Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial.

PURPOSE: The goal of chemotherapy for metastatic breast cancer (MBC) is to prolong survival and maintain health-related quality of life. This study aimed to evaluate long-term health status of patients with MBC who participated in the phase III randomized SELECT BC trial. METHODS: In the SELECT BC trial, patients were randomly allocated to the S-1 or taxane (paclitaxel or docetaxel) arm. Health status was assessed by EQ-5D at pre-treatment, 3 and 6 months after randomization, and every 6 months thereafter to the extent possible. Least square mean scores were assessed to compare EQ-5D index values between groups. Time to deterioration analysis was also performed by defining the minimally important difference of EQ-5D as 0.05 or 0.1. RESULTS: The number of patients for EQ-5D analysis was 175 and 208 in the taxane and S-1 arms, respectively. Least square mean EQ-5D index values up to 60 months were 0.741 (95 % CI [0.713-0.769]) in the taxane arm and 0.748 [0.722-0.775] in the S-1 arm. The EQ-5D index value during PFS up to 12 months in the S-1 was superior to the corresponding index value in the taxane (0.812 [0.789-0.834] vs. 0.772 [0.751-0.792], P = 0.009). Time to deterioration analysis also revealed that S-1 significantly delayed the deterioration of EQ-5D index value during the period before progression (P = 0.002 and 0.003). CONCLUSIONS: Our findings suggest that the EQ-5D index value was higher in patients treated with S-1 during first-line chemotherapy. Considering non-inferiority of S-1 in terms of OS, obtained quality-adjusted life years may be greater in the S-1 arm.

Prevalence and clinical significance of supra- or infraclavicular drainage on preoperative lymphoscintigraphy in women with breast cancer.

OBJECTIVE: Preoperative sentinel lymph node (SLN) mapping by lymphoscintigraphy is helpful to evaluate extra-axillary SLNs over a wider range than the blue dye method. However, the clinical value of extra-axillary SLNs remains uncertain. The goal of this study was to determine the prevalence and clinical significance of supra- or infraclavicular drainage on preoperative lymphoscintigraphy in women with breast cancer. MATERIALS AND METHODS: We retrospectively reviewed the files of 942 consecutive breast cancer women who underwent preoperative lymphoscintigraphy for SLN biopsy at our institution between April 2004 and March 2015. RESULTS: Supra- or infraclavicular drainage was detected in 5/942 women (0.5%) on preoperative lymphoscintigraphy. An axillary hot spot was detected in all five women, and a positive axillary SLN was detected in four women. Breast tumor locations were the upper inner or outer quadrants in four women and the lower outer quadrant in one woman. The median follow-up period was 75 months (mean: 92; range: 26-111 months). Recurrence outside the axilla was found in three (60%) women. The woman with a negative SLN status did not undergo adjuvant chemotherapy, but developed extra-axillary lymph node recurrence 3 years after primary surgery. No patient died of metastatic breast cancer at the last follow-up. CONCLUSIONS: The detection of the supra- or infraclavicular SLNs on lymphoscintigraphy may provide additional staging information to tailor individual treatment regimens with regard to the potential risk of recurrence or metastasis of breast cancer.

REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer.

The overexpression of reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3), a tumor suppressor gene, induced apoptosis in human prostatic and testicular cancer cells. The aim of this study is to examine the potential of REIC/Dkk-3 as a therapeutic target against breast cancer. First, the in vitro apoptotic effect of Ad-REIC treatment was investigated in breast cancer cell lines and the adenovirus-mediated overexpression of REIC/Dkk-3 was thus found to lead to apoptotic cell death in a c-Jun-NH(2)-kinase (JNK) phosphorylaion-dependent manner. Moreover, an in vivo apoptotic effect and MCF/Wt tumor growth inhibition were observed in the mouse model after intratumoral Ad-REIC injection. As multidrug resistance (MDR) is a major problem in the chemotherapy of progressive breast cancer, the in vitro effects of Ad-REIC treatment were investigated in terms of the sensitivity of multidrug-resistant MCF7/ADR cells to doxorubicin and of the P-glycoprotein expression. Ad-REIC treatment in MCF7/ADR cells also downregulated P-glycoprotein expresssion through JNK activation, and sensitized its drug resistance against doxorubicin. Therefore, not only apoptosis induction but also the reversal of anticancer drug resistance was achieved using Ad-REIC. We suggest that REIC/Dkk-3 is a novel target for breast cancer treatment and that Ad-REIC might be an attractive agent against drug-resistant cancer in combination with conventional antineoplastic agents.

PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer.

Trastuzumab is the only HER2/neu-directed therapy to have received Food and Drug Administration approval for the treatment of patients with metastatic breast cancer. The efficacy of trastuzumab depends on the HER2/neu status of the tumour and the patient's prior treatment, but even when patients are selected on the basis of HER2/neu gene amplification, the single-agent response rate ranges from 12 to 30% and few patients respond to trastuzumab monotherapy. Here, we propose PTEN as a predictive biomarker for trastuzumab efficacy. Human breast cancer SKBR3 and drug-resistant SKBR3/R cells were investigated. We also examined clinical samples from patients who had been treated with trastuzumab and analysed the relationship between trastuzumab efficacy and PTEN level. The PI3K/Akt signalling pathway was observed to be highly active in the drug-resistant cells, and their level of PTEN was low. Delivery of antisense PTEN duplex siRNA significantly decreased the trastuzumab chemosensitivity of parental SKBR3 cells, and marked activation of Akt signalling pathway was also recognised. Moreover, immunohistochemical investigation revealed that trastuzumab treatment was remarkably successful in cells with elevated PTEN expression. Along with the immune-system-associated cytotoxic mechanism, several mechanisms have been proposed for the effect of trastuzumab. PTEN activity might play an important and major role in its HER2/PI3K/Akt-mediated antitumour effect, and could be a useful biomarker for predicting the efficacy of trastuzumab in the treatment of breast cancer.

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.

[Two cases of advanced and metastatic breast cancers treated by docetaxel in combination with intra-arterial infusion of adriamycin].

Two cases of advanced and metastatic breast cancers were treated by docetaxel (TXT) in combination with intra-arterial infusion of adriamycin (ADM). Patients received 60 mg/body TXT i.v. and 30 mg/body ADM ia (AT therapy) bi-weekly. Clinical responses were observed in these two patients and the durations of responses were over 20 weeks. Critical toxicities of grade 2 leukopenia and alopecia were observed but grade 4 severe toxicities were not. Thus AT therapy can be easily and safely performed with outpatients. This therapy can improve the response rate and time to progression; therefore phase I or phase I/II clinical trials of AT therapy in Japan are recommended.

Prognostic value of vascular endothelial growth factor expression in primary lung carcinoma.

To investigate whether an association exists between vascular endothelial growth factor (VEGF) expression and tumor prognosis in primary lung carcinoma, we used immunohistochemical techniques to analyze microvessel density and VEGF expression in lung carcinoma tissue from 98 patients. Tissue had been fresh-frozen at the time of operation and preserved for more than 5 years. The results indicated that VEGF expression was positive for 50 of the 98 patients (51.0%), with 27 (27.6%) being weakly positive and 23 (23.5%) being strongly positive. The microvessel density in tissue showing weakly positive and strongly positive VEGF expression was significantly higher than that in VEGF-negative tumor tissue (P < 0.05: negative vs. weakly positive, P < 0.01: negative vs. strongly positive), we showed demonstrating that VEGF expression was significantly associated with intratumoral microvessel density. The 5-year survival rates were 8.7% for strongly VEGF-positive patients, 43.9% for weakly VEGF-positive patients and 79.2% for VEGF-negative patients, respectively (P < 0.01: negative vs. weakly positive or strongly positive). Furthermore, multivariate analysis employing multiple regression analysis indicated that VEGF expression correlates highly with the overall survival rates of patients with primary lung carcinoma. Two variables, N status and VEGF expression, were found to be significant prognostic factors (P < 0.01). The results of this study suggest that VEGF expression is associated with intratumoral microvessel density. VEGF expression may constitute important independent prognostic evidence that can help us in predicting the outcomes of patients with primary lung carcinomas.

Local recurrence of renal cell carcinoma causing massive gastrointestinal bleeding: a report of two patients who underwent surgical resection.

We report two cases of local recurrence of renal cell carcinoma, which invaded the gastrointestinal tract. The intervals to local recurrence after primary nephrectomies were 5 and 13 years. Both cases developed massive gastrointestinal bleeding. Blood transfusions and arterial embolization were performed; however, continuous melena prevented improvement in their general condition. Although distant metastases were observed in both cases, tumor resections combined with intestine invasion were performed. Although this surgical approach does not significantly improve the prognosis, even in patients who have remaining metastatic lesions, it may provide palliation and improve the quality of survival.

Anti-HER2 antibody enhances the growth inhibitory effect of anti-oestrogen on breast cancer cells expressing both oestrogen receptors and HER2.

Anti-oestrogen is effective for the treatment of oestrogen receptor (ER)-positive breast carcinomas, but most of these tumours become resistant to anti-oestrogen. It has been suggested that anti-oestrogen therapy may induce a HER2 signalling pathway in breast cancer cells and this may cause resistance to anti-oestrogen. Thus, it is conceivable that combined therapy with anti-oestrogen and anti-HER2 antibody might be more effective. In the present study, we investigated the effect of combined treatment with a humanized anti-HER2 monoclonal antibody, rhumAbHER2 (trastuzumab), and an anti-oestrogen, ICI 182,780, on the cell growth of three human breast cancer cell lines which respectively express different levels of ER and HER2. The combined treatment enhanced the growth inhibitory effect on ML-20 cells, which express a high level of ER and a moderate level of HER2, but showed no additive effect on either KPL-4 cells, which express no ER and a moderate level of HER2, or MDA-MB-231 cells, which express no ER and a low level of HER2. It is also suggested that both the antibody and anti-oestrogen induce a G1-S blockade and apoptosis. These findings indicate that combined treatment with anti-HER2 antibody and anti-oestrogen may be useful for the treatment of patients with breast cancer expressing both ER and HER2.

Hyperthyroidism in a patient with TSH-producing pituitary adenoma coexisting with thyroid papillary adenocarcinoma.

A 27-year-old woman who presented with a left thyroid nodule was found to have hyperthyroidism caused by a syndrome of inappropriate secretion of TSH. The levels of free T3, free T4 and TSH were 9.50 pg/mL, 4.05 ng/dL and 2.16 microU/mL, respectively. Magnetic resonance imaging of the head revealed a pituitary macroadenoma. The TSH response to TRH stimulation was normal and responses of other anterior pituitary hormones to stimulation tests were also normally preserved. Administration of octreotide with iodine successfully reversed hyperthyroidism prior to total resection of pituitary adenoma, which was followed by hemithyroidectomy of the left thyroid five months later. Histologically, the resected pituitary adenoma was a TSH-producing adenoma (TSH-oma) and the thyroid nodule was a papillary adenocarcinoma. Serum TSH diminished to undetectable levels immediately following pituitary adenomectomy but gradually normalized over nine months. Coexistence of a TSH-oma with thyroid cancer is very rare and only two similar cases have previously been documented. This combination raises the possibility that TSH may be involved in tumorigenesis in the thyroid gland.

Effects of experimental chemoendocrine therapy with a combination of a pure antiestrogen and 5-fluorouracil on human breast cancer cells implanted in nude mice.

The antitumor effects of an experimental chemoendocrine therapy combining a new pure antiestrogen ICI 182780 and 5-fluorouracil (5-FU) were studied on MCF-7 human breast cancer cells implanted in nude mice. ICI 182780 had a dose-dependent antitumor activity, which was potentiated by the concomitant use of 5-FU. When compared with the control group, the estrogen receptor (ER) level in the ICI 182780 group was lower and that in the combination group was markedly lower. Cell cycle analysis by flow cytometry (FCM) resulted in a lower percentage of S-phase cells (%S) in the treated mice. No significant difference was observed in the 5-FU concentrations in tumor cells, while the 5-FU content in RNA was significantly higher in the combination group. The changes in free thymidylate synthetase (TS) concentration indicated TS synthesis after the administration of 5-FU to be more greatly suppressed in the combination group than in the 5-FU group. These results suggest that ICI 182780 and 5-FU exert their combination effect mainly on ER-positive cells, and that the suppression of TS synthesis in tumor cells and the potentiation of the 5-FU-induced metabolic dysfunction of RNA are thus involved in the mode of action of this combination therapy.

[A case report of dumbbell neurogenic tumor of the superior mediastinum].

A 15-year-old female was admitted because of the superior mediastinum mass on chest X-rays and sensory loss of ulnar side of the left arm. Computed tomographic scanning and magnetic resonance imaging revealed that the tumor was dumbbell-shaped and invaded the vertebral canal through the intervertebral foramen between C 7 and Th 1. At first laminectomy of vertebrae (C 6-Th 1) was made in a prone position and intra-spinal portion of the tumor was resected. Then the patient was placed in a supine position and the chest was opened by left hemicollar incision and sternotomy to the 2nd intercostal space. The tumor was divided into two parts at the level of 1st rib and completely removed. The pathological diagnosis was schwannoma. This procedure is safe and useful for dumbbell type tumor located in superior mediastinum, especially in case of large tumor from neck to the thoracic cavity.

Hyperparathyroid crisis in a patient with a giant brown tumor of the iliac bone: a case report.

We observed a patient with a giant brown tumor of the iliac bone due to hyperparathyroidism. There was a risk of pathologic fracture due to huge cysts produced by bone absorption. In hyperparathyroid crisis, control of severe hypercalcemia is difficult without resection of the parathyroid gland.

Suppression of Estrogenic Activity by Medroxyprogesterone Acetate in Tamoxifen-treated Patients after Surgery for Breast Cancer to Reduce the Risk of Endometrial Cancer Development.

BACKGROUND: Postoperative adjuvant tamoxifen (TAM) therapy in breast cancer patients may lead, albeit rarely, to endometrial cancer. Preventive measures are urgently needed. METHODS: The study subjects were postmenopausal women who had undergone surgery for breast cancer. The control group (n=10) received no further therapy. Patients who had completed adjuvant TAM therapy were assigned to a medroxyprogesterone acetate (MPA;400 mg/day orally for 4 weeks) group (n =15) or no MPA treatment group (no MPA group)(n=15). Uterine cervix cytodiagnosis was performed after completing the TAM therapy(initial), and 4(4-week)and 16(16-week)weeks later. The serum 17beta-estradiol (E2) and progesterone concentrations were measured initially and at 4 weeks. The karyopyknotic index (KPI), eosinophilic index (EI) and maturation index (MI) were calculated from Papanicolaou-stained specimens. RESULTS: The background parameters showed no biases. There were no differences in the PKI or El between the no MPA and MPA groups. However, regarding the MI, after 4 weeks in the MPA group, the intermediate cells were significantly increased, while the superficial cells tended to be significantly decreased. Regarding the percent change from the initial value, after 4 weeks in the MPA group, the KPI and superficial cells were significantly decreased, and the intermediate cells were significantly increased. The estrogen activity level and the progesterone concentration were significantly lower in the MPA group compared with the no MPA group. CONCKLUSIONS: The MPA administration clearly lowered the estrogenic activity, indicating that MPA therapy should be effective in reducing the risk of TAM-associated endometrial cancer.

[Suppression of postoperative liver metastases from colon cancer by continuous intraportal infusion of an angiogenesis inhibitor FR-118487].

A rabbit VX2 colon cancer model with spontaneous liver metastases was used to evaluate the antitumor effect of an angiogenesis inhibitor, FR-118487. FR-118487 (1 mg/kg/day) was infused continuously into the portal vein for a week after resection of primary colon cancer lesions (FR group). The incidence of liver metastases was 71.4% (5/7) in FR group, and 100% (7/7) in control group. The number and the weight of liver metastatic nodules were 31.0 +/0 36.0 and 1.4 +/- 1.8 g in FR group versus 83.7 +/- 73.9 and 6.5 +/- 4.9 g in control group, respectively. The metastases in FR group were significantly decreased in weight compared with those in control group (p < 0.05). No anastomotic leakage was recognized in either group. No side effects of FR-118487 such as body weight loss were found. Continuous intraportal infusion of FR-118487 in the early postoperative period may be effective to suppress liver metastases from colon cancer by inhibiting the angiogenesis concerning liver metastases.

Immunohistochemical detection of ribonucleotide reductase in human breast-tumors.

Ribonucleotide reductase (RNR) consists of two non-identical subunits, R1 and R2 and is one of the key enzymes involved in DNA biosynthesis. RNR activity is considerably higher in malignant tumors than in normal tissues in the rat suggesting that RNR may play an important role in the pathogenesis of human tumors. In order to obtain immunological reagents to study the localization and level of expression of RNR in various human tissues, a synthetic peptide containing sequences corresponding to the COOH-terminal region of the human R2 subunit was used to generate rat monoclonal antibodies. The generated rat monoclonal antibodies (IgG) inhibited RNR enzymatic activity purified from murine P388 leukemia cells. These antibodies were used to immunohistochemically examine the distribution of RNR in a small panel of 8 malignant and 4 benign human breast tumors. Positive immunostaining for RNR was observed in the cytoplasm of human breast carcinoma cells in which a specific 44 kDa specific band of R2 subunit was also detected by Western blot analysis. The immunostaining was blocked by preabsorption of the antibody with an excess amount of the synthetic peptide immunogen. In 8 of 8 breast carcinomas, positive immunostaining for the R2 subunit was observed whereas noninvolved, adjacent breast tissue showed no staining with this antibody. In addition, few of the benign breast lesions exhibited staining with this antibody. These data indicate that these antibodies can immunohistochemically detect RNR in frozen or formalin-fixed, paraffin- embedded tissues and that there is a differential expression of RNR between breast tumors and non-involved breast tissue. Immunohistochemical detection of RNR using these antibodies may therefore be useful for the diagnosis of human breast tumors.

[Intraperitoneal chemotherapy for gastric carcinoma combined with peritoneal dissemination by intraperitoneal catheter with a subcutaneous reservoir].

Peritoneal dissemination is one of the leading causes of death among the gastric cancer patients. To improve the prognosis of these patients, we employed intraperitoneal repeated chemotherapy by intraperitoneal catheter with a reservoir implanted subcutaneously at the initial operation in 10 patients with peritoneal dissemination. At the initial operation, CDDP (50 or 100mg body), diluted in warm saline (total, 1,000ml), was administered intraperitoneally. Three to four weeks later, 50 to 70 mg/m2 of CDDP with saline was injected via the device, followed by 5-days of continuous intravenous administration of 5-FU (250 to 350 mg/m2). This therapy was repeated at 3- to 4-week intervals. One to seven cycles were used in this study. Among the highly disseminated cases, four of eight patients were alive more than one year, two died of cancer within four months and 2 are under treatment. Therapeutic toxicity was manifested as anorexia, nausea and vomiting. All the laboratory data were better than Grade 2 level. Thus, intraperitoneal repeated chemotherapy by CDDP is a safe and effective treatment for patients with peritoneal dissemination.

[Four cases of recurrent breast cancer effectively treated by the new antitumor agent, CPT-11 (irinotecan)].

Four cases of recurrent breast cancer effectively treated by CPT-11 were reported. These cases had undergone previous chemotherapy including adriamycin. Nevertheless, they developed no tolerance to such therapies and displayed good responsitivity to CPT-11. Effects on metastatic lesions: One was bone and three were soft tissues, was observed after the end of one course therapy. The response periods were over 210 days, 431 days, 175 days and 73 days. Thus, it was suggested that early response to drug was important clinically and was significant for enhancing the quality of life of patients. Major adverse reactions were leukopenia and gastrointestinal symptoms such as nausea, vomiting and diarrhea (Grade 2-3). However, these could be well managed by symptomatic treatment and dose modification. The results suggested that CPT-11 was an effective agent against advanced or recurrent breast cancer, and especially useful for patients who had developed a tolerance to previous therapies.

[Our surgical indication for breast-conserving therapy for breast cancer--special reference to extensive intraductal component and mammographic calcifications].

To ascertain accurate indications for breast-conserving therapy, we clinicopathologically examined 597 primary breast cancers. From July 1989 to October 1993, 118 of 597 (19.8%) patients were treated with lumpectomy plus breast radiation therapy. Among 118 of these primary breast cancers, 79 tumors were histologically further investigated with deep cut sections. In 20 of 79 (25.3%) breast cancers, microscopic tumor involvement was observed at resection margins. Most of them showed an extensive intraductal component (EIC). In order to predict EIC, intraductal lesions were histologically examined and classified either as comedo type or non-comedo (e.g., papillary type, cribriform type and solid type). Among 118 primary breast cancer tissues derived from lumpectomy, 66 breast tissues were histologically classified as comedo type. Sixty of 66 (90.9%) of these comedo types showed specific microcalcifications by light microscopic examination. These irregular shaped and relatively large granulated microcalcifications were localized in intraductal lesions with central necrotic ducts. With retrospective mammographic findings, these histological calcifications of comedo type reflected specific mammographic calcifications with columnar and specular formation. These evidences suggested that detection of mammographic calcifications in comedo type breast cancers may be helpful to predict EIC, and this prediction can possibly increase the accuracy of the indication for breast-conserving therapy.

[Limited surgery for early gastric cancer].

The prognosis of the resected "early gastric cancer" is very good, especially in mucosal cancer. In Japan, the surgery for the gastric cancer generally is subtotal gastrectomy combined with R2-lymph nodal dissection. But, some cases are free of lymph nodal metastasis, and might be cured without its dissection. We analyzed resected specimens of early gastric cancer pathologically, and assessed what cancers we could do the limited operation without impairing curability. Lymph nodal metastasis of the mucosal cancer developed 2.1% of all 291 mucosal cancers, and of the submucosal cancer, 15.7% of 229 cases. Lymph vessel permeation depicted 5.2% and 82.1%, respectively. As for the mucosal cancer, less than 10 mm in maximum diameter, there were no lymph vessel permeations nor lymph nodal metastasis. In these cases, the limited operation, especially the local resection and the endoscopic resection could be available without any fear of cancer residue. In contrast, the submucosal cancer was not considered the candidate of the limited surgery.