[Breast cancer].

Neoadjuvant chemotherapy (NAC) represents a new approach based on sound theoretical, pharmacokinetic, and experimental principles. The purpose of NAC is to improve control of the primary site by downstaging and to improve control of micrometastatic disease. NAC has been standard therapy in the management of locally advanced breast cancer. Patients with earlier stage breast cancer may also benefit from treatment with NAC. Recently some investigators have mentioned that NAC can be used instead of adjuvant chemotherapy and would be most appropriate for patients who wish to preserve their breast but who have tumors too large for breast conserving surgery. In this article, we reviewed the present status of NAC (indication, clinical response, pathologic response, survival, possibility of breast conservation, prognostic/predictive factors, neoadjuvant endocrine therapy) and discussed several unanswered questions on NAC (survival benefit, optimal number of treatment cycles, optimal regimens) and future direction. Combined modality therapy including NAC appears to provide excellent local control, the possibility of breast conservation, and, probably, an increased survival rate, at least for some subsets of patients. Furthermore, through sequential sampling, NAC provides indeed the opportunity to identify molecular mechanisms associated with pathologic response and to study the possibility to guide the choice for induction treatment and patient populations submitted to neoadjuvant chemotherapy.

Validity and reliability of single-item questions about physical activity.

The Japan Collaborative Cohort Study for Evaluation of Cancer Risk Sponsored by Monbusho (JACC Study) included in its self-administered questionnaires some single-item questions concerning physical activity. We examined the validity of the questions among 1,730 Japanese adults and the reliability of the questions among 1,075 Japanese adults. The validity of the sports and physical exercise questions was estimated by comparing the self-administered questionnaire responses with the time spent on the activity and the energy expenditure index for the previous 12-month period, elicited by the interviewing method used in the Japan Lifestyle Monitoring Study with a minor modification. The Spearman's rank correlation coefficients ranged from 0.43 to 0.60, showing moderate correlations. On the other hand, test-retest reliability was estimated by comparing the responses from two separate surveys conducted roughly one year apart. Weighted kappa coefficients of sports and physical exercise questions, classified according to sex and age, ranged from 0.39 to 0.56, showing moderate reliability; and those of a question about walking ranged from 0.25 to 0.39, showing fair reliability. We suggest that measuring physical activity level with these single-item questions may be appropriate for establishing baseline data that reflects long-term physical activity in a large-scale cohort study targeting lifestyle-related diseases.

Long-term treatment of ischemic dilated cardiomyopathy with continuous positive airway pressure.

An 81-year-old man with ischemic dilated cardiomyopathy complained of frequently awakening from sleep due to choking; subsequent polysomnography revealed Cheyne-Stokes respiration (CSR) with sleep apnea. With continuous positive airway pressure (CPAP) through a nasal mask, both the CSR and symptoms disappeared. After 6-12 months, chest X-ray and echocardiographic findings continued to improve without any change in pharmacological treatment. For three years, CPAP had been effective to eliminate CSR during sleep. Long-term CPAP treatment, which is rarely applied for congestive heart failure in Japan, is useful in alleviating the adverse effects of CSR and, thereby, maintaining a good quality of life in these patients.

[The role of daunorubicin in induction therapy for adult acute myeloid leukemia].

The relationship between the total dose of daunorubicin (DNR) in induction therapy and the treatment outcome were evaluated based upon individualized doses of DNR during induction therapy for patients with acute myeloid leukemia(AML). Ninety-two previously untreated adult AML patients admitted to our hospital were analyzed for the dose of DNR required for complete remission (CR), the CR rate, disease-free survival (DFS) and overall survival (OS). The induction therapy consisted of DNR (40 mg/m2/d, i.v., from D 1 until the marrow was hypoplastic), Ara-C, prednisolone, and/or 6-thioguanine. Eighty-three out of 92 patients were assessable. Sixty-three patients entered CR (76%), of whom 52 attained CR with the first course of induction therapy. The 10-year DFS and OS rates were 31.2% and 42.3%, respectively. The median total dose of DNR in the induction therapy was 280 mg/m2 (120-480 mg/m2), which was not influenced by initial WBC count, or FAB type. These results indicate that when the dose is linked to the observed tumor response, the optimal dose of DNR in the induction therapy is around 280 mg/m2 (40 mg/m2 x 7 times), which is higher than the conventional dose of 40-60 mg/m2 for 3 days. The higher dose of DNR in the induction therapy for adult AML should be selected when the feasibility of a new drug is evaluated in a randomized trial.

Relationship between Helicobacter pylori infection and smoking and drinking habits.

BACKGROUND: Helicobacter pylori is a major cause of various gastroduodenal diseases. Some risk factors related to H. pylori infection have been reported; however, studies on the relationship between H. pylori infection and smoking or drinking habits have given conflicting results. In the present study, these relationships were investigated by collecting sera and information from 8837 subjects. METHODS: Serum H. pylori immunoglobulin G antibody was measured by an enzyme-linked immunoassay. In addition to sex and age, information on smoking and drinking habits was collected by questionnaire. Age- and sex-adjusted odds ratios (95% confidence interval) of smoking and alcohol consumption were calculated for H. pylori seropositivity using logistic regression models. RESULTS: Current smokers had a 0.82 (0.74-0.91)-fold greater risk of H. pylori seropositivity than those who had never smoked. Current cigarette consumption showed a dose-dependently negative association with H. pylori seropositivity, and the association between smoking and H. pylori infection was strong in younger subjects. Current drinkers had a 0.88 (0.79-0.98)-fold greater risk of H. pylori seropositivity than those who had never drunk alcohol. The volume of alcohol consumed showed a negative association with H. pylori seropositivity. CONCLUSIONS: In the current study, smoking was negatively associated with H. pylori infection. The risk of H. pylori seropositivity decreased linearly with cigarette consumption per day. Increased gastric acidity in the stomach through smoking may be a cause of the dose-dependently negative association between H. pylori and smoking. Drinking was negatively and dose-dependently associated with H. pylori positivity, although the effect of drinking was weaker than that of smoking.

Insufficient diagnostic accuracy of imported serological kits for Helicobacter pylori infection in Japanese population.

Although there are many reports of the high diagnostic accuracy of commercially available serologic kits for Helicobacter pylori infection in Western countries, they rarely has been investigated in oriental population. Accordingly we examined their usefulness in 492 Japanese patients with dyspeptic symptoms. Diagnostic accuracy of 4 imported serologic kits (HEL-p TEST, HM CAP, G.A.P IgG, Helico G2) was investigated using the (13)C-urea breath test as the gold standard. When intermediate results were excluded, the sensitivity, specificity and accuracy of these serologic tests ranged from 88.6% to 97.8%, 67.9% to 85.9%, and 87.9% to 91.4%, respectively, which were comparable with reported median accuracy in the Western population. However, there were many intermediate results in these tests, ranging from 5.3% to 23.0%. Their usefulness seemed to be limited in our patient population because of the large number of intermediate results.

[Clinical outcome of catheter fragmentation and aspiration therapy in patients with acute pulmonary embolism].

The clinical usefulness of catheter fragmentation and aspiration therapy was studied in 8 patients with acute pulmonary embolism who received thrombolytic therapy using urokinase or tissue-type plasminogen activator (t-PA) (thrombolysis group) and 8 patients who underwent catheter fragmentation and aspiration therapy using a percutaneous transluminal coronary angioplasty (PTCA) guide catheter (catheter group). The patients were selected from 20 patients with a definite diagnosis of acute pulmonary embolism based on pulmonary arteriography and nuclear imaging. Urokinase (48 x 10(4) to 96 x 10(4) unit/day) or t-PA (12 x 10(6) unit/day) was administered intravenously for mean 4 days in the thrombolysis group. Pulmonary artery pressure was first measured using a Swan-Ganz catheter via the jugular vein or the femoral vein in the catheter group. Then, a PTCA guide catheter was advanced into the pulmonary artery, and the thrombus was disrupted repeatedly using a Radifocus wire, followed by manual aspiration. Subsequent treatment consisted of intravenous infusion of heparin (10,000 to 15,000 unit/day) and urokinase (24 x 10(4) to 48 x 10(4) unit/day) for mean 6 days. Partial revascularization was achieved in all patients in both groups. Five patients in the thrombolysis group died within 1 month due to respiratory failure, re-embolization, and/or hemorrhagic complications. One patient in the catheter group died of hemorrhagic shock. Pulmonary artery systolic pressure in the catheter group was significantly reduced from 47.4 to 26.5 mmHg (p < 0.01). Catheter treatment of acute pulmonary embolism associated with acute circulatory failure such as shock can lead to rapid hemodynamic improvement. In contrast, thrombolysis is an effective treatment, but bleeding problems are common and caution is required. Catheter fragmentation and aspiration therapy is effective for acute pulmonary embolism, is minimally invasive, and should be considered the treatment of first choice.

[Acute vincristine neurotoxicity in a non-Hodgkin's lymphoma patient with Charcot-Marie-Tooth disease].

A 44-year-old, previously healthy man with a diagnosis of non-Hodgkin's lymphoma (NHL, diffuse large B-cell type, stage IIA) was treated with combination chemotherapy including vincristine (VCR). After receiving a cumulative dose of VCR, he experienced rapid and marked weakening which progressed to quadriplegia and bulbar palsy. Prior to this therapy, the patient had no neurological problems, and his siblings were asymptomatic. Physical examination identified pes cavus (hollow foot), and electrodiagnostic studies showed markedly slower nerve conduction velocity of myelinated fibers, with abundant "onion bulb" formations. Chromosomal analysis detected 17p11.2-12 duplication, thus yielding a diagnosis of Charcot-Marie-Tooth (CMT) 1A. CMT disease is a familial neuromuscular disorder, and the incidence is approximately 1 in 2,500. We concluded that if CMT disease is diagnosed, vincristine should be avoided due to the potential severity of neurotoxicity to small doses.

[Prognostic significance of CD7 expression in adult acute myeloid leukemia].

To evaluate the prognostic significance of CD7 expression in de novo acute myeloid leukemia (AML), we studied 63 patients with AML who had been admitted to our hospital between September 1989 and January 1996. Even of the patients were later eliminated from the study (9 due to insufficient surface marker analyses, and 2 due to early death). The remaining 52 patients (median age: 42.5 years) were evaluated for morphologic subtype, immunophenotypic classification, complete remission (CR), disease-free survival (DFS) and overall survival (OS). All 52 patients were grouped by the French-American-British classification system: 10 as M1, 16 as M2, 11 as M3, 8 as M4, 5 as M5, and 2 as M6. Ten of the patients expressed CD7 on their leukemia cells (positive rate > or = 25) and were classified as CD7(+)AML, with morphological subtypes as follows: 3 as M1, 6 as M2, and 1 as M3. Thirty-three of the 42 patients with CD7 + AML (78.6%) and 6 of the 10 patients with CD7 + AML (40%) achieved CR. DFS and OS rates for the patients with CD7(+)AML were 22.1% and 35.4%, respectively; those for the CD7(+)AML patients were 53.3% and 44.4%, respectively. No significant differences in gender hematological findings, clinical manifestations such as hepatosplenomegaly, lymphadenopathy, or incidence of central nervous system involvement, CR rate, and DFS distinguished patients with CD7(+)AML from those with CD7(+)AML. These suggest that CD7 expression is unlikely to be a prognostic factor in AML.

Role of daunorubicin in the induction therapy for adult acute myeloid leukemia.

PURPOSE: To evaluate the relationship of total-dose of daunorubicin (DNR) to the induction therapy and treatment outcome, we have administered individualized doses of DNR during induction treatment to patients with acute myelogenous leukemia (AML). PATIENTS AND METHODS: Ninety-two previously untreated adult patients with AML who entered our hospital were analyzed for the dose of DNR required to achieve complete remission (CR), the CR rate, disease-free survival (DFS), and overall survival (OS). Induction therapy consisted of DNR 40 mg/m2 daily intravenously from day 1 until the marrow was hypoplastic, cytarabine (Ara-C), prednisolone (PRD), and/or 6-thioguanine (6-TG). RESULTS: Eighty-three of 92 patients with adult AML were assessable for this study. Sixty-three (76%) patients achieved CR. Fifty-two of 63 CR patients achieved the CR in the first course of induction therapy, and 11 patients required the second course of induction therapy. The 5-year and 10-year DFS rates were 31.2% and 5-year and 10-year OS rates were 45.1% and 42.3%, respectively. The median total dose of DNR in the induction therapy was 280 mg/m2 (120 to 480 mg/m2). DNR dose did not influence the response to therapy and was not influenced by the initial WBC count or French-American-British (FAB) system classification. CONCLUSION: These results indicated that when the dose was linked to observed tumor response, the optimal dose of DNR in the induction therapy was approximately 280 mg/m2 (40 mg/m2 for 7 days), which is greater than the conventional dose of 40 to 60 mg/m2 for 3 days.

[Phase I study of paclitaxel].

Paclitaxel, a novel antimicrotubule agent that enhances tubulin polymerization and microtubule stability, was administered as a 24-hour infusion in a phase I study. Twelve patients received 32 courses at 50, 100, 150, and 200 mg/m2. A premedication regimen of dexamethasone, diphenhydramine, and ranitidine was used to prevent the acute hypersensitivity reactions (HSRs). The dose-limiting factor was leukopenia (granulocytopenia) associated with Grade 4 infection. The maximum tolerated dose was 200 mg/m2. Other non-hematological effects included peripheral neuropathy, myalgia, alopecia, and elevations of transaminase and alkaline phosphatase. Severe HSRs were not observed. The paclitaxel plasma concentration declined with a half-life of 10.0 to 24.9 hours. Excretion into urine within 72 hours was in the range of 7.28 to 11.34% of paclitaxel dosage. Two patients with breast cancer at the 200 mg/m2 dose level had partial responses. The recommended dose of paclitaxel for phase II study, when administered as a 24-hour infusion, is considered to be 150 mg/m2 every 3 weeks.

Clinico-pathological study of the role of infarct expansion in patients with cardiac rupture following acute myocardial infarction.

The purpose of this study was to clarify whether the infarct expansion with cardiac rupture following acute myocardial infarction pathomorphologically differed from expansion without rupture. Eighteen autopsied patients with rupture were classified into acute phase (time between the onset of myocardial infarction and death < or = 36 h) and subacute phase (> 36 h). These patients were compared with 25 patients with no rupture using new parameters of expansion: radius index, cavity index, expansion area index and thinning-dilatation index of the left ventricle. In the acute phase, each parameter was significantly higher in the ruptured group than in the non-ruptured group (radius index: 0.49 +/- 0.28 vs 0.14 +/- 0.16, p < 0.005, cavity index: 0.21 +/- 0.09 vs 0.08 +/- 0.06, p < 0.005, expansion area index: 0.75 +/- 0.25 vs 0.34 +/- 0.23, p < 0.001, thinning-dilatation index: 2.89 +/- 1.31 vs 1.53 +/- 0.52, p < 0.001). However, in the subacute phase there were no differences in these parameters between the two groups. These data suggest that in the acute phase, but not the subacute phase, the degree of expansion and the proportion of expansion to infarcted area are associated with rupture.

Reliability of data obtained by radionuclide angiocardiography in follow-up studies with special reference to intra- and interobserver variations.

The reproducibility of the data obtained by radionuclide angiocardiography was studied in terms of the intra- and intervariations of three technicians. Three parameters were chosen: the left ventricular ejection fraction (LVEF), the 1/3 filling fraction (1/3FF), and the ratio of the time from end systole to the point of peak filling rate against the entire diastolic period (TRPFR). First, each technician studied an independent consecutive series of 40 patients for the initial analysis. The original data of each patient, composed of 26 frames for one beat, were stored on an optical disc for the intra- and intervariation studies. In this study, analysis of the volume curve was performed by using both 3rd order and 4th order Fourier series. The region of interest (ROI) for the left ventricle, which was set for the initial analysis, was recorded by Polaroid photography to be used as a reference for the later analyses for the variation studies. The least variation was noted in the LVEF not only for the intravariation study but also for the intervariation study, no matter which order of the Fourier series was used. However, the 3rd order Fourier series seemed to give better curve fitting to avoid fluctuation of the diastolic parameters. The results indicate that we can expect more steady and reliable information from LVEF than from the diastolic parameters, even when various technicians perform the follow-up study of a particular patient.

Two thrombin-activated Ca2+ channels in human platelets.

The regulation of extracellular Ca2+ entry into fura-2-loaded human platelets was examined following stimulation with thrombin. In the presence of external Ca2+, stimulation of platelets with thrombin resulted in a rapid increase, followed by a plateau, in intracellular Ca2+ concentration ([Ca2+]i). Pretreatment with wortmannin, a specific inhibitor of myosin light chain kinase, suppressed only the plateau phase and had no effect on the initial rapid increase in [Ca2+]i. In Ca(2+)-free EGTA buffer, thrombin induced a transient and relatively small increase in [Ca2+]i caused by Ca2+ release from internal stores. When Ca2+ was added subsequently to the Ca(2+)-free medium within 10 min after thrombin activation, a marked increase in [Ca2+]i was seen, reflecting thrombin-stimulated external Ca2+ entry. With the Ca(2+)-free medium, wortmannin did not affect either the Ca2+ mobilization from the internal stores or the rapid external Ca2+ entry at early time points (within 5 s) after thrombin stimulation, whereas it significantly inhibited Ca2+ entry when Ca2+ was added later (at 3 min). Wortmannin inhibition of this late Ca2+ entry and that of 20-kDa myosin light chain phosphorylation after thrombin stimulation were dose- and preincubation time-dependent and correlated well with each other. These results suggest that two different channels are responsible for Ca2+ entry in human platelets at the early and late phases of thrombin stimulation and that the channel responsible for the late phase of Ca2+ entry may be activated by a mechanism involving myosin light chain kinase.

[Phase I and pharmacokinetic study of SM-5887 by 5-day schedule].

Pharmacokinetics of SM-5887, a new totally synthetic anthracycline derivative, was studied in a phase I setting by 5-day schedule. The maximum tolerated dose was 25 mg/m2/d (total dose: 125 mg/m2/body) and the dose-limiting toxicity was myelosuppression which was consistent with the results of the phase I study by a single dose. In terms of subjective side effects, decreased nausea/vomiting and increased stomatitis were observed. In pharmacokinetic study, AUC of active form of SM-5887 increased on day 5 compared to that day 1. This result suggested that 5-day schedule of SM-5887 produced an accumulation of the active form. Five-day treatment schedule of SM-5887 seems to be more tolerable and further clinical study was recommended.

[High-dose thio-TEPA with escalating doses of epirubicin and autologous hematopoietic stem cell transplant for refractory cancers].

We studied high-dose chemotherapy with autologous hematopoietic stem cell transplant for patients (pts) with non-Hodgkin's lymphoma (NHL) and breast cancer (BC) refractory to conventional therapies. The conditioning regimen consisted of thio-TEPA 6 mg/kg/day for 3 consecutive days with escalating doses of epirubicin (EPI) in dose steps of 120, 150, 180 and 210 mg/m2 on day 1. Mucositis was dose limiting toxicity at 210 mg/m2 on this regimen, and the recommended dose of EPI was judged to be 180 mg/m2. No cardiotoxicities were observed. There were 3 with complete responses (CR), one partial response (PR) in pts with NHL, 3CR and 5PR in pts with BC. The median duration of response was 8 months (mos) and 4 mos, respectively. Hematological recovery was significantly earlier in the pts receiving both autologous bone marrow transplant (ABMT) and peripheral blood stem cell transplant (PBSCT) than ABMT alone. This approach made it possible to overcome the prolonged PLT recovery, which was one of the major problems on ABMT.

[A case report of corrected transposition of the great arteries without any associated defects in a 36-year-old man and the review of adult cases reported in Japan].

We report a case in a 36-year-old man of corrected transposion of the great arteries (CTGA) without any associated defects. We also review clinical characteristics and later complications of adult CTGA cases reported in Japan. The patients was referred to our hospital for further examination of the abnormal ECG found during regular medical check-up. His ECG showed left axis deviation, first degree AV block, abnormal Q waves in the left precordial leads, and disappearance of septal q waves in the left precordial leads. His exercise capacity was found to be more than 12 METS by treadmill exercise testing. His roentgenogram revealed an egg-shaped ventricle with normal CTR (45%). The following findings were obtained by two-dimensional echocardiogram and heart catheterization: 1) the functional left ventricle had the characteristics of the anatomical right ventricle, 2) The positions of the left and right atrioventricular valves were reversed, 3) Other cardiac anomalies such as VSD, pulmonary stenosis, tricuspid regurgitation (TR) were not proved. Therefore, he was diagnosed as having CTGA without any cardiac defects (SLL type). At present, with ages more than 15 years, 36 cases of CTGA without cardiac anomalies have been reported in Japan including this case. But most cases had significant TR. This case was the 7th reported case without the accompaniment of TR. Among 36 cases, TR was found in 71%, complete AV block in 20%, and congestive heart failure was noted in 45%. Prognosis of CTGA without any defects is dependent on the appearance of TR, advanced AV block, and congestive heart failure. As these later fatal complications are observed very often, it is important to detect the patient of CTGA accurately.(ABSTRACT TRUNCATED AT 250 WORDS)