Haruhiko Miyayama

Higher plasma vascular endothelial growth factor levels correlate with menopause, overexpression of p53, and recurrence of breast cancer.

PurposeVascular endothelial growth factor (VEGF) is an important factor involved in angiogenesis. Many studies have reported that the expression of VEGF in breast cancer is an unfavorable prognostic factor. However, there are few studies that have analyzed blood VEGF levels because most used serum VEGF, generally thought to originate from platelets. We measured plasma VEGF levels, which evaluate the level of tumor-derived VEGF, in various breast diseases.MethodWe analyzed 15 patients with benign breast disease, 187 patients with primary breast cancer, 32 patients with no postoperative recurrence, and 56 patients with recurrence. Plasma VEGF levels were measured by ELISA.ResultsPlasma VEGF levels were higher in malignant than in benign breast disease, and were also high in patients with recurrence or distant metastasis. In primary cases, higher VEGF levels were clearly correlated with menopause and overexpression of p53, and postmenopausal patients with high levels had a significantly lower disease-free survival rate.ConclusionThese results suggest that plasma VEGF levels in breast cancer have a clinical significance in that they are associated with the extent or metastasis of malignant lesions and are involved in angiogenesis in postmenopausal patients.

p53 expression status is a significant molecular marker in predicting the time to endocrine therapy failure in recurrent breast cancer: A cohort study

BackgroundHormone receptor status has been one of the most important factors in predicting the response to endocrine therapy in breast cancer patients. However, half of those patients with estrogen receptor-positive tumors do not respond to endocrine therapy. There have been no universal factors for predicting resistance to endocrine therapy in this population. Recently, p53 status has been extensively used as a predictive factor for response to systemic therapy, because tumor cells lacking p53 function do not respond to systemic therapy due to a failure in apoptosis. We therefore studied the relationship between the efficacy of endocrine therapy and biological factors, including p53.MethodsThe expression of p53, Ki67, and human epidermal growth factor receptor (HER)2 was examined by immunostaining in the primary tumors of 53 patients who received endocrine therapy for recurrent or advanced breast cancer. The following clinical factors were also analyzed: site treated, disease-free interval, and response to first-line endocrine therapy. To evaluate the significance of these factors, time to endocrine therapy failure (TTEF), or the total duration of sequential endocrine therapies was adopted as representing the clinical outcome.ResultsThe median TTEF was 16.1 months (range, 2.5–89.9 months). Multivariate analysis showed significantly reduced TTEF associated with no response to first-line endocrine therapy (P = 0.006 and P = 0.002 in all patients and in recurrent patients, respectively) and associated with positive p53 expression (P = 0.066 and P = 0.004, respectively).Conclusionp53 expression status was a significant molecular marker as well as the response to first-line endocrine therapy for predicting TTEF in recurrent breast cancer with hormone-sensitive disease.

An Analysis of Serum Interleukin-6 Levels to Predict Benefits of Medroxyprogesterone Acetate in Advanced or Recurrent Breast Cancer

Treatment of advanced or recurrent breast cancer with medroxyprogesterone acetate (MPA) shows high response rates and the accessory effects of appetite stimulation, improvement in performance status (PS) and bone marrow protection. In recent years, interleukin-6 (IL-6) has been reported to cause cachexia. In this study, to clarify the significance of IL-6 in advanced or recurrent breast cancer, the relationship between the IL-6 level and clinical findings or effect of MPA was investigated. Sixty-five patients with recurrent or advanced breast cancer participated in a prospective study. The age of patients ranged from 28 to 79 years with an average age of 51.3 years. IL-6 level was investigated in these patients dosed with 800 mg/day of MPA and in 17 postoperative nonrecurrent patients. Serum MPA level was measured by high-performance liquid chromatography and IL-6 level was measured prior to MPA administration, 4 weeks (in 59 cases) and 12 weeks (in 32 patients) after MPA administration by ELISA. Serum IL-6 level was significantly higher in recurrent cases, especially in those with visceral metastasis. Further, in patients for whom MPA therapy was effective, the IL-6 level prior to the treatment was clearly low. The IL-6 level was significantly increased after 4 weeks. However, response to MPA was significantly higher and PS was improved in those cases demonstrating less increased IL-6 levels after 4 weeks. In addition, the effect of MPA was significantly related to a higher serum concentration of MPA-positive ER, and longer disease-free interval, although there was no significant predictive factor for the clinical effect of MPA therapy in multivariate analysis. In conclusion, MPA therapy was effective in cases demonstrating a low IL-6 level and less increased IL-6 levels after 4 weeks. PS was improved in those cases in which the degree of IL-6 increase was suppressed by MPA, and many such cases showed low IL-6 levels prior to MPA therapy. Furthermore, PS was improved even in nonresponders to MPA. Therefore, it is suggested that MPA therapy might be useful in treating recurrent breast cancer, and its benefits might be mediated by IL-6.

Parvovirus B19‐associated haemophagocytic syndrome with prominent neutrophilia

Summary We describe a patient with both haemophagocytic syndrome and acute myocarditis probably associated with parvovirus B19 infection. The patient had a marked neutrophilia instead of neutropenia more usually observed in virus‐associated haemophagocytic syndrome (VAHS). Endogenous serum concentrations of macrophage colony‐stimulating factor (M‐CSF), granulocyte colony‐stimulating factor (G‐CSF), and tumour necrosis factor‐α (TNF‐α) were higher than normal, suggesting that these cytokines may be involved in the genesis of the observed syndrome.

Elevated Serum CA15-3 Levels Correlate with Positive Estrogen Receptor and Initial Favorable Outcome in Patients who Died from Recurrent Breast Cancer

BackgroundThe clinical usefulness of circulating tumor markers in breast cancer as recurrence indicators during follow-up or monitoring treatment response is still an open question. There are some patients with normal tumor marker levels who have apparent recurrence foci. In this study, we evaluated the relationships between CEA or CA15-3 levels and clinicopathological factors or outcome in patients who had died from recurrent breast cancer.MethodsTwo hundred-twenty deceased patients who had had recurrent or advanced breast cancer and who had been treated between 1986 and 2000 were enrolled in a retrospective study. Serum CEA and CA15-3 were measured regularly during the clinical course until death.ResultsThe rates of CEA and CA15-3 positivity were 41.4% and 50.9% at the time of recurrence, and rose to 67.3% and 76.8% after recurrence, respectively. The CA15-3 and CEA positivity rates significantly correlated with ER and PgR status. Serum CA15-3 status correlated significantly with survival after recurrence. Patients with CA15-3 negativity had poorer prognoses than CA15-3 positive patients. Multivariate analysis revealed that CA15-3 status was one of the significant factors for survival after recurrence.ConclusionsTumor markers, especially CA15-3, might reflect the biological characteristics of tumors such as ER or PgR status, and may be useful prognostic predictors in recurrent breast cancer. Elevated CA15-3 levels correlated with positive estrogen receptor and favorable outcome in deceased patients with recurrent breast cancer.

Apoptosis in breast cancer and its relationship to clinicopathological characteristics and prognosis.

Apoptosis is essential to maintain homeostasis in living organisms and occurs in a variety of tissues in response to both physiological and pathological stimuli. In breast cancer, most cytotoxic drugs and hormonal treatments induce apoptosis. We studied the relationships between apoptosis and clinicopathological variables or prognosis in 143 patients with operable breast cancer.

Radiological findings of retroperitoneal leiomyoma and leiomyosarcoma: report of two cases.

Radiologic findings in cases of retroperitoneal leiomyosarcoma and leiomyoma were reported. These cases showed very similar findings: irregularly marginated large masses with central cyst formation and no calcification on CT and ultrasonography. Angiography showed tumor vessels and tumor stains. Cystic region due to central necrosis or hemorrhage was the most prominent radiologic finding in these cases. However, it was difficult to distinguish leiomyosarcoma from leiomyoma on the basis of the radiologic findings alone.

An evaluation of DNA polymerase α as a prognostic predictor in early breast cancers smaller than 2 cm

We examined the relationship between proliferative activity determined by DNA polymerase α and clinicopathologic variables in breast cancer patients, and evaluated the usefulness of DNA polymerase α as a prognostic predictor in 337 early breast cancers with tumors smaller than 2 cm, which had favorable outcomes. About 60% of tumors had lower proliferative activity. A significant correlation was found between DNA polymerase α and ER, PgR, histological type, or the degree of infiltration into lymphatic vessels which reflect the prognosis. Cancers with higher DNA polymerase α activity were associated with shorter disease-free and overall survival times. In a multivariate analysis the DNA polymerase α was found to be an independent and significant factor in early breast cancer.

Intraoperative cytologic diagnosis of sentinel lymph node metastasis in breast cancer-Combination of imprint cytology and immunocytochemistry-

目的:乳癌における術中迅速センチネルリンパ節 (sentinel lymph node: SLN) 捺印細胞診への免疫細胞化学 (immunocytochemistry: ICC) 併用の有用性を検討した.方法:2003年6月から2004年2月までのICCを併用した術中迅速SLN捺印細胞診134例を対象に, 迅速組織診断, 永久標本ならびに免疫組織化学 (immunohistochemistry: IHC) との成績を比較した.成績:永久標本におけるSLN転移陽性は37例 (HE・IHCともに陽性28例, IHCのみ陽性9例) で, そのうち細胞診陽性はPapanicolaou (Pap.) 染色のみが29例であったが, ICC併用により33例となり, 感度は78. 4%から89. 2%と向上した. 残り4例はmicrometastasis症例であった. また永久標本でのSLN転移陰性は97例で, その内細胞診陰性は94例, 特異度は96. 9%であった. 残り3例はPap. 染色では疑陽性だったが, ICCにて全例陽性を呈しmicrometastasisの可能性が示唆された.結論:孤在性の癌細胞や小型で異型性の乏しい癌細胞など, 洞組織球との鑑別を要す場合でも習熟すればPap. 染色だけで十分だが, ICCを併用することで明らかな精度向上が認められる. 特に永久標本で確認されたmicrometastasis11例中7例をICCで検出できたことより, ICC併用はSLNの術中迅速診断に有用と考える.

Comparative analysis on cytological findings between early recurrent cases and non recurrent ones in breast cancer.

術前の乳腺穿刺吸引細胞診 (FNAs) で早期再発群と非再発群を比較することで, 両者間の細胞所見に相違が見出せるかどうかを検討した. 対象は1990～1996年に根治的手術が行われた症例の中から, 術前にFNAsが施行された58症例を抽出し, リンパ節転移および再発の有無により4群に分類し, 細胞学的に12の形態的項目 (核長・短径, 核形, 核面積, 核の大小不同, 核小体長・短径, 核小体面積, N/C比, 2.5μm以上の核小体出現率, 核分裂指数, 壊死の有無) に関して検討した. その結果9項目でリンパ節転移の有無に関係なく早期再発群の方が非再発群に比べ有意に大きい値を示した (P<0.001).その項目を中心に細胞学的異型度のスコア化 (各項目0～1, 0～3) を試み, スコア合計を5以下, 6以上で区切ると有意に早期再発群の推定が可能となった (P<0.001). またこの再現性をrnodified Blackのnuclear gradingsystem (NGS) と比較検討した結果, modified Black法によるNGSを用いた場合の一致率は13/58 (22.4%) だったのに対し, われわれのscoring systemを用いた場合は, 45/58 (77.6%) と高い一致率が得られた (P<0.001). つまり細胞学的異型度はn因子から独立した予後因子であり, われわれのscoring systemは早期再発群の推定に有用である.