Predictive value of estrogen receptor status as assessed by ligand-binding assay in patients with early-stage breast cancer treated with breast conserving surgery and radiation therapy.

It is important to determine which factors are predictive for the prognosis of patients treated with breast conserving surgery (BCS) and radiation therapy (RT) in order to make a decision as to the adjuvant treatment. Although estrogen receptor (ER) is known to be a predictive marker for antiestrogens in breast cancer, the prognostic effect of hormone receptors has not been fully analyzed in Japanese breast cancer patients treated with BCS and RT. A total of 153 breast cancer patients having up to three positive nodes in the axilla as identified histologically and treated with both BCS and RT with or without systemic therapy were enrolled in this study. All tumors were measured for ER and progesterone receptor (PR) using ligand-binding assay (LBA). ER was inversely related to patients' age, however, PR was not related to any clinical features. When ER was classified into negative, weakly positive and strongly positive categories, with cut-off levels of zero and 50 fmol/mg protein, the relapse-free survival (RFS) was significantly better in patients with tumors having strongly positive ER than in patients with tumors having negative ER. Multivariate analysis revealed that ER as well as nodal status, was an independent predictive factor for RFS, however, PR was not. As a result, we believe that ER measured by LBA is valuable for predicting prognosis of early-stage breast cancer patients treated with BCS and RT.

Favorable quality of life after repeat hepatic resection for recurrent hepatocellular carcinoma.

BACKGROUND/AIMS: The appropriate choice of treatment for recurrent hepatocellular carcinoma after hepatic resection remains controversial. The aim of this study is to clarify prognostic factors and quality of life in patients with tumor recurrence after hepatic resection for hepatocellular carcinoma. METHODOLOGY: We retrospectively analyzed 188 patients with hepatocellular carcinoma who underwent curative hepatic resection between 1988 and 1997. Statistical analysis was performed to identify prognostic factors involved after recurrence. Furthermore, quality of life after treatment for recurrence was compared between patients with repeat hepatic resection or hepatic arterial infusion chemotherapy. RESULTS: In 123 patients with recurrence, unfavorable predictors after recurrence are pTNM Stage III/IV at initial surgery, receiving chemotherapy before initial surgery and presence of extrahepatic recurrence. In contrast, favorable predictors are 3 years or more of disease-free interval and repeat hepatic resection. The incidence of deteriorated performance status in the repeat hepatic resection group was lower than in the hepatic arterial infusion chemotherapy group because of better psychological function in patients undergoing repeat hepatic resection. CONCLUSIONS: Repeat hepatic resection provides a good prognosis and a favorable quality of life in patients with recurrence after hepatic resection for hepatocellular carcinoma.

Tamoxifen-failed male breast cancer with a high level of circulating estrogen: report of a case.

We report herein the case of a 40-year-old man with grade II invasive ductal carcinoma of the breast (pT1, pN0, M0: stage I) in whom a recurrence developed shortly after completion of a 2-year course of tamoxifen and 5-fluorouracil therapy following a mastectomy. Although the metastatic tumor was estrogen receptor-positive, hormone therapy combined with chemotherapy had no significant effect on tumor growth, and the patient died from disseminated tumors 2 years 6 months after completion of the adjuvant therapy. It is noteworthy that the circulating estradiol level increased from 18.0 to 892.3 pg/ml during the period of tumor progression and dissemination. We interpret these findings as an indication of high aromatase activity in the metastatic tumors. We suggest that extending tamoxifen treatment to 5 years or longer be recommended for the standard adjuvant hormone therapy of male breast cancer to prevent the early recurrence of hormone-responsive disease.

Recurrence of breast cancer following local excision alone for ductal carcinoma in situ.

OBJECTIVE: To assess recurrence of breast cancer following local excision alone for ductal carcinoma in situ. METHODS: Eighteen patients who received complete resection for noninvasive ductal carcinoma between 1982 and 1997 were investigated in this study. The mean age of the patients was 45 (29-78) years old. The initial presentation was a clinically palpable tumor in 4 patients, nipple discharge in 6, and microcalcification on mammograms in 8. Patients with palpable tumor underwent wide excision with at least a 2-cm free margin. Patients whose mammograms showed microcalcification underwent lumpectomy, and those who showed nipple discharge underwent duct-lobular segmentectomy. Five patients who underwent lymph node dissection up to level I or II had no lymph node metastasis. The mean follow-up period was 86 months. RESULTS: Local recurrence in the conserved breast was seen in five (27.8%) of 18 patients. The actuarial five-year event-free survival was 76.2%. The histological type of the recurrent tumor was ductal carcinoma in situ in three patients and invasive carcinoma in two. There was no difference in age at initial operation or histological subtype between patients with and without recurrent disease, but patients presenting with nipple discharge initially had a significantly shorter ipsilateral disease-free interval than those presenting with tumor or microcalcification on mammograms. All patients with local recurrence in the conserved breast were treated with breast-conserving surgery or subcutaneous mastectomy. CONCLUSION: Local recurrence frequently occurs in patients presenting with nipple discharge treated by duct-lobular segmentectomy for noninvasive ductal carcinoma. Either wide excision with a larger free margin or adjuvant radiation therapy following duct-lobular segmentectomy should be considered for these patients.

Serum concentration of pyridinoline cross-linked carboxyterminal telopeptide of type I collagen in patients with metastatic breast cancer.

The serum concentration of pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP) was examined in 83 patients with metastatic breast cancer. ICTP levels were significantly higher in patients with bone metastases than in those without bone metastasis. In patients with bone metastasis, significantly higher ICTP levels were observed in those with multiple lesions than in those with a solitary lesion and these levels reflected therapeutic response. Sequential monitoring of ICTP revealed that this elevation was correlated with disease progression. Combined with imaging studies, monitoring of ICTP appears to offer additional information for detection of bone metastasis and evaluation of therapeutic response to bone metastasis.

Sudden hemorrhage of the breast caused by breast cancer: a case report and review of the literature.

A rare case of sudden hemorrhage caused by breast cancer is reported. A 71-year-old woman noted bleeding from her left breast. Physical examination of the left breast showed a localized open cavity accompanied by bleeding and coagulation. The patient had no history of breast trauma or anticoagulation therapy. Incisional biopsy followed by histological examination resulted in a diagnosis of granulation tissue with no cancer cells present. Mammography and ultrasonography indicated probable breast cancer. As a result, a second incisional biopsy was performed, which suggested invasive ductal carcinoma without histological skin invasion. A modified radical mastectomy was performed under a diagnosis of stage II breast cancer. Breast cancer with sudden hemorrhage is rare. We review the literature and discuss the cause of this unusual manifestation.

A case report of advanced male breast cancer with an objective response to tamoxifen treatment.

A 70-year-old man presented with a firm tumor in his right breast first noticed eight years ago. The tumor had enlarged gradually and had produced an ulcer with bleeding. On physical examination, a huge tumor entirely occupied the right breast and extensively had infiltrated the chest wall. Chest X-ray and CT showed massive pleural effusion and multiple small nodular lesions in the lung. Invasive ductal carcinoma of the breast was diagnosed by incisional biopsy,confirming advanced breast cancer with lung metastases and bilateral pleural effusion(T4cN2M1, Stage IV). Because ER and PgR levels were 110 fmol/mg and 190 fmol/mg, respectively, and because his general condition was poor, we selected medical treatment with tamoxifen(TAM). Thirty-two weeks later, the tumor had showed pronounced reduction with scarring. The patient underwent local excision of the scar tissue. The quality of life of the patient was favorably improved and no severe adverse events were observed. The tumor in the chest wall recurred two months after the end of TAM treatment, possibly because the patient did not accept continuous TAM therapy. The patient died from complications of brain metastasis 32 months after the start of TAM treatment. We report a rare case of advanced male breast cancer and on the effectiveness of continuous TAM treatment.

Primary squamous cell carcinoma of the breast during lactation: a case report.

A case of primary squamous cell carcinoma of the breast during lactation is reported. The patient was a 32-year-old woman, in post-partum lactating 18 months after delivery, who was referred to our hospital following detection of a lump in her left breast during physical examination in mass screening for breast cancer. The tumor, palpated in the upper outer quadrant of the left breast, was firm, well-defined and 2.8 x 2.6 cm in size. Ultrasonograms identified an irregular-shaped hypoechoic lesion and mammograms revealed a well-defined, circumscribed tumor. Based on these findings, breast cancer was suspected and an excisional biopsy was performed. The resected specimen was a firm, solid and circumscribed tumor with central hemorrhage. Microscopic findings demonstrated that the tumor consisted of an invasive ductal carcinoma with marked squamous metaplasia, such as keratinization and squamo-columnar junction. Breast-conserving surgery was performed and no lymph node involvement was noted. Both estrogen and progesterone receptors of the tumor were negative. Generally, the size of both squamous cell carcinoma and carcinoma during the lactation period tends to be larger than ordinary carcinomas. In this case, the cancerous lesion was detected at a relatively early stage. Although the cancerous lesion was detected at a relatively early stage and no lymph node involvement was noted, lung metastases occurred within 12 months of the surgery. Malignant potential is generally considered to be high in cases of squamous cell carcinoma of the breast with lactation and thus intensive treatment potentially resulting in severe side effects was considered to be necessary for this patient.

Highest microvessel count as a long-term prognostic factor in Japanese breast cancer patients.

The aim of this study was to determine whether microvessel density (MVD) could add useful information in predicting the prognosis of breast cancer patients. In our study, MVD was calculated by counting microvessels per x200 field in the highest neovascularized area of the tumor (highest microvessel count, HMC). HMC significantly increased according to the increased number of positive nodes. Higher HMC significantly correlated with worse relapse-free survival (RFS) of patients with negative node, one to three positive nodes in the axilla or with stage I and II tumors. HMC, however, was not predictive for RFS of patients with four or more positive nodes or with stage III tumors. Multivariate analysis revealed that HMC was second only to nodal status and tumor size as being predictive for RFS. These results suggest that HMC could be used in selection of patients with early-stage breast cancer who are at high risk for having occult metastasis.

Effects of lentinan on colorectal carcinogenesis in mice with ulcerative colitis.

Lentinan; i.e., polysaccharides extracted from a kind of black mushroom shiitake, has been clinically applied as an antitumor and antimetastatic drug, and has been reported to prevent both chemical and viral carcinogenesis. It is known that lentinan affects the tumorous vascular system resulting in the induction of hemorrhagic necrosis which is dependent on T-cells in the tumor. Repeated mucosal necrosis-regeneration sequence in chronic ulcerative colitis induced with 3% dextran sulfate sodium led to colorectal carcinogenesis in azoxymethane-pretreated mice. In the present study, the additive treatment with lentinan in the azoxymethane-dextran sulfate sodium treated mice enhanced the colorectal high-grade dysplasia, though not significantly, and the splenic weight. This may show the proliferation of pathogenic splenic T cells resulting in a change for the worse of ulcerative colitis, anemia induced with hemorrhage and colorectal carcinogenesis; i.e., high-grade dysplasia of the mucosa and/or invasive adenocarcinomas of the colorectum. The present results may recommend chemoimmunotherapy while using lentinan, but not immunotherapy using lentinan alone, is indicated for the management of cancer patients.

Does macrophage-colony stimulating factor stimulate rat haematopoietic cells?

It is known that colony stimulating factors (CSFs) stimulate the myeloid cells of bone marrow and splenic cells in rodents. The effects of macrophage (M)-CSF on the activities of thymidylate synthase and thymidine kinase, involved in de novo and salvage pathways for pyrimidine nucleotide synthesis, respectively, in haematopoietic cells of bone marrow and spleen were investigated in rats. A single M-CSF injection did not elevate the mRNA expression levels of the enzymes in bone marrow cells 6 h after treatment, but it enhanced the splenic thymidylate synthase mRNA expression. M-CSF stimulated the splenic thymidylate synthase activity without an increase of the peripheral granulocytes. The effect of M-CSF on granulocytes is considered to be weak compared with that of granulocyte (G)-CSF, because of the indirect secretion of endogenous G-CSF from the cells with M-CSF receptors stimulated by exogenous M-CSF. Since M-CSF was able temporarily to lead progenitor cells from long G1-phase into S-phase, M-CSF might accelerate the anticancer effects when used together with anticancer agents.

Immunohistochemical study on primary and recurrent tumors in patients with local recurrence in the conserved breast.

One hundred and seventy patients received breast-conserving therapy in the Second Department of Surgery, Gunma University School of Medicine. Six (3.5%) out of the 170 patients showed breast recurrence. We investigated the breast recurrent cases clinicopathologically. The age at the initial operation ranged from 38 to 78 (mean 57) years. One patient was clinical stage I and the others were clinical stage II. Surgical margin at the initial operation was negative in two patients and positive in four. Histological type was invasive ductal cancer in all cases. Three patients had lymph node involvement. The interval from the initial operation to breast recurrence ranged from 19 to 68 months. Five cases were nodular type and one was diffuse type of breast recurrence. Histological type of breast recurrence was the same as the initial one. We performed salvage surgery for all breast recurrent patients, mastectomy for four patients and local resection for two. One patient who showed diffuse type of recurrence could not be controlled with any surgical treatment, and later died of breast cancer. We investigated the expression of estrogen receptor, progesterone receptor, pS2, c-erbB-2 and p53 on both initial and recurrent specimens of the six patients. The expression of each protein on the recurrent specimens was the same as the initial one. We conclude that breast recurrence after breast-conserving therapy has its origin in the residue of cancer cells at the initial operation, even if surgical margins are histopathologically negative.

"Ductectatic" mucinous cystadenocarcinoma of the pancreas: a case report, 5-year follow-up period.

It is unknown whether the "ductectatic" mucinous cystadenoma and cystadenocarcinoma of the pancreas will develop into the classical megacystic type, and there is no report of long-term follow-up of this entity. A case of mucin-producing cystic tumor of the pancreas with pancreas divisum in a 65-year-old man is presented who was followed-up for 5 years prior to diagnosis of cancer and surgery. Computed tomography, ultrasonography and endoscopic retrograde pancreatography during the 5-year period had demonstrated insidious growth of the tumor. The histopathological diagnosis after surgery was the "ductectatic" mucinous cystadenocarcinoma of the pancreas. It was difficult for us to differentiate it from the classical megacystic type. The patient died of liver metastasis 54 months after surgery.

Regulation of estrogen receptor and epidermal growth factor receptor by tamoxifen under high and low estrogen environments in MCF-7 cells grown in athymic mice.

The purpose of this study was to investigate whether tamoxifen (TAM) treatment causes a downregulation of estrogen receptor (ER) and whether TAM induces epidermal growth factor receptor-1 (EGFR). We investigated the expression of ER and EGFR after the treatment of TAM in MCF-7 tumors grown in athymic mice under high and low estrogen environments. MCF-7 tumors were grown in ovariectomized athymic mice by implanting a sustained release 17beta-estradiol (E2) pellet. The E2 pellets were removed after 3 weeks of E2 treatment. Animals were then divided into the following 4 groups: i) an E2 (0. 72 mg/pellet) pellet [E2(+)]; ii) an E2 and a TAM (5 mg/pellet) pellets [E2(+)TAM]; iii) no treatment [E2(-)]; iv) a TAM pellet [E2(-)TAM]. A significant reduction in tumor size was observed in the estrogen-depleted group [E2(-) and E2(-)TAM] compared with the estrogen-completed group [E2(+) and E2(+)TAM]. TAM inhibited estrogen-stimulated growth in the estrogen-completed mice. No additional reduction of the tumor by TAM was observed in the estrogen-depleted mice. Both ER and EGFR protein levels in the tumors of the estrogen-depleted mice were higher than in the estrogen-completed mice. Expression of ER and EGFR protein was increased by TAM in the estrogen-completed mice, however it was decreased by TAM in the estrogen-depleted mice. Changes of ER and EGFR protein levels were similar in all treatments. Transforming growth factor-alpha (TGF-alpha) in tumors, which is known as a ligand of EGFR and as an estrogen-inducible protein in ER positive MCF-7 cells, was decreased by TAM in the estrogen-completed mice, by contrast, it was increased by TAM in the estrogen-depleted mice. Downregulation of ER was observed in TAM-treated mice in an estrogen-depleted environment, this action of TAM was similar to E2. These results suggest that increase of EGFR expression does not lead to a loss of ER after short-term TAM treatment in MCF-7 tumors.

Mitogen-activated protein kinase cascade in breast cancer.

The mitogen-activated protein (MAP) kinase is considered to play a central role in diverse cellular events including carcinogenesis and tumor progression. Indeed, expression of MAP kinase, tyrosine-phosphorylated MAP kinase, and Raf-1 protein was greater in cancerous human tissues than in the surrounding noncancerous glands. In a 7,12-dimethylbenz[a]anthracene-induced rat mammary carcinoma model, estrogen promoted and ovariectomy and antiestrogen, tamoxifen (TAM) inhibited the tumor growth. Ovariectomy suppressed expression of MAP kinase, tyrosine-phosphorylated MAP kinase and Raf-1, whereas estrogen as well as TAM induced expression of MAP kinase and Raf-1 under castrated conditions. Since it was reported that MAP kinase was activated during the progression of breast carcinoma cells, such estrogenic actions of TAM toward the MAP kinase cascade might be responsible for malignant progression.

The mechanisms of antitumor effects of luteinizing hormone-releasing hormone agonist (buserelin) in 7, 12-dimethylbenz(a)anthracene-induced rat mammary cancer.

We evaluated the mechanism of antitumor effects of buserelin, which is one of LH-RH agonists, on a hormone dependent breast cancer model, using 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary cancer. Rats developing solid mammary tumors within 5-7 weeks following the DMBA administration were divided into groups weekly, and treated without delay. The tumor bearing rats were randomized into five groups with regard to tumor size or average weight (15 rats per group). Each group received one of the following treatments during 4 weeks: a) no treatment (NT); b) ovariectomy (Ovx); c) buserelin; d) Ovx and 17beta-estradiol (E2) (Ovx+E2); e) Ovx+E2+buserelin. Tumor regression immediately began at one week after both buserelin treatment and ovariectomy. A significant reduction of tumor size was observed in both buserelin-treated rats and Ovx rats compared with NT rats (p<0.01). No significant difference of tumor size was observed between buserelin-treated rats and ovariectomized rats. No reduction of tumor size was observed in Ovx+E2 rats and Ovx+E2+buserelin rats. Although the mean uterine wet weight of the buserelin group was significantly higher than that of the Ovx group, it was significantly lower than that of the NT group. The mean uterine wet weight of the NT group, the Ovx+E2 group and the Ovx+E2+buserelin group was similar and was significantly higher than that of the Ovx group. Buserelin did not inhibit exogenous estrogen-dependent tumor growth in DMBA-induced rat mammary cancers. These results suggest that buserelin has no direct effects on DMBA-induced rat mammary cancers, and the main mechanism of action of buserelin for tumor-reduction is due to ovarian estrogen deficiency.

The efficacy of technetium-99m-MIBI scan and intraoperative methylene blue staining for the localization of abnormal parathyroid glands.

The efficacy of the technetium-99m-2-methoxyisobutylisonitrile (Tc-MIBI) scan and intraoperative methylene blue staining was analyzed in a consecutive series of 15 patients with primary hyperparathyroidism who underwent neck surgical exploration. A total of 17 abnormal parathyroid glands were removed, 7 of which were confirmed histologically as adenomas and 10 as hyperplasias. The Tc-MIBI scan and the thallium-201-technetium-99m subtraction (Tl/Tc) scan preoperatively localized 11 (69%) of 16, and 6 (40%) of 15 abnormal parathyroid glands, respectively. The Tc-MIBI scan correctly localized two ectopic abnormal parathyroid glands which were not localized by the Tl/Tc scan or ultrasonography (US). However, it also demonstrated false-positive accumulations caused by thyroid diseases in two patients. There were 4 abnormal parathyroid glands not detected by the preoperative imaging techniques, whereas all 17 abnormal parathyroid glands were stained with methylene blue, the infusion of which caused no adverse effects or toxicity. In conclusion, Tc-MIBI scanning and intraoperative methylene blue staining are effective techniques for the localization of abnormal parathyroid glands in patients with primary hyperparathyroidism.

Effects of interferon-alpha on cellular proliferation and adhesion of breast carcinoma cells.

We examined the potent inhibitory effects of interferon-alpha (IFN-alpha) on both cellular adhesion and cell proliferation of MCF-7 breast carcinoma cells. When MCF-7 cells were exposed to IFN-alpha at a concentration of 5x10(3) IU/ml for 5 days, cell proliferation was markedly inhibited. Cell attachment assay demonstrated that incubation with IFN-alpha for up to 48 h reduced alpha2beta1 integrin-mediated cellular adhesion. However, fluorescence activated cell sorter (FACS) analysis revealed that incubation with IFN-alpha for 24 h had no effect upon the cell surface expressions of either alpha2 and beta1 integrin on MCF-7 cells. These antiproliferative and antiadhesive actions of IFN-alpha may be applied to treatment for patients with metastatic breast carcinoma.

Clinical significance of immunohistochemical Bcl-2 expression in invasive breast carcinoma.

The immunohistochemical expression of bcl-2 protein, and its correlations with clinicopathological features and prognosis were studied in patients with invasive breast carcinoma. Bcl-2 positive expression significantly correlated with hormone receptor positivity and histological tumor differentiation, and inversely correlated with p53 overaccumulation. No correlation was observed between bcl-2 expression and patient age, menopausal status, tumor size, and lymph node metastasis. Survivals of stage I to III patients who had not received adjuvant hormonal therapy showed no difference between bcl-2-positive and -negative tumors, even if patients were divided as with or without adjuvant chemotherapy, or with or without nodal involvement. In consequence, immunohistochemical bcl-2-positivity correlates with positive hormone receptors and well differentiated phenotypes in invasive breast carcinoma, however, it might not predict response to adjuvant chemotherapy and not be a favorable predictive value in patients treated without adjuvant hormonal therapy.

Treatment for accidental occlusion of the hepatic artery after hepatic resection: report of two cases.

Two patients in whom accidental hepatic artery occlusion (HAO) occurred after hepatic resection (Hx) were reported. A 59-year-old female who underwent Hx for hepatocellular carcinoma with underlying liver cirrhosis developed HAO on postoperative day (POD) 14 and died of hepatic failure on POD 23. The autopsy findings showed multiple necrosis in the remnant liver and an extraluminal hematoma of the hepatic artery, suggesting an injury caused by Pringle's maneuver. The second case was a 53-year-old male who underwent Hx for cholangiocarcinoma without any underlying liver disease. He developed HAO on POD 6, and radiological studies indicated a pseudoaneurysma formation and severe stenosis of the hepatic artery. It was speculated that the cause of the HAO was intraluminal injury of the hepatic artery during an angiographic study conducted prior to Hx. Partial arterialization of the portal vein was performed, following which his liver function test results improved. In both cases, measuring the serum hepatocyte growth factor level and the hepatic vein oxygen saturation proved useful, not only for determining the degree of liver injury, but also for predicting the outcome after treatments for HAO. Furthermore, the partial arterialization of the portal vein for HAO after Hx may rescue the normal remnant liver.