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PURPOSE/AIM: 1. To review the sonographic criteria of axillary lymph node status in breast cancer patients. 2. To understand imaging pathologic correlations that the false-negative cases of axillary ultrasonography. CONTENT ORGANIZATION: The sonographic criteria, the accuracy of sonographic axillary ultrasonography, imaging pathologic correlations in false-negative cases, measurement of largest malignant focus size in lymph node, classification of ratio of malignant focus size, ratio of micro metastasis. SUMMARY: 1. Recently, lymph node evaluation that using serial section and immunohistochemical stains makes it difficult to detect imaging modalities. 2. Ultrasonography is limited how to detect the example of sentinel lymph node biopsy non-indications.

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This study has been initiated to evaluate the safety, clinical and pathologic response as well as the relation of response (pCR or non-pCR) and survival (overall and relapse-free) of fluorouracil, epirubicin and cyclophosphamide (FEC) followed by docetaxel (DOC) as preoperative chemotherapy in patients with operable breast cancer. Japanese patients with primary breast cancer, Tlc-3N0M0 or T1-3NIM0, age 20-60, PS 0-1 were included in this study. Preoperative chemotherapy consisted of 4 cycles of FEC (500 mg/m(2), 100 mg/m(2), 500 mg/m(2)) every 3 weeks followed by 4 cycles of DOC (75 mg/m(2)) every 3 weeks. Since June 2002, 200 patients were enrolled in this study, and the time of this interim analysis, 80 patients were evaluable for safety and clinical efficacy. The overall clinical response rate was 71.4% (14% CR, 44% PR, 42% SD/PD), and the only G3,4 toxicities, neutropenia and febrile neutropenia were observed in 54% and 14% of patients, respectively. Eighty nine patients were evaluable for pathologic response by central review. Pathologic response was evaluated among invasive tumors on multiple cross-section specimens based on a modified version of the Japanese grading system for Japanese Breast Cancer Society. The pathologic response rate was 17%. In this ongoing trial, FEC followed by DOC was active and well tolerated.

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The objective of this study was to evaluate the different profiles of serum lipids resulting from the administration of selective estrogen receptor modulators (SERMs). Postmenopausal primary breast cancer patients (n = 197) with node-negative, hormone receptor-positive who were treated at our department or in other related medical institutions from April 1997 through March 2001 were given adjuvant therapy. The adjuvant therapy included 1 year's administration of tamoxifen (TAM) 20 mg or toremifene (TOR) 40 mg. The profiles of serum lipids such as total cholesterol (TC), high-density lipoprotein cholesterol (HDL) and triglyceride (TG) were observed. After 1 year administration TC had significantly decreased (p < 0.001) both in the TAM group and the TOR group, but no significant difference was found between these groups (p = 0.249). HDL had significantly decreased in the TAM group (p < 0.001), while it had significantly increased in the TOR group (p < 0.001), and a significant difference was found between the groups (p < 0.001). TG had significantly increased in the TAM group (p < 0.001) but significantly decreased in the TOR group (p < 0.001). The medication was switched in those who still had abnormal lipid metabolism and given to them for another year. After 1 year from the crossover TC and HDL had increased to the levels of before administration (p < 0.001) and TG had decreased in those (n = 57) whose medication was switched from TAM to TOR. While TC had decreased and TG had increased in those (n = 23) whose medication was switched from TOR to TAM (p < 0.001). The above findings have suggested that TOR provides better profiles of lipid metabolism than TAM.

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BACKGROUND: Mammary ductoscopy (mammoscopy) is an ideal diagnostic method for intraductal lesions. The usefulness of mammoscopy for intraductal lesions was evaluated. METHODS: Mammoscopy was performed in 315 cases with nipple discharge. The mammoscopic findings of 46 breast cancer cases (47 lesions) and 109 intraductal papilloma cases (119 lesions) were compared with pathological findings. RESULTS: Carcinoma was recognized by mammoscopy in 38 of 47 lesions (80.9%). Intraductal masses were detected by mammoscopy in 115 of 119 intraductal papilloma lesions. The shape of the mass was classified as hemispheric, papillary, or flat protrusion. The hemispheric and papillary shapes were most common in cases of intraductal papilloma and the flat protrusion type was most common in cases of carcinoma. The amount of material collected by intraductal biopsy under mammoscopic observation was smaller in carcinoma than in intraductal papilloma because the carcinoma lesions were usually located in peripheral duct-lobular units and had weak tissue cohesion compared with that of intraductal papilloma. Of 133 intraductal biopsies performed for 69 intraductal papillomas, 17 biopsies yielded material insufficient for diagnosis in. The effectiveness of treatment by intraductal biopsy was recognized in 38 of 46 intraductal papillomas in which clinical follow-up continued for more than two years (82.6%). The therapeutic results of biopsy were poor in cases of multiple intraductal masses in multiple duct-lobular units. CONCLUSIONS: Mammoscopy contributes not only the diagnosis in cases of nipple discharge, but is also of benefit in the treatment of intraductal papilloma.

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A 62-year-old woman who underwent standard radical mastectomy for left breast cancer developed pleural and pulmonary metastases 16 years later. She complained of slight dyspnea, and computed tomography of the chest revealed a tumor with marked pleural effusion. Her serum level of carcinoembryonic antigen was also increased (49 ng/ml). Systemic chemotherapy with cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) was performed, but she did not show a marked response to CAF therapy. Therefore, she was orally administered UFT and CPA for 5 consecutive days followed by 2 drug-free days. Pleural disseminated foci and a lung tumor were reduced in size on chest CT and the CEA level was decreased within the normal limit. Recently, it was reported that UFT demonstrated significant antiangiogenic activity. This effect may play an important role in the efficacy seen in this patient.

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Two patients with malignancy-associated hypercalcemia from bone metastases of breast cancer, accompanied by consciousness disturbance, were treated by a combination therapy of pamidronate and salmon calcitonin. The cause of the hypercalcemia in both cases was thought to be expanded bone metastases, which induced a local osteolytic hypercalcemia (LOH). In the end, this regimen could not control the growth of the metastatic tumor, but it produced a more rapid and prolonged decrease in serum calcium level than a single agent, and resulted in lessened consciousness disturbance without adverse effects. Hypercalcemia is a life-threatening paraneoplastic syndrome which requires urgent medical treatment, since malignant hypercalcemia progresses very rapidly and induces several severe complications. In conclusion, this combination therapy was extremely effective for consciousness disturbance accompanying hypercalcemia due to widespread bone metastases of cancer.

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A 48-year-old woman who underwent breast-conserving therapy for left breast cancer developed bone, pleural, and liver metastases with local recurrence. The result was an improvement in each image with a marked improvement as seen by elevated tumor marker levels, with treatment by MPA (800 mg/day p.o.) and intermittent low-dose chemotherapy with hepatic arterial infusion. The side effects were acceptable. Normalization of imagings and an improvement in tumor markers continued for two years. Thus, in spite of being a palliative treatment, hepatic arterial infusion chemotherapy for liver metastasis from breast cancer might lead to prolongation of survival because of the improvement of other metastases due to the increased passage effect with MPA.

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A 47-year-old female underwent mastectomy after neo-adjuvant chemotherapy including an anthracycline agent for advanced breast cancer. She developed a pleural metastasis on 16 months later, which was refractory to intrathoracic cisplatinum administration and intravenous Docetaxel therapy. Brain metastases were also found. We therefore treated her with whole brain radiation therapy and oral chemotherapy with 5'-DFUR and cyclophosphamide. This combination therapy produced a marked decrease in each metastasis. The adverse effects were not remarkable. This regimen may play an important role not only from the standpoint of its effectiveness against tumor growth but also the quality of life of the patient.

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A 43-year-old female underwent muscle preserving mastectomy with 6 cycles of adjuvant CMF chemotherapy for breast cancer. She developed multiple lung metastases 16 months later. The metastases were refractory to 3 cycles of CAF administration, and worsened (PD). We therefore added high-dose toremifene to her treatment. This combination therapy brought a marked decrease in the lung metastases. After 9 cycles of CAF with high-dose toremifene therapy, lung metastatic findings had almost disappeared from her chest X-ray. Following this treatment, UFT and toremifene were orally administered for maintenance therapy. Thirty-two months later at present, no increase in these lesions has been observed. High-dose antiestrogen drugs have the potential to inhibit P-glycoprotein. The combination of high-dose toremifene with CAF is potentially effective against ADM-resistant breast cancer.

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Antioxidants have been proposed to have antiatherogenic potential by their inhibition of low density lipoprotein (LDL) oxidation. Here, we report an antioxidant, BO-653 (2,3-dihydro-5-hydroxy-2, 2-dipentyl-4,6-di-tert-butylbenzofuran), designed to exhibit antioxidative potency comparable to that of alpha-tocopherol, but yet possess a high degree of lipophilicity comparable to that of probucol. BO-653 exhibits a high affinity for LDL and is well distributed in aortic vessels in vivo. In atherosclerosis models of rabbits and mice, BO-653 has been shown to be able to suppress the formation of atherosclerotic lesions without untoward side effects. Specifically, there was no reduction of high density lipoprotein levels. This antioxidant provides additional evidence in support of the oxidized-LDL hypothesis, and itself is a promising candidate antioxidant for clinical use.

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BACKGROUND: Clustered microcalcifications are important for the detection of breast carcinomas, but few reports have described chronological changes of the microcalcifications. METHODS: The mammographic features of 18 breast cancer cases for which previous survey films were available and in which clustered microcalcifications with no tumor shadows were recognized at diagnosis were studied. Chronological changeswere analyzed by measuring the increase in the length of areas containing calcifications and the diameters of microcalcifications on mammograms using computerized image analysis. RESULTS: Chronological changes in the length of areas of microcalcifications were classified into two types by simple linear regression. Fast increase was common in the comedo type of carcinoma and slow increase was common in the non-comedo type. Three of nine cases that received follow-up examinations on two or more occasions eventually changed from slow type to fast type, and the distributionpattern of diameters of microcalcifications also changed from non-comedo type to comedo type. A follow-up study of 48 cases with a cluster of fewer than five extremely fine calcifications revealed breast carcinoma in 7 patients within 5 years. CONCLUSION: The increase of microcalcifications was generally fast in comedotype and slow in non-comedo type lesions. An increase in the extent of microcalcification was seen occasionally during the last period between follow-up examinations in mixed type tumors, indicating a conversion of the intraductal component to a more malignant grade.

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To explore the structural basis required for the holoenzyme formation of cAMP-dependent protein kinase, we have prepared rabbit anti-peptide antibodies that can block the holoenzyme formation without affecting the catalytic activity of the enzyme. The antibodies were raised against a specific site in the catalytic (C)-subunit, termed IDA (Inter-DFG-APE) region, which lies between the kinase subdomains VII and VIII. Although the C-subunit immunoprecipitated with anti-IDA antibodies could not form a stable complex with regulatory (R)-subunit, it was still susceptible to inhibition by the R-subunit or by PKI, a specific inhibitor peptide containing a pseudosubstrate site. These results indicate that there exists an IDA region-mediated interaction between the R- and C-subunits, which is distinct from that mediated through the substrate site and substrate binding site. In accordance with this idea, association of synthetic IDA peptides with the R-subunit was directly demonstrated by resonance mirror analysis. The calculated association constants of IDA peptides were high enough to suggest a possible involvement of the IDA region in the initial step of holoenzyme formation.

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The first report of external supravesical hernia was made by Astley Cooper in 1804, but it is so rare that we could not find any case reported in Japan. Here we report a case of external supravesical hernia in a male who had bladder cancer. This hernia was reported to be caused by fragility induced by operation or radiotherapy. It can be confused with inguinal direct hernia because it is not considered in the differential diagnosis. Findings such as a palpable hernia sack and the orifice can enable correct diagnosis. Surgical treatment is the only treatment of choice for this disorder.

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A 55-year-old female was admitted for right breast tumor with multiple bilateral lung metastases. Modified radical mastectomy (Auchincloss method) was carried out. And the combination chemoendocrine therapy was undertaken using CPA 100 mg p.o. days 1-18, THP 40 mg i.v. days 1, 8, 5-FU 500 mg i.v. days 1, 8 and MPA 1,200 mg p.o. daily. One month later, the lung metastases completely disappeared on chest CT gram. Nine courses of chemotherapy with the same drugs were undertaken intravenously every four weeks. This therapy has been continuously effective for one and half years now. These results suggested the importance of a severe adjuvant therapy for the initial phase of advanced breast cancer.

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Protein kinase C (PKC) was partially purified from Xenopus laevis oocytes by ammonium sulfate fractionation followed by DEAE-cellulose and hydroxyapatite column chromatography. In the latter chromatography, two distinct PKC activities were identified. Both PKC fractions contained an 80 kDa protein which was recognized by three antisera raised against the conserved regions of mammalian PKC. However, specific antisera against alpha, beta I, beta II, and gamma-subspecies of rat PKC did not recognize the protein. Kinetic properties of the Xenopus PKCs were very similar to those of the rat alpha PKC, and only a subtle difference was found in the mode of activation by arachidonic acid. When oocytes were treated with the tumor promoter, phorbol 12-myristate 13-acetate, one of the Xenopus PKCs was found to disappear very rapidly, while the other remained unchanged up to 2 hr.

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Low molecular weight urokinase (LMW-UK) was coupled to the heavy chain of plasmin to make it able to bind to fibrin. The purified conjugate (PHC-UK conjugate), which consisted of equimolar concentrations of each starting material had a molecular weight of 93,600, bound tightly to fibrin-monomer-Sepharose and was not washed off with 1 M NaCl, but was eluted specifically with epsilon-amino caproic acid. The conjugate showed higher fibrinolytic activity than HMW-UK. A control conjugate prepared by coupling human serum albumin to LMW-UK (HSA-UK conjugate) showed the same fibrinolytic activity as HMW-UK. The half-lives of these two conjugates in rabbits were about 3 times that of HMW-UK. In an experimental pulmonary embolism model in rabbits, the PHC-UK conjugate showed about 10 times higher thrombolytic activity than HMW-UK, while the HSA-UK conjugate showed similar thrombolytic activity as HMW-UK, and moreover caused severe systemic fibrinogen breakdown. Thus the significant increase in thrombolytic activity after injection of PHC-UK conjugate into rabbits may be due to its newly acquired fibrin binding activity, and not to increase in its half-life. It is concluded that the PHC-UK conjugate may be useful in treatment of thrombosis.

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A complement inhibitor, K-76, was isolated and purified from the culture supernatant of a fungus, Stachybotrys complementi, nov. sp. K-76, isolated from soil of Ishigaki Island, Okinawa. K-76 is a sesquiterpene compound and it can be oxidized to a monocarboxylic derivative (K-76 COOH), the sodium salt of which is very soluble and much less toxic than K-76. K-76 and K-76 COOH both inhibited complement activation by either the classical or alternative pathway. They inhibited generation of the factor chemotactic to human polymorphonuclear leukocytes from human serum by aggregated immunoglobulin. When sensitized erythrocytes were treated with complement in the presence of K-76 COOH, the resulting unlysed cells were found to be in the state of EACl, 4b, 2a, 3b. Thus K-76 COOH is considered to block mainly the C5 intermediate step. K-76 COOH did not inhibit any proteases or esterases tested, except when tested at high concentration.

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