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In Japan, there are still no reports of long-term outcome for hypofractionated radiotherapy to the whole breast after breast-conserving surgery (BCS). We report our institution's results from evaluation of the efficacy and safety of hypofractionated radiotherapy for Japanese women.Data in the medical records of 327 patients were retrospectively reviewed. The patients were treated with hypofractionated radiotherapy between January 2003 and December 2006 at the Kawasaki Medical School Hospital and were followed for more than 3 years. The median age was 54 years old (the age range was 28-80 years). The whole breast was irradiated with a total dose of 42.56 Gy/16 fx with boost irradiation to positive margins. Adjuvant therapy consisted of chemotherapy and/or hormone therapy and was administered to 300 patients, based on their stage or pathological findings.Follow-up periods ranged from 21 to 92 months; the median follow-up period was 60 months. At 5-year follow-up, overall survival, cause-specific survival, relapse-free survival, and local control were 96.0, 97.5, 95.3, and 99.7% respectively. Grade 2 radiation pneumonitis occurred in five patients. Grade 2 radiation dermatitis occurred in 17 patients. Severe late complications were not observed.In our study, hypofractionated radiotherapy led to good results without severe toxicity. We believe hypofractionated radiotherapy after BCS is safe and efficient treatment for Japanese women.

To clarify the current trends in TSH suppression therapy for Japanese papillary carcinoma patents, a questionnaire survey was conducted among hospitals employing councilors of the Japanese Society of Thyroid Surgery.The questionnaire consisted of 11 clinical questions divided into two sections.One hundred and seventy-two questionnaires were mailed, and 89 hospitals (51.7%) responded and were included in the analyses. Total thyroidectomy (38.4%) was less common compared with non-total thyroidectomy. TSH suppression therapy was performed in 72 hospitals (80.7%). In 30 hospitals (41.7%), all patients were treated with TSH suppression therapy. The patients with advanced disease (33.3%), at high risk (28.6%) and with total thyroidectomy (19.0%) were selected at the remaining 42 hospitals. The majority of responding hospitals did not have a standard policy regarding the serum level of TSH for each patient (70.0%). The common criterion for the adjustment of serum TSH was the risk classification (73.9%). The duration of TSH suppression therapy was not specified in most hospitals (75.8%).Our survey demonstrated that TSH suppression therapy is a common adjuvant therapy, but that the criteria for adjustment, the indications for and the duration of this therapy have not been standardized in Japan.

Objective: The cell cycle profile test is suggested to be an independent prognostic indicator for breast cancer patients. To further clarify the prognostic value, we applied this to breast cancer patients treated with postoperative 5-fluorouracil-based chemotherapy. Methods: A total of 153 breast cancer patients, who were treated with postoperative 5-fluorouracil-based chemotherapies, were randomly selected. Specific activities of cyclindependent kinases 1 and 2 in the tumor samples were analyzed. Patients were divided into three categories (low, intermediate or high risk) based on cell cycle profile analysis. Results: The proportions of the cell cycle profile categories were 39% for low risk, 10% for intermediate risk and 45% for high risk, respectively. Although the cell cycle profile test did not show a significant predictive power for relapse-free survival (high vs. low risk; P ¼ 0.052), the cell cycle profile categories were significant prognostic factors in a subgroup of 98 patients with fewer than three involved nodes (high vs. low risk, P ¼ 0.004). Multivariate analyses also indicated that a cell cycle profile parameter (high vs. low risk) was an independent prognostic indicator from the number of involved nodes and clinical stage in this subgroup (hazard ratio ¼ 2.46, P ¼ 0.01). Interestingly, the prognostic power of the cell cycle profile test was significant in 75 patients treated with oral 5-fluorouracil derivatives alone (hazard ratio ¼ 6.29 for high vs. low risk, P ¼ 0.02). Conclusions: These findings suggest that the cell cycle profile test is useful for predicting a higher risk of relapse in patients treated with postoperative 5-fluorouracil-based chemotherapy.

To elucidate the clinicopathological significance of Y416Src and Y527Src expression in breast cancer, and to evaluate their usefulness as potential predictive markers for Src inhibitors.c-Src is a non-receptor tyrosine kinase; the active form of c-Src can catalyse tyrosine phosphorylation. The expression and activity of c-Src correlates with cell adhesion, survival, angiogenesis, migration, invasion and osteoclast function. There are limited clinicopathological data on Src expression and breast cancer characteristics.An immunohistochemical study was performed to determine the expression of c-Src, Y416Src, and Y527Src in 215 consecutive breast cancer cases. The correlation of their expression with various clinicopathological factors was analysed statistically.c-Src was expressed in all 215 cases (100%). Y416Src was expressed in 174 cases (80.9%) and was highly expressed in 30 cases (14.0%). Y527Src was expressed in 138 cases (64.2%) and was highly expressed in 11 cases (5.1%). High expression of Y416Src was significantly associated with metastatic disease (p=0.0327), whereas high expression of Y527Src was significantly associated with metastatic disease (p=0.0004), clinical stage (p=0.0062), as well as HER2 status (p=0.0149). High expression of either Y416Src or Y527Src was significantly correlated with poor overall survival (p=0.0049 and p0.0001, respectively). In the 192 curatively operated cases, Y416Src expression was significantly associated with poor disease-free survival (p=0.0088).Although further studies to assess Src activity are necessary, investigation of Src inhibitors for breast cancer including in-vivo models should be encouraged more.

目的 : 大腸癌大動脈リンパ節（216LN）転移は遠隔転移の扱いであり通常化学療法の対象となるが，外科的切除により長期予後が得られることがある．そこで当科で216LN転移巣に対して大動脈周囲の系統的郭清を行った症例を検討し手術適応について考察した．対象 : 当科で経験した大腸癌症例580例中（2003年12月-2010年3月），他臓器遠隔転移がなく216LNを系統郭清した9例．男：女＝4：5，平均年齢63歳，原発巣は横行結腸2例，S状結腸3例，直腸4例．結果 : 216LN転移は，再発6例（初回手術時Stage II：1例，IIIa：1例，IIIb：4例），同時性（Stage IV）3例であった．StageIV症例のうち2例は原発巣との同時切除，1例は原発巣切除後1年間化学療法を行ったのち216LN郭清を施行した．216LN郭清後の2年生存率は64％で（異時的郭清例：85％，同時郭清例：0％），最長生存期間は6年9か月であった．生存6例（全例無再発），死亡3例であったが，両者に年齢・性別・原発巣占居部位・組織型の差はなく，相違点として216LN切除を原発巣と異時的に施行した症例の予後が有意に良好であったことがあげられた（p=0.035）．結論 : 大腸癌術後に216LNのみに再発し，また原発巣とは異時的に郭清術を施行した症例は良好な長期予後が得られ，積極的な外科的治療の対象と思われた．

Since the concept of gene profile-based intrinsic subtypes was proposed, various studies on pathological characteristics have been performed. Particularly, triplenegative (TN) breast cancer, which is negative for all hormone receptors [estrogen receptor (ER) and/or progesterone receptor (PgR) and human epidermal growth factor 2 (HER2)], has been attracting attention because effects of endocrine and targeting therapies cannot be anticipated and thus selecting a treatment method is difficult. TN cancer accounts for about 10%-15% of all invasive breast cancer cases in Japanese, which is significantly lower than the incidence reported in the United States. Cytokeratin (CK) 5/6 or epidermal growth factor receptor (EGFR) is positive in 80%, being classified as basal-like carcinoma, but it should be understood that TN breast cancer and basal-like carcinoma are not necessarily the same. Criteria for positivity judgment of ER, PgR, and HER2 were established to select treatment in cases positive for each marker, and greater importance is attached to strict accuracy control. Inversely, the level of negative findings to judge TN varies among the judgment criteria. In any case, the prognosis of TN breast cancer is poor. Pathologically, TN breast cancer shows certain morphological characteristics, such as high grade and a pushing margin, and abnormalities of BRCA1 and p53 are frequently noted. At present, as no effective therapeutic strategy has been established for TN breast cancer, further clarification of the molecular biological characteristics of such cancers is needed. In addition, the incidence of TN-type ductal carcinoma in situ (DCIS) is low, suggesting that TN does not remain preinvasive DCIS for a prolonged period and that it transforms to invasive cancer in an early stage. Because mammary gland basal cells have characters of progenitor or stem cells that differentiate into both luminal epithelium and myoepithelial cells, these cells may be utilized for the differential diagnosis of the benignity or malignancy of intraductal lesions in routine pathological practice. As proliferation markers, such as Ki-67, and multiple gene arrays for gene signature are also utilized to select adjuvant therapy, analysis may progress further in the future.

A 64-year-old man was admitted to Dongo Hospital (Nara, Japan) with colonic cancer, following the onset of abdominal pain, diarrhea and fever. A pedunculated polyp was detected in the sigmoid colon by colonoscopy, and laparoscopy-assisted sigmoidectomy with regional lymph node resection was performed. Histopathologically, the tumor exhibited massive invasion of the submucosa, and multiple lymph node metastases were detected. The tumor mainly consisted of a micropapillary component. Immunohistochemically, MUC1 was expressed at the stromal edge of the micropapillary component and showed the characteristic 'inside-out' pattern of a micropapillary carcinoma. The multiple lymph node metastases were predominantly composed of carcinoma with a micropapillary pattern. Our case suggests that when a micropapillary component is identified in a pre-operative biopsy specimen, even for a pedunculated early colorectal cancer, the extent of surgical resection should be carefully considered due to the high potential for nodal metastasis.

Our previous study indicated that concurrent administration of 4-OH-tamoxifen (TAM) and 5-fluorouracil (5-FU), but not doxorubicin (Dox), resulted in additive antitumor effects on endocrine-responsive breast cancer cells. We further clarified the effects of combined administration of endocrine therapy with chemotherapeutic agents in this study. Concurrent treatment with 4-OH-TAM and paclitaxel (Ptx) was investigated in estrogen receptor (ER)-positive breast cancer cells. Additionally, the combined effects of estrogen depletion from culture medium mimicking estrogen ablative therapy with 5-FU, Dox, and Ptx were investigated. Concurrent treatment with 4-OH-TAM and Ptx yielded less than additive antitumor effects in ER-positive breast cancer cells, as observed with Dox in our previous study. More interestingly, estrogen depletion with 5-FU, but with neither Dox nor Ptx, yielded additive antitumor effects on these cells. We also performed preliminary experiments to elucidate the mechanisms of action responsible for the combined antitumor effects observed. Ptx up-regulated the level of expression of one of the molecules related to TAM resistance, Eph-A2, as observed with Dox in our previous study. Estrogen depletion down-regulated the level of expression of one of the molecules related to 5-FU resistance, thymidylate synthase, as observed with 4-OH-TAM in our previous study. These findings, together with those of our previous study, suggest that concurrent treatment with endocrine therapy, administration of TAM, or estrogen ablative therapy and 5-FU but neither Dox nor Ptx may yield additive antitumor effects on endocrine-responsive breast cancer.

Purpose The primary aim of this study was to compare the effectiveness of oral uracil-tegafur (UFT) with that of classical cyclophosphamide, methotrexate, and fluorouracil (CMF) given as postoperative adjuvant treatment to women with node-negative, high-risk breast cancer. Patients and Methods Women with node-negative, high-risk breast cancer were randomly assigned to receive either 2 years of UFT or six cycles of CMF after surgery. The primary end point was relapse-free survival (RFS). Overall survival (OS), toxicity, and quality of life (QOL) were secondary end points. The hypothesis was that UFT was not inferior to CMF in terms of RFS. Results Between October 1996 and April 2001, a total of 733 patients were randomly assigned to receive either treatment. The median follow-up time was 6.2 years. The RFS rates at 5 years were 88.0% in the CMF arm and 87.8% in the UFT arm. OS rates were 96.0% and 96.2%, respectively. The hazard ratios of the UFT arm relative to the CMF arm were 0.98 for RFS (95% CI, 0.66 to 1.45; P = .92) and 0.81 for OS (95% CI, 0.44 to 1.48; P = .49). The toxicity profiles differed between the two groups. The QOL scores were better for patients given UFT than those given CMF. Conclusion RFS and OS with oral UFT were similar to those with classical CMF. Given the higher QOL scores, oral UFT is a promising alternative to CMF for postoperative adjuvant chemotherapy in women with node-negative, high-risk breast cancer.

Monocyte chemotactic protein-1 (MCP-1) is a chemokine ligand that has been associated with aggressive behavior in breast and prostate cancer. The present study was performed to determine if there is a relationship between the expression of MCP-1 in papillary thyroid carcinoma (PTC) and factors indicative of aggressive behavior in this disease.The subjects of this study were 115 patients with PTC. MCP-1 expression was determined using a semiquantitative scoring system for immunohistochemical staining of MCP-1 in resected PTC samples. There were four levels of immunohistochemical staining intensity, and the population of cells that positively stained for MCP-1 was graded at four levels. The scores for the intensity of immunohistochemical staining for MCP-1 and for the percentage of cells that stained for MCP-1 were used to generate a range from 0 to 9 for scoring MCP-1 expression.Positive staining for MCP-1 was observed in the cytoplasm of PTC cells and stroma cells in 79.2% of the specimens. Expression levels of MCP-1 in PTC cells were positively correlated with tumor size (p0.05) and lymph node involvement (p0.05). In addition, the expression of MCP-1 in PTC cells level was an independent predictive factor for recurrence of PTC in an analysis that included age, sex, tumor size, extrathyroidal infiltration, and lymph node involvement (p0.005).MCP-1 expression in PTC may stimulate the aggressive behavior of this tumor or it may be a marker for aggressive behavior. Previous reports with non-thyroid tumor cells favor the hypothesis that MCP-1 expression promotes aggressive behavior in PTC.

症例は69歳男性．膀胱三角部に浸潤するS状結腸進行癌Stage IIIbに対し，2008年1月にS状結腸切除D3・膀胱合併切除・尿路再建術を行った．術後2日目に高熱および全身痙攣を呈し昏睡となった．画像上，脳出血・梗塞などは認めず，髄液は無菌性髄膜炎の所見を呈したことから抗ウイルス薬による治療を行い，状態は改善した．後日髄液から単純ヘルペスウイルスDNA陽性を確認した．続いて術後18日目に敗血症性ショックを呈した．当初感染源は不明であったが血液培養よりMRSAを検出し，バンコマイシン投与および透析治療を行った．その後左腸腰筋膿瘍を確認し保存療法により軽快した．2008年4月に退院し，現在再発兆候は認めていない．結腸癌術後早期のウィルス性髄膜炎と腸腰筋膿瘍の合併は他に例がない．遠因として術前の長期担癌状態による低栄養や免疫力低下が推測され，また徹底した原因検索・早期治療と栄養の継続投与により救命し得たと考えられた．

症例は69歳, 男性. 2006年1月に胃癌 (4型) に対し, 当院消化器外科で幽門側胃切除+R-Y吻合を施行. 病理は低分化腺癌T3 N0 P1 H0 M0 CY1 Stage IV. 術前からかゆみ, 関節痛も存在し, さらにCa, intact-PTHの高値を指摘されており, 術後に当科紹介となった. 腎結石の既往が3回あり. 頸部に明らかな腫瘤を触知しない. 血液検査ではCa 10.2mg/dl, intact-PTH 128pg/mlと高値を示した. 頸部超音波検査では左下副甲状腺嚢胞を疑う所見であった. 2006年2月に手術. 術中病理検査で, 左下の副甲状腺 (PT) だけでなく, 左上のPTも嚢胞性腫瘤であったため, 過形成の可能性を考慮し, 対側の検索を行った. そこで右下のPTも腫大していたため, 4腺全摘を行った. 術後経過は良好で, Ca, intact-PTHは速やかに低下した. 永久病理検査では, 左下PTは嚢胞であり, 他は過形成であった. その後当院消化器外科で胃癌に対して化学療法を行ったが, 胃癌術後3カ月で永眠された.

The sequential addition of tamoxifen (TAM) to chemotherapy seems superior to its concurrent addition in patients with breast cancer. This study was conducted to clarify the hypothesis that there are differential interactions among TAM and chemotherapeutic agents.Estrogen receptor (ER)-alpha-positive or -negative breast cancer cells were treated with 4-hydroxy TAM (4OHT), 5-fluorouracil (FU) and/or doxorubicin (Dox). Changes in the expression levels of genes related to sensitivity and resistance to TAM, 5-FU or Dox were tested.Concurrent treatment of 4OHT with 5-FU but not with Dox additively inhibited the growth of ER-alpha-positive cells. 5-FU did not change the expression levels of any tested genes related to either sensitivity or resistance to TAM. Although Dox did not change the expression levels of any genes related to the sensitivity to TAM, Dox significantly increased the expression levels of some genes related to TAM resistance, Eph A-2, ER-beta, Fos and vascular endothelial growth factor. 4OHT significantly decreased thymidilate synthase (TS) activity.Although the antitumor effect of concurrent 4OHT and 5-FU was additive, that of concurrent 4OHT and Dox was less than additive in ER-alpha-positive cells. The increased expression of genes related to TAM resistance by Dox might be responsible for the interaction. Decreased TS activity by 4OHT might increase the antitumor activity of 5-FU. These findings may provide a preclinical rationale for concurrent use with 5-FU and TAM.

BACKGROUND: Serum CA15-3 has been one of the most reliable tumor markers used in monitoring breast cancer patients; however, its sensitivity in detecting metastases is limited. To increase its sensitivity, the combined measurement of other tumor markers with CA15-3 was investigated. METHODS: Serum CA15-3, carcinoembryonic antigen (CEA) and sialyl Lewis X (CSLEX) were simultaneously measured in a prospective series of 455 postoperative breast cancer patients with or without metastasis. The diagnostic parameters sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for detecting metastases were compared. The correlation of values between pairs of tumor markers was analyzed. The efficacy of combined measurement of two different tumor markers was also evaluated. RESULTS: The sensitivity for detecting metastases was 61.5, 56.9 and 52.3%; specificity was 97.2, 93.6 and 96.2%; PPV was 78.4, 59.7 and 69.4%; NPV was 93.8, 92.9 and 92.4%; and accuracy was 92.1, 88.8 and 89.9% for CA15-3, CEA and CSLEX, respectively. The values for CA15-3 were significantly correlated with those for CEA (P < 0.001) but not those for CSLEX. The combined measurement of CSLEX and CA15-3 increased the sensitivity by 17.0% but that of CEA and CA15-3 increased the sensitivity by only 10.8%. All diagnostic parameters for the combined measurement of CSLEX and CA15-3 were higher than those for the combined measurement of CEA and CA15-3. CONCLUSIONS: These findings suggest that CSLEX may be more useful than CEA in combination with CA15-3 in monitoring breast cancer patients. The results of this study suggest that CSLEX may be more useful than CEA in combination with CA15-3 in monitoring breast cancer patients.

BACKGROUND 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. METHODS Patients (N = 1901)with unilateral breast cancer ≤ 3 cm in diameter who underwent BCT at 18 Japanese major breast cancer treatment institutes from 1986 to 1993 were registered in this study. Survival rates, the incidences of IBTR and distant metastases, and annual rates of IBTR and distant metastases after primary operation were calculated by the Kaplan–Meier method. A Cox proportional hazards model was used to estimate the risks of IBTR and distant metastases. A Cox model was also used to estimate the risks of distant metastases after IBTR in the group of IBTR. RESULTS At a median follow-up time of 107 months, the 10-year overall and disease-free survival rates were 83.9% and 77.8%, respectively. The 10-year cumulative rates of IBTR were 8.5% in the patients with postoperative irradiation and 17.2% in the patients without irradiation. The 10-year cumulative distant metastasis rate was 10.9%. On multivariate analysis, young age, positive surgical margin, and omission of radiation therapy were significant predictors of IBTR. In addition, IBTR significantly correlated with subsequent distant metastases (hazard ratio, 3.93; 95% confidence interval, 2.676–5.771; P < 0.0001). Among patients who developed IBTR, initial lymph node metastases and short interval to IBTR were significant risk factors for subsequent distant metastasis. CONCLUSIONS Young age, positive surgical margin, and omission of radiation therapy seemed to be important factors in relation to local control. The authors' results also indicated that IBTR is significantly associated with subsequent distant metastasis. Patients with positive nodal status at primary operation or with short interval from primary operation to IBTR are at especially high risk of distant metastasis. It remains unclear, however, whether IBTR is an indicator or a cause of subsequent distant metastases. Cancer 2006. © 2005 American Cancer Society.

This retrospective study analyzes the predictive factors after curative surgery for papillary thyroid carcinoma (PTC).We analyzed 386 patients who underwent a curative operation for PTC in our hospital between 1977 and 1997, subject to the inclusion criteria.According to univariate analysis, pathological lateral cervical lymph node involvement (P0.0001), dedifferentiation of the tumor (P0.002), male sex (P0.0001), a large tumor (P0.005), and an age of over 50 years (P0.05) were significant factors. Cox's proportional hazard model showed that a man (P0.05), aged over 50 years (P0.05), who had a large primary tumor (P0.05) with dedifferentiation (P0.05), and pathological lateral cervical lymph node metastasis (P0.005) was more likely to have recurrence of PTC.Determining whether lymph node metastasis exists could be useful for predicting recurrence in patients who have undergone curative resection of PTC.

Ipsilateral breast tumor recurrences (IBTR) after breast-conserving treatment include two different entities: true recurrence (TR) thought to occur when residual cancer cells grow gradually to detectable size and new primary (NP) thought to be de novo cancer independently arising in the preserved breast. The patients with ipsilateral breast tumor recurrence (IBTR) are potentially at high risk for subsequent distant metastasis, but many studies do not distinguish between these types of recurrence. The aim of this study is to clarify the biological difference between TR and NP, and to show the clinical significance of classifying IBTR into these two types of recurrence.A total of 172 patients with IBTR after breast-conserving therapy from the cohort of a long-term large scale study (Research of cancer treatment from the Ministry of Health, Labor and Welfare of Japan (no.13-9)) were analyzed. We classified IBTRs as TR or NP based on tumor location and pathological findings. The characteristics of the primary tumors of TR and NP were compared. Survival rates and risk factors of each type of IBTR were examined by the Kaplan-Meier method. The results of salvage surgery were also analyzed.Of the 172 patients, 135 patients were classified as TR and 26 as NP. Eleven cases could not be categorized. The primary tumor of TR was characterized by a high rate of lymph node metastasis (37.8%) and short disease-free interval (mean DFI; 46.6 months) while that of NP showed a rather low lymph node positivity (8.7%) and longer DFI (62.1 months). The risk factors for TR were young age, positive surgical margin, omission of irradiation and positive lymph node metastasis. Those for NP were young age, omission of irradiation and contralateral breast cancer after the primary operation. The 5-year survival rates after IBTR were 71.0% in TR and 94.7% in NP (p=0.022). Salvage operation was performed in 136 IBTRs. Eighty-one patients underwent salvage mastectomy and 55 patients underwent repeat lumpectomy. Five-year survival rates after salvage operation were 75.7% for mastectomy and 84.2% for lumpectomy (N.S.). Twenty percent of patients who underwent repeat lumpectomy developed secondary local relapse within 5 years after salvage treatment. The risk factors for secondary local relapse were analyzed. Limited to cases of IBTR which received radiation therapy after the primary operation, NP was the only factor influencing secondary local relapse by univariate analysis.TR and NP show clinically quite different features; time to occurrence, characteristics of the original tumor, prognosis and risk factor profile for IBTR were all different. Classifying IBTR as TR or NP can provide clinically significant data for the management of IBTR.

A high expression level of epidermal growth factor receptor (EGFR)/HER1 has been suggested to lead to a shorter survival time and resistance to endocrine therapy in patients with breast cancer. To test the hypothesis that inhibition of the EGFR signalling pathway affects the antitumour effect of endocrine therapy, an EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib, and an oestrogen receptor (ER) antagonist, fulvestrant, were administered to human breast cancer cells. A total of five human breast cancer cell lines were used. The effects of single or combined treatments with gefitinib and/or fulvestrant on cell growth, cell cycle progression and apoptosis were analysed. Changes in the expression levels of cyclin-dependent kinase inhibitors, p21 and p27, an antiapoptotic factor, Bcl-2, and a proapoptotic factor, Bax, were also investigated. All cell lines tested were sensitive to gefitinib (50% growth inhibitory concentration, 10-28.5 microM). Breast cancer cell lines with a high expression level of HER1 or HER2 were more sensitive to gefitinib than the others. Gefitinib induced a significant G1-S blockade in ER-positive KPL-3C cells. Gefitinib induced significant apoptosis in HER1-overexpressing MDA-MB-231 cells. Gefitinib additively increased the antitumour effect of fulvestrant in all three ER-positive cell lines in a medium supplemented with 17beta-oestradiol. The combined treatment promoted cell cycle retardation in KPL-3C cells, which is associated with an upregulation of p21 by fulvestrant and gefitinib, respectively. Apoptosis was associated with downregulation of Bcl-2 by gefitinib in MDA-MB-231 cells. These results suggest an additive interaction between the EGFR-TKI gefitinib and the antioestrogen fulvestrant in ER-positive breast cancer cells.

乳房原発悪性リンパ腫は,乳房悪性腫瘍の0.04～0.5%,節外性悪性リンパ腫の約2.1%を占める稀な疾患である.なかでも,妊娠・授乳期に発症する報告は非常に少なく,またその多くはBurkitt lymphomaで通常頻度の高いdiffuse B-cell lymphomaの報告はほとんどない.今回われわれは,妊娠期に発症した乳房原発悪性リンパ腫1例を経験した.症例は30歳,女性,妊娠13週. 2002年1月左乳房腫瘤自覚.穿刺吸引細胞診class IV,悪性リンパ腫を疑われ当科紹介受診.摘出生検施行.病理検査結果diffuse large B-cell lymphoma. stage IE期.妊娠中絶後CHOP施行.妊娠期乳房原発悪性リンパ腫の稀な症例であった.乳房原発悪性リンパ腫は乳癌との鑑別が困難である.今回われわれは摘出生検後,化学療法を施行できたが,無駄な拡大手術を避け,適切な治療を選択することが必要であると思われた.

Epidermal growth factor receptor (EGFR)/HER1 is expressed at high levels in at least 20% of breast cancers. This high expression correlates with a poor prognosis in patients with breast cancer. Experimental and clinical findings suggest that aberrant activation of tyrosine receptor kinases, such as HER1 pathway, play a causal role in the development of antiestrogen resistance in breast cancer. Recent preclinical and clinical evidence shows that inhibition of growth factor signaling pathways suppresses the growth of malignant cells without serious toxicities. To test the hypothesis that inhibition of the HER1 signaling pathway enhances the antitumor effect of endocrine therapy, a promising signal transduction inhibitor (STI) of HER1 tyrosine kinase, gefitinib, and an estrogen receptor (ER) antagonist, fulvestrant, were administered to human breast cancer cells. Our experimental results have revealed that gefitinib additively enhances the antitumor effect of fulvestrant in estrogen receptor (ER)-positive breast cancer cells under estrogen-supplemented conditions. An additive increase in the protein expression level of a cyclin-dependent kinase inhibitor, p21 may play a key role of this additive cytostatic effect. The rationale and future perspectives of the combined use of STIs with endocrine therapy in breast cancer are discussed.

We report a unique case of metastatic papillary thyroid carcinoma of the submandibular lymph nodes with extensive squamous metaplasia. A 48-year-old man was referred to our hospital for treatment of a thyroid tumor and right submandibular masses. A tumor, 2 cm in its largest dimension, was palpated in the right lobe of the thyroid gland. The masses in the submandibular region measured up to 3 cm in diameter. Each submandibular tumor had a cystic cavity containing slightly opaque fluid. Aspiration cytology of the thyroid established a diagnosis of papillary carcinoma. Aspirated material from the cystic cavity of one of the submandibular masses contained only keratinized material with a thyroglobulin level of 175 ng/ml. The patient underwent a total thyroidectomy with modified radical neck dissection. Microscopic examination of the resected specimen confirmed a diagnosis of papillary carcinoma of the thyroid, as well as well-differentiated squamous cell carcinoma with cystic changes in the submandibular lymph nodes. Focal immunoreactivity for thyroglobulin, combined with the absence of any other possible primary lesions in the head and neck region, suggested metastatic papillary thyroid carcinoma of the submandibular lymph nodes with extensive squamous metaplasia.

The Cell Cycle Profiling - Risk Score (C2P-RS) based on CDK1 and CDK2 specific activities was significantly associated with relapse in breast cancers. We evaluated the prognostic value of the C2P-RS classification using a Japanese cohort including node-negative, hormone receptor-positive breast cancers treated with adjuvant endocrine therapy alone as systemic therapy. Of 266 patients, 22 (8.3%) relapsed within 5 years after surgery. The distribution of each C2P-RS group was 71.8% in the low group, 12.0% in the intermediate group, and 16.2% in the high group. The 5-year relapse-free survival rate in the low C2P-RS group (97.3%) was significantly higher than that in the intermediate C2P-RS group (84.3%) or the high C2P-RS group (74.4%) (P 0.001). The univariate analysis demonstrated that age, tumor size, histologic grade, and HER2 had no significant correlations with relapse but the C2P-RS classification (P 0.001) and Ki-67 (P = 0.009) were significantly associated with relapse. Multivariate analysis showed only that the C2P-RS classification was a significant independent prognostic indicator. The C2P-RS classification might be a significant predictor of earlier recurrence in node-negative, hormone receptor-positive breast cancers treated with endocrine therapy.

The aim of this study was to determine the significance of HBME-1 immunostaining in the differentiation between intranodal benign thyroid tissue and metastatic papillary thyroid carcinoma in the lymph node. Immunohistochemically we examined normal-appearing intranodal thyroid tissue in four patients who did not show evidence of papillary carcinoma histologically or clinically. We also examined follicular-pattern-predominant papillary carcinoma with metastatic foci in the lymph nodes. Normal-appearing intranodal thyroid tissue and normal thyroid showed no immunopositivity for HBME-1. In contrast, all papillary carcinomas in both the lymph nodes and thyroid demonstrated strong positivity for HBME-1. HBME-1 was predominantly positive for the luminal surface of the tumor cells. The immunopositivity of the cuboidal and low columnar carcinoma cells was more intensive than that of the flat-shaped cells in the lymph nodes and thyroid. The results probably indicate that HBME-1 immunostaining is helpful in distinguishing between intranodal benign thyroid tissue and metastatic papillary carcinoma in lymph nodes. We emphasize that the HBME-1 reactivity should be evaluated in connection with the histological findings, and that positive and negative controls stained in parallel are necessary.

Purpose: Although several combination treatments with docetaxel and other antitumor agents have been tested in experimental and clinical studies, their synergistic effects are still ill-defined. The degree of synergism between docetaxel and two oral fluoropyrimidines, tegafur and 5′-deoxy-5-fluorouridine (5′-dFUrd), was investigated in the KPL-4 human breast cancer xenograft model. Methods: Because this KPL-4 cell line secretes interleukin-6 (IL-6) and induces cachexia, the effects of the combined treatment on serum IL-6 levels and cachectic markers were investigated. In addition, the expression levels of thymidine phosphorylase (dThdPase), a key enzyme for converting 5′-dFUrd to 5-fluorouracil, were determined. Female nude mice bearing KPL-4 tumors were treated orally with 5′-dFUrd (60 mg/kg, five times a week) or tegafur (100 mg/kg, five times a week) and by intraperitoneal injection of docetaxel (5 or 10 mg/kg, once a week). Results: Although docetaxel (5 mg/kg) alone did not decrease either tumor growth or serum IL-6 levels, docetaxel (5 mg/kg) plus 5′-dFUrd or tegafur enhanced tumor growth inhibition and decreased serum IL-6 levels more than 5′-dFUrd or tegafur alone. Docetaxel (5 mg/kg) alone slightly increased the percentage of dThdPase-positive tumor cells, but the combined treatment with docetaxel plus 5′-dFUrd or tegafur significantly decreased the percentage of dThdPase-positive cells in the KPL-4 tumors. Conclusion: These findings indicate that docetaxel may stimulate dThdPase expression in tumor tissues and may enhance the antitumor activity of oral fluoropyrimidines. In addition, combined treatment with docetaxel and oral fluoropyrimidines may decrease serum IL-6 levels and may ameliorate IL-6-induced cancer cachexia.

A novel oxime derivative of radicicol, KF58333, binds to the heat shock protein 90 (Hsp90) and destabilizes its associated signaling molecules. These effects play a critical role in the growth inhibition of tumor cells. To further investigate the effects of this agent, it was administered to two human breast cancer cell lines, KPL-1 and KPL-4, both in vitro and in vivo. KF58333 dose-dependently inhibited the growth and vascular endothelial growth factor (VEGF) secretion, concomitantly with a decrease in VEGF mRNA expression, in each cell line. This agent also suppressed the increase of VEGF secretion and expression induced by hypoxia (1% O(2)). Intravenous injections of this agent into nude mice bearing either KPL-1 or KPL-4 xenografts significantly inhibited the tumor growth associated with a decrease in the Ki67 labeling index and microvascular area and an increase in apoptosis and the necrotic area. These findings indicate that the antitumor activity of this radicicol derivative may be partly mediated by decreasing VEGF secretion from tumor cells and inhibiting tumor angiogenesis. To explore the action mechanisms of the anti-angiogenic effect, the expression level of hypoxia-inducible factor (HIF)-1alpha was investigated. KF58333 provided a significant decrease in the HIF-1alpha protein expression under both normoxic and hypoxic conditions. In contrast, the mRNA expression of HIF-1alpha was not decreased by this agent. It is suggested that the post-transcriptional down-regulation of HIF-1alpha expression by this agent may result in a decrease of VEGF expression and tumor angiogenesis.

Predictive markers and variables for response to anticancer therapy provide cancer patients with refinement of therapeutic options and a decreased likelihood of receiving an ineffective therapy. The best-established predictive marker for response to endocrine therapy for breast cancer is the status of estrogen receptors (ER) in the primary breast tumor. However, although patients with ER-positive tumors have a greater than 50% objective response rate to endocrine therapy, other patients can not obtain an objective response. Therefore additional markers, such as better molecular biologic markers, are needed. Our previous study using multivariate analysis revealed that the ER status of primary tumors and the dominant site of metastasis are independent predictors for response to first-line endocrine therapy and that a response to first-line endocrine therapy is only an independent predictor for response to second-line endocrine therapy. However, all these factors are already well-established predictive markers for response to endocrine therapy. Recently, a number of new hormonal agents, such as more selective aromatase inhibitors and specific antiestrogens, have been developed and introduced. However, several questions, such as the best sequences when using hormonal agents, remain to be elucidated. On the other hand, several molecular biologic markers predicting response to endocrine therapy, such as the expression of the HER family of tyrosine kinase receptors, pS2, Bcl-2, and vascular endothelial growth factor, have been reported. To elucidate the most effective use of endocrine therapy for recurrent breast cancer, classical and new predictive factors for response to endocrine therapy are reviewed, and the clinical implications of these factors are discussed.

A new human thyroid carcinoma cell line, KTC-1, was established from the malignant pleural effusion of a recurrent thyroid carcinoma patient. Cytogenetic analysis revealed a normal karyotype, and no p53 mutation in exons 5‐9 was detected. This cell line is tumorigenic in athymic nude mice. Histological findings by light and electron microscopy, such as the absence of follicular structures and the existence of intranuclear cytoplasmic inclusions and psammoma bodies, indicated transplanted tumors to be a poorly differentiated papillary thyroid carcinoma. A low expression level of thyroglobulin was detected by immunocytochemistry and RT-PCR. Messenger ribonucleic acid (mRNA) expression of thyroid transcription factor-1 and PAX-8 was also detected. No mRNA expression of TSH receptors, thyroid peroxidase, or Na 1 /I 2 symporter was detected. Interleukin-6 and leukemia inhibitory factor were secreted into the medium. These findings suggest this cell line to be functionally poorly differentiated. Moreover, all-trans-retinoic acid increased the mRNA expression of thyroglobulin and decreased both the mRNA expression and secretion of interleukin-6 and leukemia inhibitory factor while significantly stimulating growth. RT-PCR analysis of retinoic acid receptors (RARs) revealed that KTC-1 cells express a moderate level of RARa and -g, but a low level of RARb. This cell line may be useful for studying redifferentiation therapy for thyroid carcinoma. (J Clin Endocrinol Metab 85: 2889 ‐2896, 2000)

A 63-year-old woman was admitted to the hospital because of appetite loss, dry mouth, and slight disturbance of consciousness on February 3, 1999. There was a previous history of undergoing a total thyroidectomy for differentiated thyroid cancer and multiple bone metastasis followed by TSH inhibition regimen and internal irradiation with 131I (3 times) in December 1995. Thereafter she had been followed up in our outpatient clinic until this admission. On admission, blood and biochemical examinations showed inflammatory findings and hypercalcemia. Chest x-ray film revealed multiple pulmonary metastasis. On 67Ga scintigraphy, faint accumulation in the bilateral middle and lower lung fields and left iliac region were demonstrated. Histological findings of metastasized portion of the left iliac bone were not contradictory to those of undifferentiated cancer. In the clinical course after admission, the metastatic lung lesion abruptly enlarged, respiratory condition became worse, and the patient died on March 12, 1999. Increases in various serum cytokines such as G-CSF and PTHrP were confirmed that might cause inflammatory findings including leukocytosis and hypercalcemia.

Background and objectives Differences in the expression levels of Thyroglobulin (Tg), Thyroid peroxidase (TPO) and thyrotropin receptor (TSH-R) in primary and recurrent specimens under a suppressive serum TSH condition were elucidated in 26 papillary carcinoma patients. Methods Immunohistochemical detection was performed by use of each monoclonal antibody against Tg, TPO, and TSH-R. The staining concentrations of the three markers in each specimen were measured for comparison. Results The mean staining concentrations of Tg, TPO, and TSH-R in the entire primary tumor were 103.92, 104.6 and 89.25, respectively. Five cases showed stronger expression of all the differentiation markers and eight cases showed weaker expression of all these markers in recurrent tissue than in primary tumors. The weaker expression of TSH-R at the recurrent site as compared with that at the primary site significantly demonstrated the shortness of the disease free interval or overall survival. There were significant differences between the death due to cancer and the weaker expression of TSH-R in the recurrent tumor as compared with that in the primary tumor. Conclusions Under the TSH suppressive condition, the markers were not expressed uniformly among recurrent tumors. Even under that state, however, low expression of TSH-R in the recurrent tissue was strongly related to a poorer outcome in the patients.

Anti-oestrogen is effective for the treatment of oestrogen receptor (ER)-positive breast carcinomas, butmost of these tumours become resistant to anti-oestrogen. It has been suggested that anti-oestrogen therapy may induce a HER2signalling pathway in breast cancer cells and this may cause resistance to anti-oestrogen. Thus, it is conceivable that combinedtherapy with anti-oestrogen and anti-HER2 antibody might be more effective. In the present study, we investigated the effect ofcombined treatment with a humanized anti-HER2 monoclonal antibody, rhumAbHER2 (trastuzumab), and an anti-oestrogen, ICI 182,780, onthe cell growth of three human breast cancer cell lines which respectively express different levels of ER and HER2. The combinedtreatment enhanced the growth inhibitory effect on ML-20 cells, which express a high level of ER and a moderate level of HER2, butshowed no additive effect on either KPL-4 cells, which express no ER and a moderate level of HER2, or MDA-MB-231 cells, whichexpress no ER and a low level of HER2. It is also suggested that both the antibody and anti-oestrogen induce a G1–S blockadeand apoptosis. These findings indicate that combined treatment with anti-HER2 antibody and anti-oestrogen may be useful for thetreatment of patients with breast cancer expressing both ER and HER2. © 2000 Cancer Research Campaign

BACKGROUND: Four different endocrine therapeutic agents have been used in Japan since 1996. However, a consensus regarding proper use of these agents has notyet been established. Therefore, a questionaire survey of Japanese breast cancer authorities on endocrine therapy and a multi-institute survey to investigate the efficacy of a single first-line endocrine therapy for recurrent breast cancerwere conducted. MATERIALS AND PATIENTS: A total of 279 questionaires were sent to the Councilors of the Japanese Breast Cancer Society. The clinico-pathological data of 77 breast cancer patients who underwent a single first-line endocrine therapy were collected from five institutes. RESULTS: The response rate to this questionaire survey was 67.4%. The resultsshow that many authorities consider that: 1) both ER and PgR in primary tumors should be measured, 2) patient age, the disease-free interval and postoperative adjuvant therapy do not provide enough information for the selection of endocrine therapies, 3) antiestrogen and LH-RH agonists should be used as first-line endocrine therapies, 4) combined endocrine therapies, such as an antiestrogen plus an LH-RH agonist, should be used, 5) the optimal sequence of use of endocrine therapeutic agents is most controversial. The objective response rate to first-line endocrine therapies was 40.3% and the duration of response was over 15 months.The objective response rate to second-line endocrine therapies was 42.1%. A multiple regression analysis of predictive factors for the efficacy of first-line endocrine therapies indicated two factors, the disease-free interval and dominantsite of metastasis, to be significant. Conclusions: This questionaire survey suggests that clinical trials to investigate the optimal sequence of use of endocrine therapies and to clarify the usefulness of combined endocrine therapies should be conducted. Single first- or second-line endocrine therapies for recurrent breast cancer are effective and should be carried out by general clinicians.

We retrospectively analyzed the outcome for patients with locally invasive papillary carcinoma. The study group comprised 40 patients with locally invasive papillary thyroid carcinoma first diagnosed between 1981 and 1995. The enrolled patients were divided into two groups according to whether they underwent complete resection (n = 19) or not (n = 21). All patients were followed-up for a maximum of 206 months and a minimum of 33 months until 1998. There were no significant differences among these two groups with regard to age, sex, or tumor size. Recurrence of the disease was recognized in four patients in the complete resection group and ten in the incomplete group. There were no significant differences in the recurrence rate between both groups. Five patients from the incomplete resection group died of disease, and all patients from the complete resection group were alive. The percentage of surviving patients in the complete resection group was significantly higher than that in the incomplete group. The 15-year survival rates of the complete resection group and incomplete resection group were 100% and 74.2%, respectively. The 15-year survival rate of patients younger than 45 years in the incomplete resection group was 100%. The 15-year survival rate of the complete resection group was significantly higher than that of the incomplete group. In conclusion, complete resection without tumor residue should be performed for patients older than 45 years.

A new human breast cancer cell line, KPL-4, was recently isolated from the malignant pleural effusion of a breast cancer patient with an inflammatory skin metastasis. This cell line can be cultured under serum-free conditions and is tumorigenic in female athymic nude mice. Flow cytometric analysis revealed the expression of Erb B-1, -2 and -3. Dot blot hybridization showed a 15-fold amplification of the erbB-2. Reverse transcription-polymerase chain reaction analysis showed a detectable level of mRNA expression of all the Erb B family receptors. In addition, all the receptors were autophosphorylated under a serum-supplemented condition. Unexpectedly, transplanted KPL-4 tumours induced cachexia of recipient mice. A high concentration of interleukin-6 (IL-6) was detected in both the culture medium and the serum of mice. The weight of tumours significantly correlated with the serum IL-6 level. The antiproliferative effect of a humanized anti-Erb B-2 monoclonal antibody, rhuMAbHER2, was investigated. This antibody significantly inhibited the growth of KPL-4 cells in vitro but modestly in vivo. Loss of mouse body weight was partly reversed by rhuMAbHER2. These findings suggest that KPL-4 cells may be useful in the development of new strategies against breast cancer overexpressing the Erb B family receptors and against IL-6-induced cachexia. © 1999 Cancer Research Campaign

Recently the measurement of calcium level in blood has become easy, and resultantly the rate of occurrence of primary hyperparathyroidism has been increasing. We have retrospectively evaluated 53 cases of primary hyperparathyroidism in term of preoperative diagnosis. Hypercalcemia was recognized in all cases and hypophosphatemia in 36 cases (67.9%). The sensitivities of intact PTH, C-PTH and HS-PTH were 95.3%, 38.9% and 95.2%, respectively. The mean size of the resected tumors was 2.3±1.1cm in diameter, and the mean weight was 1, 241±2, 061mg. There was a signigicant correlation between the value of intact PTH and the mean weight and there were significant correlations between the value of HS-PTH and the both mean size and weight. Clinically. 35.8% of patients had no specific signs or symptoms (chemical type). 47.2% had a renal stone and 17.0% showed bone change. The histological types of recected parathyroid tumors were adenoma in 92.5% of the patients, hyperplasia in 7.5% and no carcinomas. In 49 adenoma cases, the sensitivities of ultrasonogram, CT, Tl-Tc scitigram, Tc-MIBI and MRI were 85.7%, 77.5%, 81.8%. 95.2% (100% in ectopic adenoma) and 58.3%, respectively. Tc-MIBI was the most reliable method. Ectokic adenomas were recognized in 16.7%, and 87.5% of these ectopic adenomas were detected in the thymus. It appears efficacious to start at the thymus for exploration of ectopic adenoma.

We report a case of columnar cell carcinoma of the thyroid. A 47-year-old Japanese man had a nonencapsulated thyroid mass that infiltrated the surrounding tissues extensively. Seventeen months after thyroidectomy he died of respiratory failure resulting from tracheal invasion. An autopsy showed distant metastases to the liver, lung, esophagus, and pancreas. Histologically, the thyroid mass consisted of tall columnar atypical cells with marked nuclear stratification, About one-fifth of tumor cells were immunopositive for M18-1. The MIB-1 -positive index of our case was extremely high, compared with that of ordinary papillary carcinoma. This case indicates that biological growth activity in columnar cell carcinoma may be similar to that of undifferentiated carcinoma of the thyroid, since the MIB-1 -positive index is close to each other.

Mutations in either of two recently identified genes, BRCA1 and BRCA2, are thought to be responsible for approximately two-thirds of all cases of autosomal-dominantly inherited breast cancer. To examine the nature and frequency of BRCA1 and BRCA2 mutations in Japanese families exhibiting a high incidence of breast cancer, we screened 78 unrelated families in this category for mutations of these two genes. Examining the entire coding sequences as well as exon-intron boundaries of both genes by polymerase chain reaction (PCR) single-strand conformation polymorphism (SSCP) and multiplex-SSCP analysis, we identified possible disease-causing alterations in BRCA1 among affected members of 15 families and in BRCA2 in another 14 families. In 15 of those 29 families, the affected individuals carried missense mutations, although most germline mutations reported worldwide have been deletions or nonsense mutations. Our results, indicating that missense mutations of BRCA1 and BRCA2 tend to predominate over frameshifts or nonsense mutations in Japanese breast cancer families, will contribute significantly to an understanding of mammary tumorigenesis in Japan, and will be of vital importance for future genetic testing.