Mikihiro Kusama

Ipsilateral breast tumor recurrence (IBTR) after breast-conserving treatment for early breast cancer : Risk factors and impact on distant metastases

The clinical features of ipsilateral breast tumor recurrence (IBTR) after breast conserving therapy (BCT) for early stage breast cancer were analyzed from long‐term follow‐up of BCT in Japan. The purpose of this study was to clarify risk factors of IBTR and the impact of IBTR on development of distant metastases in this ethnic group.

Mammary ductoscopy for diagnosis and treatment of intraductal lesions of the breast

BackgroundMammary ductoscopy (mammoscopy) is an ideal diagnostic method for intraductal lesions. The usefulness of mammoscopy for intraductal lesions was evaluated.MethodsMammoscopy 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.ResultsCarcinoma 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 ductlobular 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.ConclusionsMammoscopy contributes not only the diagnosis in cases of nipple discharge, but is also of benefit in the treatment of intraductal papilloma.

Effects of toremifene (TOR) and tamoxifen (TAM) on serum lipids in postmenopausal patients with breast cancer.

This study clarified the difference in the effects on serum lipids between toremifene (TOR) and tamoxifen (TAM). To remove influencing factors, we investigated adjuvant therapy for hormone receptor-positive patients with breast cancer without lymph node metastasis. The subjects were 65 patients who were enrolled in a multicenter randomized comparative study between April 1997 and March 2001. As adjuvant therapy, 20 mg of TAM or 40 mg of TOR was administered for 1 year. The levels of triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-1 (Apo A-1), apolipoprotein A(Apo B), and lipoprotein a (Lp(a)) were measured prior to administration and 3, 6, and 12 months after the start of administration. TC, LDL-C, Lp(a) and Apo B significantly decreased from the third month of administration compared with values before the start of administration in both the TOR and TAM groups. HDL-C significantly increased from the third month only in the TOR group. TG significantly increased in the TAM group but significantly decreased in the TOR group in the 12th month of administration. When these two groups were compared, HDL-C was significantly higher ( p < 0.01) and TG was significantly lower ( p < 0.01) in the TOR group in the 12th month. Improvement of abnormal values of TG, HDL-C and LDL-C was better in the TOR group than in the TAM group after administration for 12 months. The effect on lipid metabolism showed different profiles between the two selective estrogen receptor modulators (SERMs), and TOR gave better results than TAM.

Crossover trial for lipid abnormality in postmenopausal breast cancer patients during selective estrogen receptor modulators (SERMs) administrations.

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 years 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.

A case control study on risk factors involved in inflammatory breast recurrence after breast-conserving surgery

Recurrence that poses the biggest problem after breast-conserving surgery is local recurrence. Particularly, in the case of inflammatory breast recurrence which is rare but has a specific pathologic nature, it is important to elucidate the pathology and risk factors and to consider appropriate countermeasures. In the present study, we classified 133 cases of recurrence following breast-conserving surgery, collected from 18 key hospitals/institutes in Japan. Recurrence types were divided into three groups, namely, inflammatory breast recurrence, noninflammatory breast recurrence and distant metastasis only, and the risk factors involved in recurrence were investigated by the case control study allotting 2 controls to each case. The study population consisted of 9 cases of the inflammatory type, 64 cases of the noninflammatory type and 60 cases of distant metastasis. The significant risk factor for inflammatory breast recurrence was positive lymph node metastasis, which was significantly more frequent in lymphatic invasion-positive cases unlike in the distant metastasis group. The positive surgical margin and nonradiation therapy which have been shown to be significant risk factors for noninflammatory breast recurrence were entirely unrelated with inflammatory breast recurrence. In addition, the inflammatory-type recurrence time was as short as about 12 months irrespective of whether radiation therapy was performed or not. The inflammatory type was accompanied with local wide extension (cancerous embolus of the dermal lymphatic vessels), and distant metastasis (lymphangitis carcinomatosa) at the time of recurrence, and further surgery was impossible in most cases, with a significantly poorer prognosis than the other recurrence types. These findings suggest that this recurrence corresponds to the so-called ‘occult’ case of primary inflammatory breast carcinoma. We think it important to predict this recurrence by close pathological examination, particularly in patients with lymph node metastasis, and to consider appropriate measures.

Evaluation of sensitivity to 5-FU on the basis of thymidylate synthase (TS)/dihydropyrimidine dehydrogenase(DPD) activity and chromosomal analysis in micro tissue specimens of breast cancer

BackgroundPreoperative assessment of the anticancer drug sensitivity of tumors plays an important role in the selection of therapy. If evaluation of the 5-FU sensitivity of microtissue specimens obtained by techniques such as core needle biopsy could be performed, the addition of fluorouracil to adriamycin and cyclophosphamide may further enhance response rates. In order to evaluate a simple sensitivity test for the anti-tumor agent 5-fluorouracil (5-FU), we examined whether an assay of a small sample could measure mRNA to predict the activities of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD). In addition, gene abnormalities on chromosomes 1 and 18 corresponding to DPD, TS and the relationships between the gene abnormalities and the amount of mRNA and activity were examined.MethodTS and DPD activity were measured using the fluorodeoxyuridine monophosphate ligand binding assay and radio enzymatic assay, respectively, while mRNA levels were assayed by real-time polymerase chain reaction. Chromosome 1 and 18 aberrations were investigated by fluorescencein situ hybridization (FISH) with centromere probes.ResultsTS mRNA and TS activity showed a positive correlation (r = 0.518,p = 0.0017). TS activity and TS mRNA were significantly higher in the nuclear grade 3 group than in the other groups (p = 0.04,p = 0.0072, respectively). TS activity and mRNA in tumor tissue tended to decrease in the progesterone receptor positive groups (p = 0.059,p = 0.066, respectively). There was no correlation between DPD mRNA and DPD activity in tumor tissue (r = 0.139,p = 0.4423). DPD mRNA was measured as 282.88 ± 170.68 copies/cell in tumor tissue and 635.88 ± 310.04 copies/cell in normal tissue, and was thus significantly higher in normal tissue (p < 0.001).ConclusionsTS mRNA showed a positive correlation with TS activity, suggesting that this method of using small amounts of tissue can replace anti-cancer drug sensitivity tests.

Computerized image analysis of clustered microcalcifications on mammography: Morphometric comparison between mammography and pathology

The clusters of microcalcifications under 2 cm in greatest dimension were analyzed in terms of size and shape by an image processor with a computer after being magnified 33 times.The mean diameter of mammographic microcalcifications was 188 μm in benign cases, 226 μm in cribriform or papillary type cancer cases, 213 μm in intermediate type cancer cases, and 324 μm in comedo type cancer cases, showing significant differences among the groups. The size distribution of mammographic microcalcifications in the comedo type was characteristic, showing a second peak in distribution between 500 and 700 μm. The radiodensity of microcalcifications compared to the breast parenchyma, the caliber of breast ducts containing the malignant calcifications, and the unit volume of calcium deposits within the ductal lumens were greater in cancer cases.The size and shape of mammographic microcalcifications were considered to be related to a combination of the caliber of breast ducts, unit volume of calcium deposits within the ductal lumens, and the density of breast ducts containing calcium deposits. Duct calibers were generally larger in cases of cancer lesions than cases of benign lesions such as duct papillomatosis, thus calcium deposits and microcalcifications were greater in the cancer lesion. Uneven distribution of size and form of microcalcifications over 250 μm in size, and increased radiodensity of calcifications were useful parameters for differential diagnosis rather than the density of calcifications.

Chronological changes of microcalcifications of breast carcinoma

BackgroundClustered microcalcifications are important for the detection of breast carcinomas, but few reports have described chronological changes of the microcalcifications.MethodsThe 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 changes were analyzed by measuring the increase in the length of areas containing calcifications and the diameters of microcalcifications on mammograms using computerized image analysis.ResultsChronological 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 distribution pattern 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.ConclusionsThe increase of microcalcifications was generally fast in comedo type 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.

Phase II study of KRN8602, 3′-deamino-3′-morpholino- 13-deoxo-10-hydroxycarminomycin hydrochloride, MX2 · HCl in patients with metastatic breast cancer

Purpose: KRN8602 (3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride, MX2 · HCl) is a newly developed anthracycline that has been found to be effective against multidrug-resistant tumor cells in vitro and in vivo. In order to clinically confirm these promising preclinical observations, we performed a phase II trial of KRN8602 in patients with anthracycline-resistant metastatic breast cancer. Methods: Of 41 patients registered with metastatic breast cancer, 37 were eligible and were given at least two cycles of KRN8602 15 mg/m2 per day at 3–4 week intervals by intravenous bolus injection on days 1, 2, and 3. Results: Of the 37 patients, 6 (16.2%, with a 95% confidence interval of 4.3–28.1%) had a partial response (PR). No complete responses (CRs) were observed. The difference between response rates according to prior history of anthracycline administration was not significant. Myelosuppression was moderately severe, with grade 3 or 4 leukopenia occurring in 65%. Severe nausea/vomiting was observed in 44% of the patients. Conclusions: The results indicate that KRN8602 has modest activity in refractory metastatic breast cancer and is associated with relatively severe toxicity. Furthermore, the preclinical finding that KRN8602 overcomes anthracycline resistance was not reliably reproduced in this clinical phase II trial.

Suppression of Cytokines Production in Peripheral and Regional Lymph Node Lymphocytes from Patients with Gastric Cancer and the Augmentative Effect of BRM

Lymphocytes of regional lymph nodes and peripheral blood were analyzed to determine the immunosuppressive state of gastric cancer patients, the a-interferon (a-INF) and interleukin-2 (IL-2) producing ability of lymphocytes of both regions were decreased in the advanced cases. As to the lymphocyte subset, remarkable suppression of helper T and NK cells was recognized.