What factor within the Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) criteria is most strongly correlated with trauma induced DIC? A retrospective study using thromboelastometry in a single center in Japan.

PURPOSE: The diagnostic criteria for disseminated intravascular coagulation (DIC) established by the Japanese Association for Acute Medicine (JAAM) is able to diagnose DIC accurately and promptly. The aim of this retrospective study is to evaluate the degree of association between each parameter of JAAM DIC criteria and the diagnosis of trauma induced DIC (T-DIC) utilizing thromboelastometry (ROTEM). METHODS: Trauma patients transported to our hospital with ROTEM performed in the emergency department between January 2013 and December 2015 were enrolled in this study. We evaluated (1) the characteristics of T-DIC, (2) the relationships between T-DIC and each parameter of the JAAM DIC criteria and (3) the diagnostic accuracies of each parameter for T-DIC by statistical measurement. RESULTS: All 72 patients (21 T-DIC and 51 control) were included in primary analysis. T-DIC was significantly related to younger age, more severe trauma scores, more cases of massive transfusions, and remarkable coagulation abnormality detected by standard coagulation tests. In the cases of T-DIC, ROTEM showed longer clotting time, lower acceleration, lower clot firmness, and inhibited fibrinolysis in EXTEM/INTEM. Within the JAAM DIC score, PT-INR ≥1.2 was the most accurate factor for T-DIC diagnosis; sensitivity 60.0%, specificity 100.0%, and accuracy 88.7%. PT-INR ≥1.2 was statistically correlated with the JAAM DIC score (p < 0.001, r = 0.709). The univariate analysis based on 1.2 of PT-INR indicated statistical differences in most categories of ROTEM, which is similar to analysis performed for the presence and absence of T-DIC. CONCLUSIONS: Among JAAM DIC criteria, the PT-INR ≥1.2 was the most accurate factor for both the diagnosis of T-DIC and the evaluation of its severity.

[Intermittent opening of a mechanical mitral valve prosthesis due to pannus formation; report of a case].

A 76-year-old woman with a history of severe mitral valve stenosis had undergone mitral valve replacement with a 27 mm St. Jude Medical (SJM) valve in 1991. Follow-up transthoracic echocardiography revealed an increase in the pressure gradient across the mitral prosthesis 16 years after the surgery. Prosthetic valve dysfunction was suspected, but transesophageal echocardiography and cineradiography failed to show mechanical valve dysfunction. Two years later, she presented with dyspnea on exertion and leg edema. Cineradiography revealed intermittent restriction of the opening of the mechanical valve leaflet approximately every 10 beats. Thus, we diagnosed intermittent prosthetic valve dysfunction and performed a reoperation. On inspection of the prosthesis, we observed semicircular pannus formation around the posterior leaflet in the ventricular side. It was considered that the pannus tissue had interfered with 1 leaflet opening of the mitral valve prosthesis, resulting in intermittent valve dysfunction. We replaced the prosthesis with a new 25 mm SJM valve. The patient was discharged after confirmation of normal prosthetic function.

Pharmacokinetics of 5-fluorouracil in elderly Japanese patients with cancer treated with S-1 (a combination of tegafur and dihydropyrimidine dehydrogenase inhibitor 5-chloro-2,4-dihydroxypyridine).

S-1 is an oral anticancer agent that combines tegafur, a prodrug of 5-fluorouracil (5-FU), and 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase. We examined the effects of aging on the pharmacokinetics of the components of S-1. The median area under the concentration-time curve (AUC) of active 5-FU did not significantly differ between 10 patients 75 years or older and 53 patients younger than 75 years (P = 0.598, Mann-Whitney U test). It is interesting to note that the median oral clearance of tegafur in patients 75 years or older was significantly lower than that in patients younger than 75 years (P = 0.011). Furthermore, the median AUC of CDHP was significantly higher in patients 75 years or older than in those younger than 75 years (P = 0.004). This effect was caused by reduced renal function in the elderly, because CDHP is excreted in the urine by glomerular filtration. The opposing effects of aging on the oral clearance of tegafur and the AUC of CDHP may offset each other, leading to unchanged systemic exposure of 5-FU.

Fixed dosing and pharmacokinetics of S-1 in Japanese cancer patients with large body surface areas.

BACKGROUND: S-1 is an oral anticancer agent that combines tegafur (FT) with 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate. The recommended initial dose of S-1 is 120 mg/day for patients with a body surface area (BSA) of > or =1.5 m(2) in Japan. METHODS: We examined the effects of using this fixed dose on the pharmacokinetics of FT, CDHP, and active 5-fluorouracil (5-FU) on the basis of actual BSA. The pharmacokinetics was compared between patients with a BSA of 1.5-1.75 m(2) and those with a BSA of > or =1.75 m(2). RESULTS: The median areas under the time-concentration curves (AUCs) of 5-FU and CDHP were significantly lower in patients with a BSA of > or =1.75 m(2) than in those with a BSA of 1.5-1.75 m(2) (P = 0.005 and 0.006, respectively; Mann-Whitney U-test). There was no difference between the groups in the median AUC of FT. CONCLUSION: Systemic exposure to 5-FU is significantly lower in Japanese cancer patients with a large BSA of >1.75 m(2) who received the recommended fixed dose of S-1.

Polymorphisms in VEGF and IL-8 predict tumor recurrence in stage III colon cancer.

BACKGROUND: Identifying molecular markers for tumor recurrence is critical in successfully selecting patients with stage III colon cancer who are more likely to benefit from adjuvant chemotherapy. The present study analyzed a subset of 10 polymorphisms within eight genes involved in the tumor angiogenesis pathway and their impact on prognosis in stage III colon cancer patients treated with adjuvant chemotherapy. PATIENTS AND METHODS: Blood samples were obtained from 125 patients with locally advanced colon cancer at University of Southern California medical facilities. DNA was extracted from peripheral blood and the genotypes were analyzed using PCR-restriction fragment length polymorphism and 5'-end [gamma-(33)P] ATP-labeled PCR protocols. RESULTS: Polymorphisms in vascular endothelial growth factor (VEGF) (C+936T; P = 0.003, log-rank test) and interleukin-8 (IL-8) (T-251A; P = 0.04, log-rank test) were independently associated with risk of recurrence in stage III colon cancer patients. In combined analysis, grouping alleles into favorable versus nonfavorable alleles, high expression variants of VEGF C+936T and IL-8 T-251A were associated with a higher likelihood of developing tumor recurrence (P < 0.001). CONCLUSION: High expression variants of VEGF C+936T and IL-8 T-251A were associated with shorter time to tumor recurrence, indicating that the analysis of angiogenesis-related gene polymorphisms may help to identify patient subgroups at high risk for tumor recurrence.

Chromoendoscopy using indigo carmine dye spraying with magnifying observation is the most reliable method for differential diagnosis between non-neoplastic and neoplastic colorectal lesions: a prospective study.

BACKGROUND AND AIMS: Differential diagnosis between non-neoplastic and neoplastic lesions is very important at colonoscopy, since removal or biopsy of non-neoplastic polyps wastes time and resources. We therefore conducted a prospective study to examine whether indigo carmine dye spraying with and without magnification is more reliable than the conventional method for differential diagnosis. PATIENTS AND METHODS: 122 patients with 206 lesions of 10 mm or smaller were recruited into this study. All lesions detected on colonoscopy were first diagnosed using the conventional view, then at chromoendoscopy using 0.2 % indigo carmine, and finally at chromoendoscopy with magnification. The diagnosis at each step were recorded consecutively. All lesions were finally categorized as neoplastic or non-neoplastic according to pit pattern; non-neoplastic lesions were biopsied for histological evaluation, and all the neoplastic ones were removed endoscopically. The accuracy rate of each type of endoscopic diagnosis was evaluated, using histological findings as reference. RESULTS: Histologically, 46 lesions (22 %) were non-neoplastic and 160 (78 %) were neoplastic. The overall diagnostic accuracies by conventional view, chromoendoscopy, and chromoendoscopy with magnification were 84.0 % (173/206), 89.3 % (184/206) and 95.6 % (197/206), respectively. CONCLUSION: Chromoendoscopy with magnification is the most reliable method for determining whether a colorectal lesion is non-neoplastic or neoplastic.

Comparison of the efficacy, toxicity, and pharmacokinetics of a uracil/tegafur (UFT) plus oral leucovorin (LV) regimen between Japanese and American patients with advanced colorectal cancer: joint United States and Japan study of UFT/LV.

PURPOSE: To compare the efficacy, toxicities, and pharmacokinetics of an oral regimen consisting of uracil/tegafur (UFT) and leucovorin (LV) between Japanese patients and patients in the United States with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: Forty-four Japanese patients and 45 patients in the United States were enrolled in concurrent nonrandomized phase II trials. UFT 300 mg/m2/d and leucovorin 75 mg/d were administered orally for 28 days followed by a 7-day rest period. The total daily dose of each drug was divided into three equal doses. Treatment was repeated every 5 weeks until disease progression. Blood samples for the pharmacokinetic study were obtained after the initial dose on day 1 of the first course. RESULTS: The response rate for the Japanese patients and the patients in the United States was 36.4% (95% CI, 22.4% to 52.2%) and 34.1% (95% CI, 20.5% to 49.9%), respectively. The only major toxicity was diarrhea, and other toxicities were mild in both populations. The incidence of grade 3 or higher diarrhea in the Japanese and Americans was 9% and 22%, respectively. Although the area under the curve and maximum concentration of fluorouracil were found to be slightly higher in the Japanese patients than the patients in the United States, and area under the curve-adjusted body surface area appeared to be comparable between the two groups. CONCLUSION: The efficacy and pharmacokinetic parameters of UFT and LV are comparable in Japanese and American patients; however, a difference in toxicity profile, specifically diarrhea, was noted. This oral regimen of UFT and LV is considered to have similar activity against metastatic colorectal cancer and to have acceptable toxicity in patients in both countries.

Phase I/II study of S-1 combined with cisplatin in patients with advanced gastric cancer.

A dose-escalation study of cisplatin (CDDP) combined with S-1, a new oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD), dose-limiting toxicities (DLTs), and objective response rate (RR) in advanced gastric cancer (AGC). S-1 was given orally at 40 mg m(-2) b.i.d. for 21 consecutive days following a 2-week rest. CDDP was planned to be given intravenously on day 8, at a dose of 60, 70, or 80 mg m(-2) depending on the DLT. Treatment was repeated every 5 weeks, unless disease progression was observed. In the phase I portion, the MTD of CDDP was presumed to be 70 mg m(-2), because 33.3% of patients (2/6) developed DLTs, mainly neutropenia. Therefore, the RD of CDDP was estimated as 60 mg m(-2). In the phase II portion, 19 patients including six patients of the RD phase I portion were evaluated. The median administered courses was four (range: 1-8). The incidences of severe (grades 3-4) haematological and nonhaematological toxicities were 15.8 and 26.3%, respectively, but all were manageable. The RR was 74% (14/19, 95% confidence interval: 54.9-90.6%), and the median survival day was 383. This regimen is considered to be active against AGC with acceptable toxicity.

Sesqui- and diterpenoids from the Japanese liverwort Jungermannia infusca.

Seven new cuparane-type (1-7), one new acorane-type (8), one new monocyclic-type (9), and one new prelacinane-type (10) sesquiterpenoid as well as two new clerodane-type (11, 12) and one new halimane-type (13) diterpenoid were isolated from the Japanese liverwort Jungermannia infusca, together with 12 known cuparane- (14-21) and aromadendrane-type (22) sesquiterpenoids and labdane- (23) and ent-kaurane-type (24) diterpenoids. The structures for 1-13 were determined using extensive NMR techniques and by chemical degradation and X-ray crystallographic analysis.

Retrospective study of hyponatremia in gastric cancer patients treated with a combination chemotherapy of 5-fluorouracil and cisplatin: a possible warning sign of severe hematological toxicities?

BACKGROUND: Some anti-neoplastic agents induce hyponatremia. The relationship between hyponatremia and other toxicities in gastric cancer patients treated with 5-fluorouracil and cisplatin (FP) was investigated retrospectively to clarify its clinical significance. METHODS: The subjects were 50 advanced gastric cancer patients treated with FP. Patients' performance status, oral intake, nausea/vomiting, diarrhea, fever, urine volume, presence of ascites or pleural effusion, laboratory data and administration of diuretics, corticosteroid and contents and volume of hydration before and during the first 5 days after chemotherapy were reviewed. RESULTS: The serum sodium level decreased after initiation of chemotherapy in all patients and the lowest level (nadir) was most frequently observed on day 8 (range, days 2-14), which preceded hematological toxicities. In 10 patients (20%) the nadir of serum sodium was lower than 125 mEq/l. We classified these 10 patients as a low-sodium group and the others into a normal-sodium group. Six (60%) and seven (70%) of the 10 patients in the low-sodium group had complications with grade 3 or 4 leukopenia and thrombocytopenia, whereas only one (3%) and two (5%) were seen in the normal-sodium group (p < 0.0001). Stomatitis and diarrhea were also slightly more severe in the former than the latter group. With respect to sensitivity and probability, receiver operating characteristic curves showed the nadir ((> or = ) or <125 mEq/l) of the serum sodium level was the best marker for both leukopenia and thrombocytopenia. CONCLUSION: Hyponatremia after initiation of chemotherapy with FP may be a warning sign of subsequent severe hematological toxicity.

Preferential acetazolamide-induced vasodilation based on vessel size and organ: confirmation of peripheral vasodilation with use of colored microspheres.

When carbonic anhydrase activity decreases, the regional blood flow (rBF) in organs increases as hypercapnia develops. However, the effects of acetazolamide (AZ)-induced vasodilation have not been estimated with respect to vessel size and organs. The aim of this study was to determine the diameter of the capillaries in various organs that respond to inhibition of carbonic anhydrase activity by AZ. White rabbits were anesthetized with urethane and ketamine and infused with AZ. While the systolic blood pressure (SBP), pH, hemoglobin concentration, and base excess did not change, the partial pressure of arterial oxygen (PaO2) increased significantly and the partial pressure of arterial carbon dioxide (PaCO2) decreased significantly with AZ. The rBF was calculated by using 3 different sizes (15, 25, and 50 microm) of colored microspheres (CM). The rBF measured with 15 microm CM in the brain, kidneys, and liver increased in response to AZ, and the rBF in these organs was different with the different sizes of CM. However, the rBF calculated by using the different sizes of CM in the stomach and abdominal muscle did not change after the administration of AZ. The AZ-induced vasodilation occurred in all sizes of vessels in the liver, in the small and medium-sized vessels in kidneys, and in the larger capillaries in the brain.

seco-Cuparane-type sesquiterpenoid from the Japanese liverwort Jungermannia infusca.

A 2,3-seco-cuparane-type sesquiterpenoid and the previously known barbatane-type sesqui- and ent-kaurane-type diterpenoids were isolated from the Japanese liverwort Jungermannia infusca (Mitt.) Steph. The structure of the 2,3-seco-cuparane-type sesquiterpenoid was determined by NMR spectroscopic analyses.

Sesqui- and diterpenoids from two Japanese and three European liverworts.

A new peroxy muurolane-type sesquiterpenoid was isolated from the ether extract of the Belgium liverwort Scapania undulata, together with three known ent-muurolanes. A new lepidozane-type sesquiterpenoid was isolated from the Japanese Porella subobtusa together with a known santalane- and two africane-type sesquiterpenoids. All structures were determined by means of NMR spectroscopic techniques. The chemosystematics of each species are discussed.

Highly elevated ultraviolet-induced mutation frequency in isolated Chinese hamster cell lines defective in nucleotide excision repair and mismatch repair proteins.

We have isolated N-methyl-N'-nitro-N-nitrosoguanidine-resistant cell lines from 43-3B Chinese hamster ovary cells, which are deficient in the ERCC1 gene involved in nucleotide excision repair. By Western blotting analysis, we found cell lines that are deficient or decreased in the amount of MSH6, or PMS2, or MSH2 proteins. Cell extracts of these cell lines show reduced efficiency of G:T mismatch repair activity. Compared with 43-3B, these cell lines exhibit highly elevated UV-induced mutation rates, indicating that mammalian mismatch repair can suppress UV-induced mutagenesis and may play a role in the fidelity of DNA replication at the sites of UV damage.

A new halimane-type diterpenoid from the liverwort Jungermannia infusca.

The isolation of 1(10)-halimadien-13xi-ol (1), a new diterpenoid from Jungermannia infusca, is reported.

Sequential methotrexate and 5-fluorouracil therapy for gastric cancer patients with peritoneal dissemination: a retrospective study.

BACKGROUND: Most gastric cancer patients with peritoneal dissemination have been excluded from clinical studies because they usually have no measurable lesions. They also have a high risk of toxicity because of complications such as intestinal obstruction and ascites. We conducted a retrospective analysis to evaluate the efficacy and feasibility of sequential methotrexate (MTX) and 5-flurorouracil (5FU) therapy for this population. METHODS: This analysis was based on 56 consecutive chemotherapy-naive patients with confirmed peritoneal dissemination of gastric cancer who were being treated with sequential MTX/5FU. The therapy comprised a weekly schedule of MTX 100 mg/m2, given as a bolus infusion 3 h prior to a bolus infusion of 5FU 600 mg/m2. Leucovorin 10mg/m2 was administered six times, every 6h, starting 24h after MTX administration. RESULTS: Evidence of peritoneal dissemination was confirmed by laparotomy in 16 patients, by cytologic examination of ascites in 11 patients, and by clinical imaging in 29 patients (15 with ascites, 13 with intestinal obstruction; in 10 of the 29 patients, detection was by barium enema or computed tomography [CT] scan). Neutropenia of grade 3 or worse and anemia were observed in 8 (14%) and 10 (18%) of the 56 patients, respectively. There was one treatment-related death due to neutropenic sepsis. Of the 26 patients with measurable lesions, 9 showed a response (36%). The median survival time and median time to treatment failure were 259 days and 167 days, respectively. Objective improvement of ascites was seen in 13 of 26 patients (50%), including 5 with showed complete disappearance of ascites. Seven of the 15 patients (47%) with intestinal obstruction showed resolution, and 8 of the 21 patients (38%) who needed nutritional support before the treatment were free of that support for a median duration of 220 days after the completion of the treatment. Forty-seven of the 56 patients (84%) could be treated at outpatient clinics. CONCLUSIONS: This regimen may be of clinical benefit for patients with peritoneal dissemination of gastric cancer.

Combination chemotherapy of irinotecan plus cisplatin for advanced gastric cancer: efficacy and feasibility in clinical practice.

BACKGROUND: A previous phase II study showed that a combination of irinotecan (CPT-11) with cisplatin (CDDP) was effective for advanced gastric cancers, but was associated with substantial neutropenia and diarrhea. The aim of this retrospective study was to evaluate the efficacy and feasibility of the combination in clinical practice. METHODS: The subjects comprised 65 patients with advanced gastric cancer treated with CPT-11 (70mg/m2, day 1, day 15) and CDDP (80mg/m2, day 1) as first-line chemotherapy between April 1993 and March 1999. Patient backgrounds, response rates, response durations, times to progression, and survival rates were investigated retrospectively. RESULTS: The overall response rate and the response rates for measurable metastatic lesions and primary sites were 43% (28/65), 48% (31/64), and 24% (10/42). Leucopenia of grade 4 and diarrhea of grade 3 or 4 were observed in 6 (9%) and 5 (8%) patients, respectively. Among the 19 patients with peritoneal metastasis, leucopenia of grade 4 and diarrhea of grade 3 or 4 were observed in only 1 of the 18 patients who received sufficient oral intake (6%). There were no treatment-related or early deaths within 30 days from the last treatment day. The median survival times of all patients, patients with an intestinal type of adenocarcinoma, and patients with a diffuse type were 365, 472, and 291 days, respectively. Multivariate analysis showed that the histological type of cancer was a significant independent prognostic factor (P = 0.0169). CONCLUSION: This retrospective study confirmed the efficacy and feasibility of this combination therapy in clinical practice.

A case of inoperable esophageal carcinoma with hepatic and nodal metastases which showed a long-term survival after chemoradiotherapy including nedaplatin.

We report a case of metastatic esophageal carcinoma successfully treated with chemoradiotherapy. A 61-year-old man, diagnosed as suffering from advanced esophageal carcinoma with liver and lymph node metastases, was treated with a combination of nedaplatin (90 mg/m2/day, 1 h drip infusion, day 1), 5-fluorouracil (800 mg/m2/day, continuous infusion, days 1-5), and radiotherapy (2 Gy/day, days 1-5, 8-12 and 15-19). The cycle was repeated twice every 5 weeks from July 2, 1997. He achieved a complete response 1 month after finishing two courses of chemoradiotherapy followed by an additional three courses of chemotherapy without radiation. Seven months after the completion of radiotherapy, pericardial effusion with negative cytology was recognized. The effusion was treated by pericardiocentesis and drainage for several days. After drainage, the effusion could be easily managed with diuretics. This patient is still alive with no evidence of disease more than 2.5 years after the initiation of the treatment.

Clerodane-type diterpenoids from the japanese liverwort Jungermannia infusca (Mitt.) Steph.

Three new clerodane-type diterpenoids have been isolated from the Japanese liverwort Jungermannia infusca (Mitt.) Steph., together with previously known compounds, nine clerodane- and four labdane-type diterpenoids, and 5-tocopherol. The structures of the new compounds were confirmed by 2D NMR experiments and X-ray crystallographic analysis.