Initial Safety Analysis of CapeOx for Elderly Patients With Advanced Gastric Cancer Patients: A Phase II Trial.

BACKGROUND: Safety of combination chemotherapy using platinum and fluorouracil has not been evaluated adequately for advanced gastric cancer (AGC) in elderly patients. PATIENTS AND METHODS: We initiated a phase II study to evaluate the efficacy and safety of capecitabine plus oxaliplatin (CapeOX) as first-line therapy for patients with AGC aged ≥70 years. Planned assessment of toxicity was made upon recruitment of the first 20 patients. RESULTS: In five out of 20 patients, unacceptable toxicity was observed, including three patients who were unable to complete the initial two courses due to adverse events. Among the other 15 patients, dose reduction due to toxicity were needed in 10 and treatment delay for adverse events also occurred in 12 patients during the first two courses. CONCLUSION: Early analyses of safety suggest that the CapeOX regimen was not tolerated without dose reduction for elderly patients with AGC in this study.

Implications of Clinical Mycophenolate Mofetil Dose According to Individual Body Weight in Japanese Renal Transplant Recipients.

BACKGROUND: Mycophenolate mofetil (MMF) is generally administered at a fixed dose of 0.5-1.5 g/d without considering individual body weight (BW) in Japanese renal transplant outpatients receiving maintenance therapy. We aimed to investigate the implications of the area under the curve of mycophenolic acid (MPA AUC):MMF dose ratio by individual BW and suggest the index of MMF dose according to individual BW. METHODS: Forty-three Japanese patients who received a renal transplant ≥6 months before the study were enrolled. Blood samples were collected at 4 time points: at predose, 20 minutes, 1 hour, and 3 hours after MMF administration. RESULTS: The mean ± standard deviation MMF dose, MPA AUC, and BW of all patients were 581 ± 207 mg/d, 36.2 ± 18.7 µg·h/mL, and 56.3 ± 11.1 kg, respectively. Patients with a lower BW tended to have a higher MPA AUC:MMF dose ratio than patients with a higher BW. There was a significant correlation between the MMF dose:BW ratios and MPA AUC (r(2) = 0.330; P < .01). The rate of MPA AUC between 30 and 60 µg·h/mL with the MMF dose:BW ratio of 10-16 mg/kg was 73.7%. CONCLUSION: Individual BW seems to affect the MPA AUC:MMF dose ratio; therefore, we need to consider individual BW when deciding on a MMF dose. The MMF dose:BW ratio of 10-16 mg/kg could predict MPA AUC between 30 and 60 µg·h/mL with a probability of approximately 75%. Therefore, it could be a useful index for outpatients, because it is difficult to draw blood frequently from such patients.

Sequences of four splits of HLA-A10 group. Implications for serologic cross-reactivities and their evolution.

Nucleotide sequences of alleles encoding four serologically defined splits of the HLA-A10 group, A26.1, A26.3, A26.4, and A10SA, were determined. It was confirmed that the alleles coding for A26.1 and A26.3 are identical with A*2602 and A*2601, respectively. On the other hand, alleles for A26.4 and A10SA are thus far undescribed. A26.4 (A*2603) was different from the other A26 splits at three positions: 74 histidine, 76 valine, and 77 aspartate. A10SA (A*2604) was different from A26.3 (A*2601) by a single substitution of arginine by leucine at position 163. A comparison of amino acid sequences of HLA-A10 cross-reacting antigens revealed that all of the A10 group antigens share specific amino acids: 142 isoleucine, 144 glutamine, 145 arginine, 149 threonine, and 152 glutamate. Moreover, A26.1, A26.3, A10SA, and A43 share 76 alanine and 77 asparagine, which is consistent with the reported serologic cross-reactivity. The close relationship between the alleles for the A10 cross-reacting group was supported by a phylogenetic tree analysis for the HLA-A alleles.

Clinical assessment of prolonged myocardial preservation for patients with a severely dilated heart.

BACKGROUND: The purpose of this study was to compare the myocardial protective effect of histidine-tryptophan-potassium and glucose-insulin-potassium cardioplegic solutions in patients with a dilated heart (left ventricular diastolic diameter > 55 mm, left ventricular systolic diameter > 45 mm) associated with prolonged cross-clamp time (longer than 200 minutes). METHODS: We selected 20 patients with dilated hearts due to severe aortic regurgitation. Glucose-insulin-potassium cardioplegia was used in 11 patients and histidine-tryptophan-potassium cardioplegia was used in 9 patients. RESULTS: After operation, the cardiac index was significantly increased in the histidine-tryptophan-potassium group (p < 0.05). Postoperative percent fractional shortening was 13.4% +/- 3.1% in the glucose-insulin-potassium group and 23.6% +/- 2.6% in the histidine-tryptophan-potassium group (p < 0.05). Creatine kinase levels were significantly lower in the histidine-tryptophan-potassium group than that in the glucose-insulin-potassium group (p < 0.05). The incidence of ventricular arrhythmia (higher than Lown's grade 2) was lower in the histidine-tryptophan-potassium group. CONCLUSIONS: These data support the superiority of the histidine-tryptophan-potassium method over the glucose-insulin-potassium method for protection of the dilated heart during prolonged ischemia in open heart operations.

Evaluation of the therapeutic effect of TAE on primary liver cancer.

The therapeutic effect of transcatheter arterial chemoembolization (TAE) performed on 31 patients with primary liver cancer was evaluated using the following procedures: (1) the alpha-fetoprotein (AFP) reduction rates and prognoses were analyzed according to the tumor reduction rates (TR), and (2) the AFP reduction rates and prognoses were also analyzed according to the tumor necrosis rates (TN) estimated by regarding every region with Lipiodol retention as being necrotic. The following results were obtained. The AFP level was 400 ng/ml or higher in 15 patients (48%). Their AFP reduction rates were as favorably high as 65.4%-99.8% (mean, 88.1%), and the AFP level was normalized in 3 patients. The cumulative survival rates after the initial treatment were relatively high, i.e., 78.4% in the 1st year, 58.1% in the 2nd year, and 38.7% in the 3rd year. These results suggested the effectiveness of the TAE treatment undertaken in this study. Regarding the TR, the tumor was reduced in size by 50% or more in only 5 patients (16%), and most patients had a TR of less than 25%. On the other hand, the majority, 25 patients (81%), had a TN ranging between 50% and less than 100%, including 7 who had a TN ranging between 50% and less than 90% and 18 who had a TN ranging between 90% and less than 100%. There was no significant correlation between the AFP reduction rate and the TN or TR. Regarding evaluation of the cumulative survival rates by TR and TN, the 1-year survival rate was lower in patients having a TR of less than 25% than in those having a TR of 25% or more. Patients having a TN of less than 50% showed a poor outcome as compared with those having a TN of 50% or more. Although the TR was found to be less than 50% in a majority of the patients when the therapeutic effect of TAE on the liver cancer was evaluated according to the TR, many of these patients showed a good outcome. Thus, the conventional efficacy evaluation, in which a tumor reduction of 50% or more is considered to be effective, should be reconsidered. On the other hand, the TN was found to be 50% or more in most of the patients, suggesting the necessity of a more detailed classification of TN. In relation to the survival rate, patients having a TN of less than 50% showed a poor outcome.

Glycine sensor in the hepato-portal system and their reflex effects on pancreatic efferents in the rat.

We earlier reported the existence of vagal arginine, alanine, and leucine sensors in the liver which modulate amino acid-induced pancreatic hormone secretion. To determine the possible existence of glycine sensors in the liver and their reflex effects, afferent discharges from the hepatic branch and efferent discharges from the pancreatic branch of the vagus nerve were recorded. Intraportal administration of 0.1, 1, and 10 mM of L-glycine solution (0.1 ml) depressed the afferent discharge rate of the hepatic branch of the nerve in a dose-dependent manner, and increased the efferent discharge rate of the pancreatic vagal branch. The results suggest the existence of glycine sensors in the hepato-portal system that exert reflex regulation on the pancreatic vagus nerve activity.

Prevalence of HCV genotype among patients with chronic liver diseases in the Tokyo metropolitan area.

We examined 613 Toranomon Hospital patients with HCV RNA-positive chronic liver disease to elucidate the viral genotype in the Tokyo metropolitan area. An epidemiological and clinical study was conducted in the 565 patients whose HCV genotype could be determined. The HCV genotypes found were type II, in 414 patients (67.5%); type III, in 103 (16.8%); type IV, in 37 (6.0%); type V, in 4 (0.7%); mixed genotype II and III, in 5 (0.8%); and mixed genotype II and IV, in 2 (0.3%). The HCV genotype could not be determined in 48 patients. Type II was most prevalent. The HCV genotype I was not found at all. There were no significant differences between genotypes in relation to sex, age, history of blood transfusion, or the progression of the disease. It was uncommon to find a history of blood transfusion in the patients with mixed genotypes; however, a high incidence of hepatic disorders was noted among the family members of these patients. Ninety-two percent of the patients with HCV genotype II tested positive for C100-3, while 70.9% of those with type III, and 43.2% of those with type IV tested positive for this antibody. HCV genotype II was most prevalent, and the positivity rate for anti C100-3 in patients with this HCV genotype was significantly higher (P < 0.00001) than that in patients with the other genotypes.

Serial hemodynamic study after aortic valve replacement in patients with narrow aortic roots.

BACKGROUND AND AIMS OF THE STUDY: The purpose of this study was to evaluate the hemodynamic performance after aortic valve replacement using different surgical options in small (19-mm diameter) annuli. METHODS: Postoperative hemodynamics were assessed in three groups according to the surgical method. A 19-mm St. Jude Medical (SJM) valve was used in nine patients (group A), a 19-mm SJM HP in nine patients (group B), and annular enlargement was performed in eight patients (group C). Echocardiography was performed and percent fraction shortening, peak pressure gradient, effective orifice area and left ventricular mass were measured. RESULTS: Postoperative peak systolic pressure gradient was decreased to 31.1+/-8.7 mmHg in group B, and to 22.3+/-11.7 mmHg in group C, but was 42.9+/-16.5 mmHg in group A (p <0.01). Percent fraction shortening and left ventricular mass index were improved in groups B and C, soon after surgery compared with group A (p <0.01). The effective orifice area significantly increased during exercise in group C, from 1.59 to 1.87 cm2 (p <0.01), but was not increased in groups A and B (N.S.). CONCLUSIONS: The small SJM HP provides a better hemodynamic performance than the standard 19 mm SJM. However, annular enlargement may be beneficial in patients with poor ejection fraction and severe ventricular hypertrophy.

Purification and properties of transketolase from pig liver. I. An attempt to resolve the enzyme into apoenzyme and cofactors.

Transketolase, sedoheptulose-7-phosphate: D-glyceraldehyde-3-phosphate glycolaldehyde-transferase [EC 2.2.1.1], was extracted from pig liver and purified 96-fold by ammonium sulfate fractionation, followed by column chromatography using DEAE-cellulose and a Sephadex G-200. Transketolase from pig liver was stable at pH 6.0 and above, whereas it was unstable at lower pH values. It could be resolved into apoenzyme and thiamine pyrophosphate in an acidic medium, in contrast to baker's or brewer's yeast transketolase which resolved in an alkaline solution. All the activity of pig liver transketolase was lost upon incubation at pH 5.0 for two hours even at 0 degrees C but about 40% of the original activity could be restored by the addition of excess thiamine pyrophosphate and CaCl2. Restoration of the activity was achieved effectively at pH 7.6-8.0.

Application of a shape memory alloy to hand splinting.

This paper describes new passive splints which have been developed using a shape memory alloy. The peculiar feature of the splints is that the way in which they change shape in use conforms to the stretching motion which it would be desirable to apply in certain conditions of deformity. The alloy consists of 55.66% by weight Nickel and 44.34% Titanium. The heat treatment of the alloy for memorising shape was implemented at 500 degrees C for one hour. This alloy was easily bent when cool, but the original shape was recovered on heating. It was used as the supporting structure of the reverse knuckle bender splint and the cock-up splint. The new splints could be easily attached to the deformed limb after cooling. The splints avoided the development of spasticity, because they gradually recovered their original shapes and corrected the deformities when the heat of the room or body heat warmed the splints. Since the shape memory alloy has the dual function of thermal sensor and kinetic power source it was a simple device. The splint was, as a result, small and smart. It was apparent from clinical use that the splint was easy to wear and could be worn with comfort for an extended period. The design of the splints and the fabrication process are described and their application is indicated.

[Pharmacokinetic and clinical studies on aztreonam in perinatal period].

Pharmacokinetic and clinical studies were carried out on aztreonam (AZT), a monobactam antibiotic with a high activity against Gram-negative bacteria. The results obtained are summarized as follows: 1. Following 2 g bolus intravenous injection, transfers of AZT to umbilical cord serum and amniotic fluid were found to be satisfactory. AZT level in amniotic fluid was higher than 1 micrograms/ml at 40 minutes after administration and it was at 3.7 micrograms/ml in 23.5 hours. 2. In the treatment of 9 patients with perinatal infections, clinical efficacies of AZT were judged excellent in 3 cases and good in 6 cases. 3. No side effects and abnormal laboratory findings due to the drug were observed in any case. These results indicate that AZT may be a useful antibiotic for the treatment of perinatal infections.

[Measurement of coefficient of variation of R-R interval in ECG for patients with impotence].

The coefficient of variation (CV = SD/mean x 100) of the R-R interval in electrocardiogram (ECG) was measured as an indication of parasympathetic nerve function in patients with impotence. Of 762 patients 104 (13.6%) had a CV value lower than 2.0. The factors which led to the low CV value were evident in 50 patients (48%), i.e. diabetes mellitus in 26, side effects by antiulcer, antidepressant or antihypertensive agent in 16, renal failure in 1, alcoholism in 2 and age over 70 years old in 4. The possible factors of the low CV value, such as neurogenic, thyroid, cardiovascular and endocrine disorders were found in 12 patients (11.5%). In the remaining 42 patients (40.4%), CV value was decreased by unknown factors. Measurement of CV of R-R interval in ECG was safe and useful as a screening test for patients with impotence to detect the dysfunction of the parasympathetic nerve system.

[Measurement of penile brachial index (PBI) in patients with impotence].

PBI was measured in 555 patients chosen at random from those who visited our impotence clinic between October 1984 and September 1986. Of 555 patients with impotence 29 (5.2%) showed a low PBI level of less than 0.6. On the basis of carefully taken history, risk factors causing the disturbance of penile blood flow were found in 13 (44.8%) of these 29 patients. They included diabetes mellitus, hypertension, surgery of pelvic organ, vertebral injury, vascular disorder of brain and gangliosympathectomy. Although penile angiography is necessary to make the definite diagnosis of vasculogenic impotence, hospitalization is usually required to perform the examination. Measurement of PBI is useful as a screening test to detect vasculogenic impotence at an outpatient clinic, because this examination is noninvasive and technically easy.

[Serum soluble interleukin-2 receptor levels in patients with renal cell carcinoma: a comparison of values before and after surgery].

This study was carried out in order to find out whether soluble interleukin II receptor (sIL-2R) levels were useful as a treatment biomarker in patients with renal cell carcinoma (RCC). The subjects consisted of 17 patients with RCC who had been scheduled for radical or partial nephrectomy. Serum levels of sIL-2R were measured before surgery and 1 and 3 months after surgery. We also analyzed the relationship of preoperative sIL-2R to pathologic TNM-stage, grading and presumptive tumor volume. The mean value of pre-operative sIL-2R in patients with RCC was 496.5 U/ml as compared with 302.7 U/ml in the control group (p = 0.056). Pre-operative sIL-2R values were 411.1 U/ml in stage I (n = 6), 481.4 U/ml in stage III (n = 11) and 1,330 U/ml in stage IV (n = 1). There was no significant difference between stage I and stage III. As compared with pathologic grading, pre-operative sIL-2R levels in patients with grade 2 were significantly higher than those with grade 1 (609.8 U/ml versus 288.7 U/ml, p = 0.016). There existed a significant correlation between preoperative sIL-2R and presumptive tumor volume (r = 0.61, p = 0.008). Three months after surgery, sIL-2R values were significantly higher than before surgery. Serum sIL-2R levels seemed to bear some relationship to the extent of disease in patients with RCC. Values of sIL-2R were significantly higher after than before surgery at least for a three-month postoperative period, suggesting a response to trauma of surgery. Further long term studies were required to clarify if sIL-2R could predict the progression of disease.

[A case report: disappearance of cancer cells confirmed by surgical resection after transcatheter hepatic artery embolization (TAE) for ruptured hepatocellular carcinoma].

The patient was a 74-year-old man. He had received medical treatment for liver cirrhosis (C types) and elevated AFP. Abdominal ultrasonography (US) revealed a 150 mm size tumor in the right lobe of the liver. After admission, anemia progressed rapidly, and we recognized bloody ascites by abdominal punction. Thus, diagnosis was a tumor rupture. Emergency angiography was performed. Farmorubicin and Lipiodol were injected, and complete TAE was added. After two TAE treatments CT-scan showed a remarkable decrement of the tumor and hypertrophy of the left lobe in the liver. Right lobectomy of the liver was then done because reserve function of the liver was good. Cancer cells changed into hyaline body and mecrotic focus. In the pathological examination of the extirpated sample, no viable tumor cells were detected.

[Long partial response (PR) in a case of multiple liver metastasis from colon cancer effectively treated by continuous hepatic intra-arterial infusion chemotherapy].

The patient was a 69-year-old man who had undergone a sigmoidectomy for cancer of the sigmoid colon on March 25, 1993. We detected the elevation of CEA after the operation. Computed tomography revealed multiple metastasis of the liver on September 3, 1996. After beginning 48-hour continuous hepatic arterial infusion using 5-FU 1,000 mg and Leucovorin 30 mg, we recognized a decrement of metastatic liver tumor. We could not detect cancer cells by needle biopsy for liver tumors on February 19, 1998. This case is maintaining good quality of life by hepatic artery infusion using 5-FU and Leucovorin, showing a long PR for about two years. We think that this case shows ideal clinical progress from chemotherapy for cancer of the digestive organs.

[Hepatocellular carcinoma following interferon therapy].

We experienced six patients with resected hepatocellular carcinoma (HCC) following interferon (IFN) therapy. Hepatitis virus C-RNA in polymerase chain reaction was positive in all patients prior to the IFN therapy. HCV-RNA became negative in two patients following IFN therapy, and was re-positive at the time of detection of HCC. In histological studies prior to the IFN therapy, pre-cirrhosis was diagnosed in four out of six patients and chronic active hepatitis 2B (CAH2B) in one according to the Europian classification. In non-cancerous portion of the liver, cirrhosis developed in five patients, and CAH2B in one. There was no significant correlation among the interval of HCC detection following IFN therapy, tumor size, tumor location, and histological findings. Patients should be carefully followed up by serum alpha fetoprotein levels or ultrasonography of the liver during and following IFN therapy.

[V gene repertoire and pathogenic autoantibodies].

The studies for autoantibody-associated V genes have failed to find any V gene which might be specific for pathogenic autoantibodies in humans; Namely, both normal subjects and patients have immunoglobulin V genes which can encode autoantibodies. Also single V gene can encode antibodies for both foreign antigens and autoantigens. However, some germline V genes such as V3-7 and VH4-21 are preferentially used for autoantibodies and may be regarded as prototype V genes for autoantibodies. Although somatic mutation in V genes is characteristic in IgG autoantibodies, 0-81 idiotype-positive IgM antibodies, which may be precursor B cells for pathogenic anti-DNA antibody also included many somatic mutations in VH genes, indicating an intrinsic abnormality in B cell development in SLE. Some studies also indicated an abnormal V gene repertoire in autoimmune states. These results may be attributed to dysregulation of autoantibody-associated B cell development.

[Experience of expandable metallic stent for tuberculosis bronchial stenosis].

A 41-year-old female who had suffered from a severe left main bronchial stenosis due to bronchial tuberculosis was treated by implantation of self-expandable metallic stent after dilating the stenosis by balloon catheter. After placing the stent symptoms such as dyspnea were disappeared completely. Four months later, the patient can tolerate to do jogging.

[Clinical experience of percutaneous transluminal angioplasty and expandable metallic stent placement for Budd-Chiari syndrome with massive thrombus in the inferior vena cava; report of a case].

A 72-year-old female who had suffered from lower extremity edema and liver cirrhosis due to Budd-Chiari syndrome with massive thrombus in IVC was treated by PTA and placement of self-expandable metallic stent. Thrombolysis therapy after PTA was very effective. Five months later, she had no clinical symptom due to IVC stenosis.