtained to determine the plasma beta-endorphin levels, and the pain threshold of each patient was measured with the electrical skin stimulation test. Furthermore, with regard to the ambulatory electrocardiographic recording, the mean of the SDs of all normal sinus RR intervals during successive 5-minute recording periods over 24 hours was analyzed and considered as an index of the autonomic function. The plasma beta-endorphin level during exercise was significantly greater in nondiabetic patients with silent ischemia than in diabetic ones. The SD mean was significantly less in the diabetic group than in the 2 nondiabetic ones. The findings suggest that the role of beta endorphin in diabetic patients with silent myocardial ischemia may be less significant than in nondiabetic ones; therefore, a diabetic neuropathy that affects the autonomic pain fibers that innervate the heart may be involved in the mechanism of silent myocardial ischemia in diabetics.