Takahiro Kasamatsu

Prognostic significance of positive peritoneal cytology in endometrial carcinoma confined to the uterus

A retrospective analysis was performed to evaluate the prognostic significance of peritoneal cytology in patients with endometrial carcinoma limited to the uterus. A total of 280 patients with surgically staged endometrial carcinoma that was histologically confined to the uterus were examined clinicopathologically. The median length of follow-up was 62 (range, 12–135) months. All patients underwent hysterectomy and salpingo-oophorectomy with selective lymphadenectomy, and only three patients received adjuvant postoperative therapy. No preoperative adjuvant therapy was employed. In all, 48 patients (17%) had positive peritoneal cytology. The 5-year survival rate among patients with positive or negative peritoneal cytology was 91 or 95%, respectively, showing no significant difference (log-rank, P=0.42). The disease-free survival rate at 36 months was 90% among patients with positive cytology, compared with that of 94% among patients with negative cytology, and the difference was not significant (log-rank, P=0.52). Multivariate proportional hazards model revealed only histologic grade to be an independent prognostic factor of survival (P=0.0003, 95% CI 3.02 – 40.27) among the factors analysed (age, peritoneal cytology, and depth of myometrial invasion). Multivariate analysis revealed that histologic grade (P=0.02, 95% CI 1.21–9.92) was also the only independent prognostic factor of disease-free survival. We concluded that the presence of positive peritoneal cytology is not an independent prognostic factor in patients with endometrial carcinoma confined to the uterus, and adjuvant therapy does not appear to be beneficial in these patients.

Paclitaxel Plus Carboplatin Versus Paclitaxel Plus Cisplatin in Metastatic or Recurrent Cervical Cancer: The Open-Label Randomized Phase III Trial JCOG0505

PURPOSE In metastatic or recurrent cervical cancer, cisplatin-based chemotherapy is standard. The JCOG0505 randomized phase III trial evaluated the clinical benefits of carboplatin-based regimen. PATIENTS AND METHODS Eligible patients had metastatic or recurrent cervical cancer and had ≤ one platinum-containing treatment and no prior taxane. Patients were randomly assigned either to conventional paclitaxel plus cisplatin (TP; paclitaxel 135 mg/m(2) over 24 hours on day 1 and cisplatin 50 mg/m(2) on day 2, repeated every 3 weeks) or paclitaxel plus carboplatin (TC; paclitaxel 175 mg/m(2) over 3 hours and carboplatin area under curve 5 mg/mL/min on day 1, repeated every 3 weeks). Primary end point was overall survival (OS). Planned sample size was 250 patients to confirm the noninferiority of TC versus TP with the threshold hazard ratio (HR) of 1.29. RESULTS Between February 2006 and November 2009, 253 patients were enrolled. The HR of OS was 0.994 (90% CI, 0.79 to 1.25; noninferiority P = .032 by stratified Cox regression). Median OS was 18.3 months with TP versus 17.5 months with TC. Among patients who had not received prior cisplatin, OS was shorter with TC (13.0 v 23.2 months; HR, 1.571; 95% CI, 1.06 to 2.32). One treatment-related death occurred with TC. Proportion of nonhospitalization periods was significantly longer with TC (P < .001). CONCLUSION TC was noninferior to TP and should be a standard treatment option for metastatic or recurrent cervical cancer. However, cisplatin is still the key drug for patients who have not received platinum agents.

Cap43/NDRG1/Drg-1 is a molecular target for angiogenesis and a prognostic indicator in cervical adenocarcinoma.

Cap43 is a nickel- and calcium-inducible gene that plays important roles in the primary growth of malignant tumors, as well as in invasion and metastasis, most likely through its ability to induce cellular differentiation. This study investigated associations of Cap43 expression with angiogenesis and other clinicopathological factors in cervical adenocarcinoma. The clinical records of 100 women who underwent surgery for cervical adenocarcinoma were reviewed retrospectively. Microvessel density and the expression of Cap43 and VEGF in the surgical specimens were evaluated immunohistochemically. The Cap43 expression level was significantly associated with angiogenesis, tumor diameter, stromal invasion, lymphovascular space invasion, lymph node metastasis, and histopathological differentiation. Kaplan-Meier analysis showed a significant association between the Cap43 expression level and survival: high Cap43 expression was related to poor survival. Our results suggest that increased expression of Cap43 is associated with angiogenesis and may be a poor prognostic indicator in women with cervical adenocarcinoma.

Radical hysterectomy for FIGO stage I-IIB adenocarcinoma of the uterine cervix.

A retrospective analysis was carried out to identify risk factors for survival and relapse in patients with FIGO stage I–IIB cervical adenocarcinoma (AC), who underwent radical hysterectomy, and to compare outcome and spread pattern with those of squamous cell carcinoma (SCC). One hundred and twenty-three FIGO stage I–IIB patients with AC and 455 patients with SCC, who all underwent primary radical hysterectomy, were reviewed. Among the patients with AC, Cox model identified tumour size (95% CI: 1.35–30.71) and node metastasis (95% CI: 5.09–53.44) as independent prognostic factors for survival, and infiltration to vagina (95% CI: 1.15–5.76) and node metastasis (95% CI: 6.39–58.87) as independent prognostic factors for relapse. No significant difference was found in survival or relapse between the AC and SCC groups, after adjusting for other clinicopathological characteristics using Cox model. No significant difference was found in the positive rates of lymph nodes or location of initial failure sites between the two groups, but ovarian metastatic rate was significantly higher in patients with pathologic stage IIB AC (P=0.02). Positive node is a common independent prognostic factor for survival and relapse of patients with AC. FIGO stage I–IIB patients with AC or SCC, who underwent radical hysterectomy, have similar prognosis and spread pattern, but different ovarian metastasis rates.

Determinants of bone loss in a rural Japanese community : the Taiji Study

Abstract: The objective of this study was to assess the rate of bone loss and characterize its determinants, among the inhabitants of Taiji, a rural Japanese community. A cohort of 2261 inhabitants aged 40–79 years was established using resident registration in 1992. Fifty men and 50 women in each of four age strata between 40 and 79 years were randomly selected and completed a self-administered risk factor questionnaire. Baseline bone density of lumbar spine and proximal femur was measured by dual-energy X-ray absorptiometry in 1993. BMD was measured again on the same participants in 1996. The rates of change of lumbar spine BMD in men in their 40s, 50s, 60s and 70s were 0.20%, 0.34%, 0.43% and 0.28% respectively. Rates in women were –0.35%, –1.02%, –0.10% and –0.20% respectively. At the femoral neck, rates of change in BMD among men in their 40s, 50s, 60s and 70s were 0.09%, –0.07%, 0.34% and 0.31% respectively. Femoral neck rates of change among women were –0.55%, 0.02%, 0.49% and –0.25% respectively. The rate of change of lumbar spine BMD was –0.24% in premenopausal women with regular periods, –1.99% in premenopausal women with irregular periods and –0.33% in postmenopausal women. Anthropometric measurements at baseline were also related significantly to change in bone density. Baseline weight and height were statistically significant predictors of bone loss rate.These data provide estimates of the rate of bone loss among Japanese men and women aged 40– 79 years. They suggest that body build and menstrual function in women are important determinants of bone loss.

Different expression patterns of KIT, EGFR, and HER-2 (c-erbB-2) oncoproteins between epithelial and mesenchymal components in uterine carcinosarcoma

Uterine carcinosarcoma histologically comprises the components of epithelial and mesenchymal malignancies, and is known to be clinically highly aggressive. To reveal the significance of the expression of tyrosine‐kinase‐receptor‐type oncoproteins in this tumor type, the incidence and distribution of the KIT, EGFR, and HER‐2 (c‐erbB‐2) oncoproteins were immunohistochemically examined in 16 surgically resected cases. For 6 cases, the EGFR and HER‐2 amplifications were also examined by fluorescence in situ hybridization (FISH). In the epithelial component, overexpressions of KIT, EGFR, and HER‐2 were detected in 4 (25%), 5 (31%), and 9 (56%) cases, respectively, whereas these overexpressions in the mesenchymal component were detected in 6 (38%), 8 (50%), and 1 (6%) cases, respectively. KIT and EGFR were co‐overexpressed in the mesenchymal component of 4 cases and in the epithelial component of 2 cases. However, HER‐2 overexpression was mostly detected in the epithelial component only, and tended to occur independently of KIT and/or EGFR overexpression. By FISH, one of the 4 cases with HER‐2 overexpression showed low‐level gene amplification. In two cases with EGFR overexpression, the gain of EGFR alleles and/or polyploidization of chromosome 7 had occurred. The expression patterns of KIT, EGFR, and HER‐2 differed between the epithelial and mesenchymal components, and the regulation of their expression appeared important in the acquisition of mesenchymal metaplasia in uterine carcinosarcoma. Structural and/or numerical alterations of chromosomes might be in part involved in EGFR and/or HER‐2 overexpression in this tumor type.

Biochemical Markers of Bone Turnover and Bone Loss at the Lumbar Spine and Femoral Neck: The Taiji Study

Abstract. The purpose of this study was to ascertain whether biochemical markers of bone turnover predict bone loss. The survey was carried out in Taiji, Wakayama Prefecture, Japan. From a list of inhabitants aged 40–79 years, 400 participants (50 men and 50 women in each of four age groups) were selected randomly. Bone mineral density (BMD) was measured, and blood and urine samples of all participants were examined to obtain values for eight biochemical markers: alkaline phosphatase (ALP), bone Gla protein (BGP), type I procollagen (carboxyterminal peptide of type I procollagen; PICP), cross-linked carboxyterminal telopeptide region of type I collagen (ICTP), and urinary excretion of calcium (Ca), phosphate (P), pyridinoline (Pyr), and deoxypyridinoline (D-Pyr). Each marker was evaluated as a predictor of the rate of bone change in lumbar spine and femoral neck BMD over a 3-year period. The value of Pyr was significantly related to the change of lumbar spine BMD in men (P= 0.009), and that of BGP was found to be significant in women (P= 0.045). By contrast, none of the bone markers significantly correlated with bone loss at the femoral neck. The coefficient of determination at the lumbar spine was 5% and 7% at the femoral neck only. We conclude that biochemical markers of bone turnover cannot predict bone loss rates in middle-aged or elderly Japanese men and women over a 3-year period with sufficient accuracy for use in clinical decision making.

Bone loss at the lumbar spine and the proximal femur in a rural Japanese community, 1990-2000: the Miyama study.

Abstract: Bone mineral density (BMD) was measured over a ten year period in a cohort study in Miyama village, Wakayama Prefecture, Japan, to provide information on rate of bone loss in the mature and elderly population. Four hundred subjects were selected by sex and age decade from the full list of residents born in 1910–1949, and aged 40–79 years at the end of 1989, with 50 men and 50 women in each age decade. Baseline BMD of the lumbar spine and the proximal femur was measured using dual energy X-ray absorptiometry (DXA) in 1990 and again in 1993, 1997 and 2000. Annual rate of change in BMD (% per year) in the lumbar spine in men in their forties, fifties, sixties and seventies was 0.17, 0.55, 0.01 and −0.16, respectively, and in women, −0.87, −0.83, −0.48 and −0.48, respectively. Thus in men, BMD at the lumbar spine increased in all age strata but the oldest, when it decreased, whereas in women, it decreased in all age strata. On the other hand, BMD at the proximal femur decreased in both sexes in all age strata. Our results show that bone loss rates differ depending on the site involved, demonstrating that different strategies are needed for the prevention of bone loss in the spine and hip. Furthermore, we found evidence of differences in BMD for given age strata between birth cohorts. Data in 1990 and in 2000 showed significant improvements for men in their sixties and for women in their fifties, suggesting that future problems of osteoporosis might be less severe than has previously been predicted in Japan.

Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102)

Background:A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival.Methods:Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1–5, vincristine 0.7 mg m−2 day 5, mitomycin 7 mg m−2 day 5, cisplatin 14 mg m−2 days 1–5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival.Results:A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80%; P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85).Conclusion:Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT.

Clinicopathological and prognostic impact of human epidermal growth factor receptor type 2 (HER2) and hormone receptor expression in uterine papillary serous carcinoma

Uterine papillary serous carcinoma (UPSC) is a rare and aggressive variant of endometrial carcinoma. Little is known about the pathological and biological features of this tumor. Human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) expression have an important role in tumor behavior and clinical outcome, but their relevance in UPSC is not clear. In the present study, the immunohistochemical expression of HER2 and HR was assessed in 27 patients with Stage I disease, 13 with Stage II disease, 25 with Stage III disease, and 6 with Stage IV disease. Correlations between HER2 and HR expression and the clinicopathological parameters of UPSC were evaluated using Coxs univariate and multivariate analyses. For all patients, the 5‐year recurrence‐free survival (RFS) and overall survival (OS) rates were 51% and 66%, respectively; in patients with Stage I, II, III and IV disease, the RFS and OS were 67%/81%, 59%/77%, 43%/54% and 0%/0%, respectively. Of all 71 patients, 14% (10/71) were positive for HER2 and 52% (37/71) were positive for HR. Overexpression of HER2 was correlated with lower OS (P = 0.01), whereas HR overexpression was correlated with higher OS (P = 0.008). In multivariate models, HER2, HR, and histologic subtype were identified as independent prognostic indicators for RFS (P = 0.022, P = 0.018, and P = 0.01, respectively), but HR was the only independent factor associated with OS (P = 0.044). Thus, HER2 and HR are prognostic variables in UPSC, with HR an independent prognostic factor for OS. (Cancer Sci 2012; 103: 926–932)