Clinical characteristics and prognostic factors of endometrial stromal sarcoma and undifferentiated uterine sarcoma confirmed by central pathologic review: A multi-institutional retrospective study from the Japanese Clinical Oncology Group.

OBJECTIVES: Low-grade and high-grade endometrial stromal sarcomas (LGESS and HGESS) and undifferentiated uterine sarcomas (UUS) are rare tumors whose pathological classification and staging system have changed recently. These tumors are reported to contain fusion genes. We aimed to clarify the genetic background, clinical features, prognostic factors, and optimal therapy of these tumors using a new classification and staging system. METHODS: We analyzed the clinical features and prognostic information of 72 patients with LGESS, 25 with HGESS, and 16 with UUS using central pathological review. Estrogen and progesterone receptors (PgRs) were examined by immunohistochemistry. JAZF1-SUZ12 and YWHAE-NUTM2A/B gene fusions were tested using real-time polymerase chain reaction. RESULTS: The 5-year overall survival (OS) rates of LGESS, HGESS, and UUS were 94%, 53%, and 25%, respectively. In LGESS, stage IV, incomplete surgery, and absence of PgR were associated with poor OS. The presence of JAZF1-SUZ12 fusion gene was not associated with OS. In HGESS, the relationship between stage and prognosis was unclear. None of the 3 patients with YWHAE-NUTM2A/B fusion gene died during follow-up. Adjuvant chemotherapy was associated with a favorable OS. Incomplete resection of UUS was associated with poor OS; however, residual tumors frequently occurred. Although most patients underwent adjuvant chemotherapy, their prognosis was extremely poor even in stage I disease. CONCLUSIONS: Prognosis of LGESS is generally good; however, stage IV, incomplete surgery, and PgR-negative tumors are associated with poor prognosis. Adjuvant chemotherapy may be useful for HGESS. Prognosis of UUS is extremely poor, even with adjuvant chemotherapy.

A multi-center retrospective study of neuroendocrine tumors of the uterine cervix: Prognosis according to the new 2018 staging system, comparing outcomes for different chemotherapeutic regimens and histopathological subtypes.

OBJECTIVE: To analyze the clinical behavior of neuroendocrine tumors (NETs) of the uterine cervix, we conducted a multicenter, retrospective study of 193 patients. METHODS: We evaluated the prognosis of NETs according to the new International Federation of Gynecology and Obstetrics (FIGO) staging system, compared the clinical response to different chemotherapy regimens, and compared different histological subtypes of NETS. RESULTS: Diagnoses of the subjects were atypical carcinoid tumor (ACT, n = 37), small cell neuroendocrine carcinoma (SCNEC, n = 126), large cell neuroendocrine carcinoma (LCNEC, n = 22), and NET, not elsewhere classified (n = 8), according to central pathological review. According to FIGO 2018, 69, 17, 74, and 33 patients were at stage I, II, III, or IV, respectively. Five-year survival was 64.5%, 50.1%, 30.2%, and 3.4% for patients at stage I, II, III and IV. About 40% of patients with stage IIIC1 survived >5 years. On multivariate analyses, locally-advanced disease, para-aortic node metastasis, distant metastasis, and <4 cycles of chemotherapy were associated with poor survival. Histological subtype and pelvic node metastasis had no prognostic significance. Response rates to etoposide-platinum (EP) or irinotecan-platinum (CPT-P) regimens were 43.8% (28/64), but only 12.9% to a taxane-platinum (TC) regimen (4/31). The response rate for ACT was 8.7% (2/23), significantly less than the 36.6% for high-grade neuroendocrine carcinomas (HGNEC: both SCNEC and LCNEC, 41/111). CONCLUSIONS: Locally-advanced, extra-pelvic disease and insufficient chemotherapy were independent prognostic factors for cervical NET. HGNEC showed good responses to EP or CPT-P but not TC. Chemotherapy was less effective for ACT, which had a prognosis identical to HGNEC.

Analysis of gastric-type mucinous carcinoma of the uterine cervix - An aggressive tumor with a poor prognosis: A multi-institutional study.

OBJECTIVE: Gastric-type mucinous carcinoma (GAS) is a novel variant of mucinous carcinoma of the uterine cervix. As shown in the original Japanese group description, in recent studies, GAS represents a more aggressive disease than the usual-type endocervical adenocarcinoma (UEA). Detailed clinicopathological features of this variant remain to be elucidated in a larger series of patients. METHODS: Patients were enrolled by the Gynecologic Cancer Study Group of the Japan Clinical Oncology Group after receiving the approval of each Institutional Review Board. The study population comprised of women with stage I to II endocervical adenocarcinomas who underwent surgery between 2000 and 2009. Representative slides were evaluated by central pathological review (CPR), categorized into either GAS or UEA, and correlated with clinicopathological features and outcome. RESULTS: Among the 393 enrolled patients with endocervical adenocarcinoma, 328 patients met the criteria for CPR and the study eligibility criteria and were included in further analysis. A total of 95 of the 328 tumors were classified as GAS. Compared with UEA, GAS was more significantly associated with bulky mass, deep stromal invasion, lymphovascular space invasion, parametrial invasion, ovarian metastasis, positive ascitic fluid cytology, pelvic lymph node metastasis, and pathological (p) T stage but was not related to the degree of histological differentiation. Disease-free survival (P < 0.0001) and overall survival (P < 0.0001) were poorer in patients with GAS than in those with UEA. CONCLUSIONS: GAS showed aggressive behavior with ominous histopathological predictors as well as decreased survival. GAS is therefore considered a distinct entity that should be distinguished from UEA. CLINICAL TRIAL INFORMATION: UMIN Clinical Trials Registry: UMIN000007987.

Prognostic factors and optimal therapy for stages I-II neuroendocrine carcinomas of the uterine cervix: A multi-center retrospective study.

PURPOSE: We aimed to determine appropriate treatment guidelines for patients with stages I-II high-grade neuroendocrine carcinomas (HGNEC) of the uterine cervix in a multicenter retrospective study. PATIENTS AND METHODS: We reviewed the clinicopathological features and prognoses of 93 patients with HGNEC of International Federation of Gynecology and Obstetrics (FIGO) stages I and II. All patients were diagnosed with HGNEC by central pathological review. RESULTS: The median overall survival (OS) and disease-free survival (DFS) were 111.3months and 47.4months, respectively. Eighty-eight patients underwent radical surgery, and five had definitive radiotherapy. The hazard ratio (HR) for death after definitive radiotherapy to death after radical surgery was 4.74 (95% confidence interval [CI], 1.01-15.90). Of the surgery group, 18 received neoadjuvant chemotherapy. Pathological prognostic factors and optimal adjuvant therapies were evaluated for the 70 patients. Forty-one patients received adjuvant chemotherapy with etoposide-platinum (EP) or irinotecan-platinum (CPT-P). Multivariate analyses identified the invasion of lymphovascular spaces as a significant prognostic factor for both OS and DFS. Pelvic lymph node metastasis was also a prognostic factor for DFS. Adjuvant chemotherapy with an EP or CPT-P regimen appeared to improve DFS (HR=0.27, 95% CI, 0.10-0.69). A trend toward improved OS was also observed, but was not statistically significant (HR=0.39, 95% CI, 0.15-1.01). CONCLUSION: Radical surgery followed by adjuvant chemotherapy with an EP or CPT-P regimen was optimal treatment for stages I and II HGNEC of the uterine cervix.

Serum starvation induces abnormal spindle location, RhoA delocalization, and extension of intercellular bridge with the midbody.

Serum starvation induces binucleation in HeLa cells, but the effects of serum starvation on mitosis and the significance of binucleation remain unknown. We investigated the effect of serum starvation on mitosis and analyzed the growth of binucleated cells. The frequency of binucleation caused by cytokinesis failure in DMEM without FBS (0% medium) was higher than that in DMEM with FBS (10% medium). In 0% medium, the metaphase spindle location was off-center, and RhoA localization significantly lacked symmetry. The frequency of the extension of intercellular bridge with the midbody in 0% medium was significantly higher than that in 10% medium. Moreover, all mononucleated mitotic cells caused bipolar mitosis and produced only mononucleated daughter cells, but binucleated cells produced various nucleated cells by multipolar mitosis in 0% medium. These results suggest that serum starvation may have various effects on mitosis, and binucleated cells may be related to formation of aneuploidy.

Is Invasive Micropapillary Serous Carcinoma a Low-grade Carcinoma?

"Invasive micropapillary serous carcinoma" has been proposed as a synonym for low-grade serous carcinoma by some expert pathologists. In contrast, Singer and colleagues reported that some serous carcinomas with conspicuous invasive micropapillary pattern (SC-IMPs) can show high-grade nuclear atypia. However, the molecular features of such tumors have not been well documented. The aim of this study was to demonstrate and emphasize the fact that high-grade serous carcinoma confirmed by immunohistochemistry and molecular analysis can show conspicuous invasive micropapillary pattern. We selected 24 "SC-IMPs" and investigated: (1) their morphologic features; (2) the immunostaining pattern of p53 protein; and (3) KRAS/BRAF/TP53 gene mutations. The 24 SC-IMPs were subdivided into low-grade and high-grade tumors based primarily on the nuclear atypia, with the mitotic rate used as a secondary feature: low grade (n=5) and high grade (n=19). Low-grade SC-IMPs were characterized by low-mitotic activity, absence of abnormal mitosis, presence of serous borderline tumor, occasional BRAF mutation, and infrequent TP53 mutation. High-grade SC-IMPs were characterized by high-mitotic activity, presence of abnormal mitosis, conventional high-grade serous carcinoma, frequent TP53 mutation, and lack of KRAS/BRAF mutation. We demonstrated that high-grade serous carcinoma confirmed by aberrant p53 immunostaining and molecular analysis can show conspicuous invasive micropapillary pattern, validating Singer and colleague's report. Serous carcinoma with conspicuous invasive micropapillary pattern should not be readily regarded as low-grade serous carcinoma. Nuclear grade is the most important diagnostic feature in the SC-IMPs.

Clinical management of atypical polypoid adenomyoma of the uterus. A clinicopathological review of 29 cases.

OBJECTIVE: The clinical management of atypical polypoid adenomyoma (APAM) of the uterus remains to be established. We collected APAM cases, reviewed the clinicopathological features, and discussed the clinical management. METHODS: Twenty-nine patients with APAM were identified by searching the tumor registry of the Japan Clinical Oncology Group (JCOG). Clinical information and histological specimens were obtained from 13 institutional members of the JCOG, and a central pathological review was performed. RESULTS: The mean age of the patients was 38 years (range, 22-58). Squamous metaplasia was present in 19 cases (65.5%), and well-differentiated endometrioid adenocarcinoma coexisted in 5 cases (17.2%). Primary treatment consisted of dilatation and curettage in 9 patients (31.0%), vaginal resection in 2 patients (6.9%), hysteroscopic transcervical resection (TCR) using hysteroscopy in 10 patients (34.5%), and hysterectomy in 8 patients (27.6%). There were recurrences in 5 (23.8%) of the 21 cases in which fertility was preserved, and the recurrent rate was 10% (1/10) in patients those were treated with TCR and 36.4% (4/11) in those the other treatment options were selected. All patients were alive after primary treatment (a mean follow-up period was 39.6 months; range, 1-202). CONCLUSION: The clinical outcome of APAM is benign. However, differential diagnosis should be performed because of its histological similarity to invasive endometrial carcinoma and the possibility of coexistence with other endometrial neoplasms. TCR is a recommended diagnostic and treatment option for patients who desire to preserve fertility.

Well-differentiated villoglandular adenocarcinoma of the uterine cervix: assessment of cytological features by histological subtypes.

OBJECTIVE: Well-differentiated villoglandular adenocarcinoma (VGA) of the cervix involves papillae lined by different types of epithelial cells that are histologically subclassified into endocervical, endometrioid, or intestinal subtypes. The objective of the current study was to evaluate the definite cytological features of VGA by histological subtype. STUDY DESIGN: We examined 8 cervical smears from patients confirmed to have pure VGA and classified them into the 3 histological subtypes. RESULTS: The cervical smears were highly cellular and had a relatively clean background. The nuclei had minimal anisonucleosis and fine granular chromatin with almost inconspicuous nucleoli. The characteristic findings of the endocervical type were a palisading arrangement consisting of columnar or spindle-shaped cells with apical or elongated nuclei. Small but clear nucleoli were identified only in the endocervical type. In the endometrioid type, tumor cells consisted of cohesive sheets with smooth edges and very round nuclei. Cytoplasmic vacuolation was never observed in the endometrioid type. The tumor cells in the intestinal type were prominent with abundant cytoplasmic mucin. CONCLUSIONS: We demonstrated that the cytological features of this tumor can vary depending on the histological subtype and one should be aware of these features in order to improve diagnostic accuracy.

Translocation of nuclear chromatin distribution to the periphery reflects dephosphorylated threonine-821/826 of the retinoblastoma protein (pRb) in T24 cells treated with Bacillus Calmette-Guérin.

The standard treatment for non-muscle-invasive bladder cancer is intravesical Bacillus Calmette-Guérin (BCG) therapy, which is considered the only intravesical therapy that reduces the risk of progression to muscle-invasive cancer. BCG unresponsiveness, in which intravesical BCG therapy is ineffective, has become a problem. It is thus important to evaluate the effectiveness of BCG treatment for patients as soon as possible in order to identify the optimal therapy. Urine cytology is a noninvasive, easy, and cost-effective method that has been used during BCG treatment, but primarily only to determine benign or malignant status; findings concerning the efficacy of BCG treatment based on urine cytology have not been reported. We investigated the relationship between BCG exposure and nuclear an important criterion in urine cytology, i.e., nuclear chromatin patterns. We used three types of cultured cells to evaluate nuclear chromatin patterns and the cell cycle, and we used T24 cells to evaluate the phosphorylation of retinoblastoma protein (pRb) in six-times of BCG exposures. The results revealed that after the second BCG exposure, (i) nuclear chromatin is distributed predominantly at the nuclear periphery and (ii) the dephosphorylation of threonine-821/826 in pRb occurs. This is the first report of a dynamic change in the nuclear chromatin pattern induced by exposure to BCG. Molecular findings also suggested a relationship between this phenomenon and cell-cycle proteins. Although these results are preliminary, they contribute to our understanding of the cytomorphological changes that occur with BCG exposure.

Information-seeking experiences and decision-making roles of Japanese women with breast cancer.

PURPOSE: To investigate the information-seeking experiences and decision-making roles of Japanese women with breast cancer, to examine the relationship between information-seeking experiences and decision-making roles, and to explore the factors that influenced taking a more active role than the preferred role during the treatment decision-making process. METHODS: In a cross-sectional study, women with breast cancer were retrospectively administered the Control Preferences Scale and the Information-Seeking Experience Scale. The Chi-Square test was used to compare differences among individual variables in decision-making roles and information-seeking experiences. Logistic regression analysis was used to explore the factors that influenced taking a more active role than the preferred role. RESULTS: One hundred and four patients with breast cancer participated in the investigation. Eighty-five patients (78%) perceived themselves as having knowledge of breast cancer and most patients (92%) sought information on breast cancer. The preferred roles in decision-making that they reported having before treatment were 18% active, 69% collaborative and 13% passive. The actual roles they perceived having experienced were 27% active, 43% collaborative and 30% passive. Although there was concordance of preferred and actual role for only 59% of the women, most patients reported that they were satisfied with their decision-making. Many women with breast cancer reported negative experiences with information seeking, including wanting more information (49%), expending a lot of effort to obtain the information needed (53%), not having enough time to obtain needed information (55%), frustration during the search for information (44%), concerns about the quality of the information (45%) and difficulty understanding the information received (49%). This study revealed that having a more active actual role than the initial preferred role was associated with emotional expression to the physician, having undergone mastectomy, and the desire for more information. CONCLUSION: Most women with breast cancer sought information on breast cancer and expressed a preference for a collaborative relationship with physicians in treatment decision-making. Patients who expressed emotion to their physician, wanted more information, and underwent mastectomy were most likely to change their actual decision-making role toward a more active choice.

[Analysis of parent-child sleeping and living habits related to later bedtimes in children].

PURPOSE: To find the relationship between parents' sleeping and living behaviors and their children's sleeping habits, and to investigate factors specifically related to children staying up late in recent Japan. METHODS: During regular health check-ups of children at three local health centers in the city A, we recruited the parents of one-and-half-year-old and three-year-old children to participate in the Child Sleep Cohort Project (ChiSCoP). Parents of 184 children who consented to participation were mailed three questionnaires by placement method. These are "sleeping diary for 10 days," "sleeping and lifetime rhythm survey," and "emotional behavior assessment scale (CBCL : Child Behavior Checklist 2rd/3rd edition)," of which valid data on 178 children were collected over two years and analyzed. ANALYSIS: Participants' demographic data, perceived and actual sleeping and living habits, and bedtime patterns were compared among the groups classified by bedtime of children. Bedtimes were classified as early (before 21 : 00), normal (21 : 00 to 21 : 59), and late (after 22 : 00). Using one-way analysis of variance with two (early vs. late) and three bedtime categories, significant differences were found among the three bedtime categories about childcare environmental factors (meal, daytime activity, TV, nap, and bath). So we performed logistic regression analysis with "late bedtime" as the dependent variable and scores of environmental factors (upper or lower than median values) as independent variables in a stepwise manner to eliminate collinear variables and to obtain adjusted odds ratios. RESULTS: 1) Among the 178 children, 96 and 82 were recruited during the physical check-up for one-and-half-year-old and three-years-old, respectively. There were 49, 72, and 57 children in the early, normal, and late bedtime groups, respectively, and no significant difference in attribute factors was found. 2) In children of the early bedtime group, proportions of those with "efforts to establish good life rhythm" (P < 0.0001), "efforts to cultivate sleeping habits" (P < 0.0001), and "keeping a regular bedtime" (P < 0.05) were significantly higher, as well as for children who had more than 105 minutes of "daytime nap" compared to children who had less (P < 0.05). 3) Children's bedtimes were significantly correlated with "mother's wake-up time on weekdays" (r = 0.33) and "mother's bedtime on weekdays" (r = 0.33). Children's wake-up times were also correlated with "mother's wake-up time on weekdays and weekends" (r = 0.49) and "mother's bedtime on weekdays" (r = 0.34), which indicates that children's wake-up times had relationship with mother's sleeping and life habits. 4) Later "wake-up time on weekends" (odds ratio = 4.9) and "regular bedtime hour" (odds ratio = 3.53) were found to be the determinant of late bedtimes of children. CONCLUSIONS: To encourage earlier bedtimes in children, it is important to take he mother's sleeping and living habits into account and to maintain a regular wake-up and bedtime schedule across weekdays and weekends.

Discrepancies in pathological diagnosis of endometrial stromal sarcoma: a multi-institutional retrospective study from the Japanese clinical oncology group.

Endometrial stromal sarcoma (ESS) is a rare uterine malignancy that requires accurate pathological diagnosis for proper treatment. This study aimed to clarify the discrepancies in the pathological diagnosis of ESS and obtain practical clues to improve diagnostic accuracy. Between 2002 and 2015, 148 patients with low-grade ESS (LGESS), high-grade ESS (HGESS), undifferentiated endometrial sarcoma (UES), or undifferentiated uterine sarcoma (UUS) diagnosed at 31 institutions were included. We performed immunohistochemistry, real-time polymerase chain reaction for JAZF1-SUZ12 and YWHAE-NUTM2A/B, and break-apart fluorescent in situ hybridization for JAZF1, PHF1, and YWHAE. Central pathology review (CPR) was performed by six pathologists. After CPR, LGESS, HGESS, UES/UUS, and other diagnoses were confirmed in 72, 25, 16, and 31 cases, respectively. Diagnostic discrepancies were observed in 19.6% (18/92) of LGESS and 34% (18/53) of HGESS or UUS/UES. Adenosarcomas, endometrial carcinomas, carcinosarcomas, and leiomyosarcomas were common diagnostic pitfalls. JAZF1-SUZ12 transcript, PHF1 split signal, and YWHAE-NUTM2A/B transcript were mutually exclusively detected in 23 LGESS, 3 LGESS, and 1 LGESS plus 3 HGESS, respectively. JAZF1-SUZ12 and YWHAE-NUTM2A/B transcripts were detected only in cases with CPR diagnosis of LGESS or HGESS. The CPR diagnosis of LGESS, HGESS, and UUS was a significant prognosticator, and patients with LGESS depicted a favorable prognosis, while those with UUS showed the worst prognosis. Pathological diagnosis of ESS is often challenging and certain tumors should be carefully considered. The accurate pathological diagnosis with the aid of molecular testing is essential for prognostic prediction and treatment selection.

Nuclear localization of E-cadherin but not beta-catenin in human ovarian granulosa cell tumours and normal ovarian follicles and ovarian stroma.

AIMS: The role of misregulated Wnt/beta-catenin signalling in human ovarian granulosa cell tumour (GCT) has not been well characterized. The aim of this study was to confirm subcellular localization of key molecules of Wnt signalling (beta-catenin and E-cadherin) in human ovarian GCTs. METHODS AND RESULTS: Tissue samples taken from 32 human ovarian GCTs and 19 human normal ovaries containing 68 follicles were stained immunohistochemically using monoclonal anti-beta-catenin and anti-E-cadherin antibodies. None of the 32 GCTs and none of the 68 ovarian follicles showed beta-catenin nuclear expression (0%). On the other hand, 28 of 32 GCTs (88%) and 53 of 68 normal ovarian follicles (78%) showed nuclear expression of E-cadherin in granulosa cells. The ovarian stroma in all 19 normal ovaries showed nuclear expression of E-cadherin but not beta-catenin. Membranous and cytoplasmic expression was observed variously in ovarian GCT, follicles and stroma. CONCLUSIONS: We have confirmed frequent nuclear localization of E-cadherin but not beta-catenin in human ovarian GCT, ovarian follicles and stroma. There is no evidence of misregulated Wnt/beta-catenin signalling (represented by nuclear expression of beta-catenin) in human ovarian GCT. Nuclear translocation of E-cadherin might contribute to ovarian folliculogenesis or granulosa/stromal cell differentiation.

Preoperative differential diagnosis of minimal deviation adenocarcinoma and lobular endocervical glandular hyperplasia of the uterine cervix: a multicenter study of clinicopathology and magnetic resonance imaging findings.

OBJECTIVE: To clarify the preoperative differential diagnosis and management of minimal deviation adenocarcinoma (MDA) and lobular endocervical glandular hyperplasia (LEGH), a multicenter study was performed. METHODS: A total of 112 patients who underwent conization or a hysterectomy for suspected MDA were collected from 24 hospitals. The pathological diagnosis in each case was determined by a central pathological review board. The diagnostic significance of clinicopathologic findings including results of magnetic resonance imaging (MRI), Papanicolaou (Pap) smears, and testing for gastric mucin was analyzed. RESULTS: The central pathological review identified 37 cases of Nabothian cyst or tunnel cluster, 54 cases of LEGH, 6 cases of MDA, 11 cases of adenocarcinoma, and 4 cases of benign disease. Lobular endocervical glandular hyperplasia was often associated with adenocarcinoma in situ, MDA, and mucinous adenocarcinoma. Three MDA patients had a recurrence, whereas none of LEGH patients had a recurrence irrespective of the type of surgery. On MRI, LEGH appeared as a characteristic multicystic lesion with an inner solid component, whereas MDA showed a predominantly solid pattern. A Pap smear or gastric mucin alone had limited diagnostic power. However, a combination of these findings is useful; that is, a cystic structure with inner solid components on MRI associated with mild glandular atypia and gastric mucin strongly suggested LEGH (24/26, 92%). A solid structure with atypical glandular cells was indicative of MDA or adenocarcinoma (5/5, 100%). CONCLUSIONS: The combination of MRI, Pap smears, and gastric mucin will improve the accuracy of the preoperative diagnosis of MDA and LEGH. Patients suspected of having LEGH may need to be treated with less aggressive methods.

Quantitative image analysis of nuclear chromatin distribution for cytological diagnosis.

OBJECTIVE: We previously reported on the classification of the nuclear chromatin distribution into 3 types, that is peripheral (P), mixed (M) and central (C), which were related to the malignancy of cervical glandular lesions. However, the classification was subjective as it was performed by visual assessment. In the present study, quantitative assessment of nuclear chromatin distribution using image analysis by computer was applied for objective classification of cervical squamous epithelial lesions, which are the most common cervical lesions. STUDY DESIGN: A total of 130 cells (44 cells of type P, 78 of type M and 8 of type C) from cytological specimens of cervical squamous epithelial lesions (dysplasia, squamous cell carcinoma) were analyzed. An image analysis program was developed as a plug-in macro program of an existing image processing software. The radial distribution (RD) value, which represents the gradient of the staining intensity from the center to the edge of a nucleus, was defined as an index of the chromatin distribution. RESULTS: The RD values calculated in type P, type M and type C cells showed significant statistical differences as assessed by the t test (p < 0.001). CONCLUSIONS: Quantification of the nuclear chromatin distribution by image analysis is fast and highly objective. The RD value could be useful as an index for malignancy.

Sentinel node detection with (99m)Tc phytate alone is satisfactory for cervical cancer patients undergoing radical hysterectomy and pelvic lymphadenectomy.

BACKGROUND: If the sentinel-lymph-node (SLN) concept is valid in cervical cancer, most patients could avoid pelvic lymphadenectomy when absence of metastasis is intraoperatively confirmed in the SLN. We assessed feasibility and accuracy of SLN detection using (99m)Tc phytate in patients with cervical cancer. METHODS: Eighty-two women with stage Ia-IIb cervical cancer enrolled in this study. All underwent hysterectomy or trachelectomy with accompanying total pelvic lymphadenectomy. On the day before surgery, we injected fluid containing (99m)Tc-labeled phytate subepithelially into four cervical quadrants outside the tumor. Intraoperatively, SLNs were identified as radioactive "hot nodes" by gamma probe. Systematic bilateral pelvic lymphadenectomy was performed after the hot node sampling to evaluate the predictive ability of hot nodes. RESULTS: A total of 157 lymph nodes were detected as SLNs in 72 of 82 patients. SLN detection rate was 88%. Detection rate was 95% for the subgroups of patients with stage Ia-Ib1 disease and smaller tumor size (

Clinicopathological characteristics of mucinous adenocarcinoma of the ovary.

OBJECTIVE: We conducted the present study to clarify the clinicopathological characteristics of mucinous adenocarcinoma. METHODS: Two hundred twenty-five patients were diagnosed with mucinous adenocarcinoma at individual institutes and underwent primary treatment between 1998 and 2003. Of these patients, 189 patients who could undergo central pathological review were enrolled in this study. Of 189 patients undergoing central pathological review, 64 patients (33.9%) were diagnosed with mucinous invasive adenocarcinoma, 45 mucinous intraepithelial carcinoma, and 42 mucinous tumor of borderline malignancy. Twenty-five patients were diagnosed with other histological subtypes, including 8 endometrioid adenocarcinoma, 5 clear cell carcinoma, 3 serous adenocarcinoma, and 4 mixed type. There were 13 cases of metastatic mucinous adenocarcinoma, including 7 pseudomyxoma peritonei. Four hundred thirty-three patients with serous adenocarcinoma were used as controls. RESULTS: Forty-five patients with mucinous invasive carcinoma were in FIGO I-II stages and 19 in III-IV stages. There was no difference in the outcome between mucinous invasive adenocarcinoma and serous adenocarcinoma in I-II stage patients and III-IV stage patients with optimal operation. In contrast, patients with mucinous invasive adenocarcinoma receiving suboptimal operation showed a significantly worse prognosis (survival rate: 27.8% vs. 61.5%). The response rate to chemotherapy for mucinous invasive adenocarcinoma was significantly lower than for serous adenocarcinoma (12.5% vs. 67.7%). CONCLUSIONS: The diagnosis of mucinous invasive adenocarcinoma was difficult. Since patients with mucinous invasive adenocarcinoma had a lower response to chemotherapy, aggressive cytoreductive surgery was an effective treatment to improve the prognosis for advanced stage patients. A new chemotherapeutic regimen should be established for mucinous adenocarcinoma of the ovary.

Nuclear co-expression of p21 and p27 induced effective cell-cycle arrest in T24 cells treated with BCG.

A proposed mechanism underlying the effect of bacillus Calmette-Guérin (BCG) treatment for bladder cancer cells is as follows: BCG-induced crosslinking of cell-surface receptors results in the activation of signaling cascades, including cell-cycle regulators. However, the clinical significance of cell-cycle regulators such as p21 and p27 is controversial. Here we investigated the relationship between BCG exposure and p21 and p27. We used confocal laser microscopy to examine the expression levels of pKi67, p21 and p27 in T24 cells (derived from human urothelial carcinoma) exposed six times to BCG. We performed dual immunofluorescence staining methods for p21 and p27 and observed the localization of nuclear and cytoplasm expressions. We investigated the priority of p27 over p21 regarding nuclear expression by using p27 Stealth RNAi™ (p27-siRNA). With 2-h BCG exposure, the nuclear-expression level of p21 and p27 was highest, while pKi67 was lowest. The percentage of double nuclear-expression of p21 and p27 in BCG cells was significantly higher than that in control cells during the 1st to 6th exposure (P < 0.05), and the expression of pKi67 showed the opposite of this pattern. Approximately 10% of the nuclear p21 was independent of p27, whereas the cytoplasmic p21 was dependent on p27. Our results suggested that the nuclear co-expression of p21 and p27 caused effective cell-cycle arrest, and thus the evaluation of the nuclear co-expression of p21 and p27 might help determine the effectiveness of BCG treatment.

Inhibition of nitric oxide synthetase at mid-gestation in rats is associated with increases in arterial pressure, serum tumor necrosis factor-alpha, and placental apoptosis.

BACKGROUND: Reduced uteroplacental perfusion and maternal cardiovascular dysfunction have been considered to be the main pathophysiological features of preeclampsia. In order to determine whether inhibition of nitric oxide synthetase (NOS) during the initial stage of placentation is associated with impaired placental development and maternal cardiovascular dysfunction, we studied the effect of N-nitro-arginine methyl ester (L-NAME), a NOS inhibitor, on morphological changes in the placenta, maternal blood pressure, and serum tumor necrosis factor-alpha (TNF-alpha) in pregnant rats during the initial stage of placentation. METHODS: Pregnant Wister rats were treated during mid-gestation (days 8-14) with either L-NAME or saline. On day 20 of pregnancy the rats were killed, and maternal blood and placentas were extracted and examined. RESULTS: In comparison with pregnant saline-treated control rats (blood pressure 119 +/- 9 mm Hg), pregnant rats treated with L-NAME displayed significant hypertension (blood pressure 178 +/- 7 mm Hg), which continued even after the withdrawal of L-NAME administration (P < 0.01). In L-NAME-treated pregnant rats, morphological examination showed decreased populations of placental trophoblast lineages, and a significant increase in placental trophoblast apoptosis. Serum TNF-alpha levels at day 20 of pregnancy were significantly higher in treated pregnant rats (21.2 +/- 9.6 pg/ml) than in control pregnant rats (3.3 +/- 2.8 pg/ml) (P < 0.01). CONCLUSIONS: Inhibition of NOS at mid-gestation in pregnant rats is associated with increases in arterial pressure, placental apoptosis, and serum TNF-alpha, all of which have been implicated as being pathophysiological features of preeclampsia.

[Analysis of late bedtime and influencing factors for it with respect to infants' development age and sleep behavior of parents and children].

PURPOSE: To understand influencing factors for late bedtime of infants having nocturnal life, with respect to each development age and sleep behavior of parents and children. We researched on sleep-awake behaviors and ten-day sleep logs of 277 subjects, who registered for a three-year cohort survey. The cohort is recruited at the time of routine examinations for 4 month, 1.5 years, and 3 years, held at three Health and Welfare centers in Fukuoka city in September and October, 2007. We conducted two-way analysis of variance and post-hoc test of Turkey's multiple comparative tests. The independent variables are three age groups (infants, 1.5 years, and 3 years) and three bedtime categories (late: after 22 o'clock, normal: between 21 and 22 o'clock, and early: before 21 o'clock), and the dependent variables are background date, sleep parameter of parents and children, and factors of sleep behavior and so on. The qualitative data including physical conditions, growth status, frequencies of each life activity are analyzed by tabulation, and fulfillment in child raring is analyzed by stepwise multiple linear regression analysis with 15 objective variables, to bring out factors to induce nocturnal life. RESULTS: Children's bedtime had significant effect for bedtime variables. The bedtime difference was about 40 minutes between the early bedtime group and the late bedtime group. The early bedtime group had the earliest wake-up time among the all age groups, followed by the normal, and then the late bedtime group. Efforts to keep regular sleep and wake-up times were made greatly in the early bedtime group, and the normal and then the late bedtime group followed after. The mothers in the late bedtime group considened an ideal bedtime was around 21h although they were not able to realize it. The lengths of TV viewing and daytime nap had also significant effects for children's bedtimes. As a result of multiple comparisons, there were significant differences between the early and the late bedtime groups and between the normal and the late bedtime groups. For the bedtime of children, only mothers' total sleep hours on weekdays had a significant negative correlation, while all the other parameters were significantly and positively correlated. DISCUSSION: The study showed influencing factors for bedtime of children were mothers' routine duties in daily life, especially wake-up time, total sleep hours, daytime napping hours of children, and the length of TV viewing. This suggests that further effort on education for sleep environment management is needed.