Shu Soeda

Tumor-associated macrophages correlate with vascular space invasion and myometrial invasion in endometrial carcinoma.

OBJECTIVE This study was conducted to determine whether tumor-associated macrophages (TAMs) correlate with clinicopathological features in endometrioid adenocarcinoma. METHODS 76 cases of endometrioid adenocarcinoma treated initially by hysterectomy with pelvic lymphadenectomy were retrospectively retrieved, and their histological features were evaluated. Immunohistochemical staining for CD68, CD34, and Ki-67 was performed on paraffin-embedded sections. TAMs were counted in two areas: in the invasive margin (margin TAMs) and in the tumor (intratumor TAMs). RESULTS Margin TAMs were significantly associated with FIGO stage (P=0.033), histological grade (P=0.008), myometrial invasion (P=0.0001), pelvic lymph node metastasis (P=0.027), and vascular space invasion (P=0.0001). Intratumor TAMs were significantly associated with intratumor Ki-67 (P=0.006) and microvessel density (P=0.020). Patients with high margin TAMs (> or = 20) had significantly worse progression-free survival (PS) and overall survival (OS) than those with low margin TAMs (< 20) (log rank test, P=0.0031 and P=0.0085, respectively). On multivariate analysis, high margin TAMs were significantly associated with vascular space invasion (P=0.013; HR, 6.05; 95% confidence interval [CI], 1.468-24.938) and myometrial invasion (P=0.041; HR, 4.03; 95% CI, 1.06-14.71). Vascular space invasion was only associated with PFS. CONCLUSION Although on univariate analysis TAMs are associated with other poor prognosticators, on a multivariate analysis, TAMs appear only to be associated with MI and VI. TAMs may play a significant role in the biology of tumor progression of endometrial adenocarcinoma, but do not appear to be independent prognostic indicators of patients survival.

Serum levels of rapid turnover proteins are decreased and related to systemic inflammation in patients with ovarian cancer

Poor nutritional status is common in ovarian cancer. It is well known that the nutritional status of a patient with malignant disease is associated with survival, and that it can be assessed by serum levels of rapid turnover proteins (RTPs), such as retinol binding protein, prealbumin and transferrin. Systemic inflammation, usually observed in the form of elevated C-reactive protein (CRP) or neutrophil/lymphocyte ratio (NLR), occurs by various mechanisms involving numerous pro-inflammatory cytokines. These include interleukin (IL)-17 and other soluble protein mediators, such as soluble IL-2 receptor (sIL-2R) and vascular endothelial growth factor (VEGF). In this study, circulating levels of RTP were decreased in advanced stages of ovarian cancer, and significant inverse correlations were found between RTP levels and serum levels of CRP or NLR. CRP levels were also correlated with serum levels of VEGF and sIL-2R. Moreover, NLR, VEGF and sIL-2R levels, and IL-17 production, were all inversely correlated with RTP levels. These findings indicate that chronic inflammation may be associated with compromised immune function, such as an impaired T-cell response, via various inflammatory proteins, including sIL-2R, VEGF and IL-17. The key mechanisms leading to cancer cachexia, in which nutritional impairment is a major clinical issue, appear to be primarily immune reactions caused by chronic inflammation. Anti-inflammatory treatments may be effective in clinically improving various symptoms associated with these mechanisms.

Production of IL1-beta by ovarian cancer cells induces mesothelial cell beta1-integrin expression facilitating peritoneal dissemination

BackgroundA crucial step in the metastatic spread of ovarian cancer (OC) is the adhesion and implantation of tumor cells to the peritoneal mesothelium. In order to study this step in the cascade, we derived a pro-metastatic human ovarian carcinoma cell line (MFOC3) from the non-metastatic FOC3 line.MethodsMolecular profiling of the isogeneic lines identified differentially expressed genes, and investigation for a role in dissemination for specific factors was achieved by development of a co-culture adhesion assay utilizing monolayers of human mesothelial cells.ResultsAfter murine intraperitoneal inoculation, the FOC3 cell line formed no metastases, but the MFOC3 subline formed metastases in > 80% of SCID mice. MFOC3 cells also adhered 2-3 times more avidly to mesothelial monolayers. This adhesion was inhibited by neutralizing antibodies to IL-1β and enhanced by recombinant IL-1β (p < 0.01). IL-1β induced mesothelial cell β1-integrin, and an antibody to this subunit also inhibited the adhesion of MFOC3 to mesothelial cells in vitro and significantly reduced metastases in vivo. Immunohistochemical analysis of a cohort of 96 ovarian cancer cases showed that negative IL-1β expression was significantly associated with an improved overall survival rate.ConclusionsThese results suggest that a IL-1β/β1-integrin axis plays a role in ovarian tumor cell adhesion to mesothelia, a crucial step in ovarian cancer dissemination.

Repeated Paracentesis in a Fetus with Meconium Peritonitis with Massive Ascites : A Case Report

Meconium peritonitis (MP) is defined as a sterile inflammatory reaction in the fetal abdomen that is seen in cases of intrauterine bowel perforation. Recently, there have been increasing numbers of fetuses with MP prenatally diagnosed by ultrasonography. Massive fetal ascites in MP may cause hydrops and hypoplastic lungs. However, antepartum management of MP has not yet been established. We encountered a fetus with MP and massive ascites. Repeated paracentesis between 29 weeks and 4 days and 31 weeks and 6 days of gestation prevented the progression to fetal hydrops and hypoplastic lungs, which may occur due to massive meconium ascites with an increased preload index. Amniocentesis was also performed in patients with polyhydramnios for treatment of preterm labor. These observations suggest that aggressive therapy can prolong the gestation period and improve MP treatment outcomes.

Non‐bacterial thrombotic endocarditis with systemic embolic events caused by adenomyosis

Non‐bacterial thrombotic endocarditis is caused by a hypercoagulable state that is sometimes related to malignancy and this type of endocarditis associated with benign tumors has not yet been reported. In this study we report the first case of non‐bacterial thrombotic endocarditis caused by adenomyosis, which is a benign gynecological condition.

Angiosarcoma of Vagina Successfully Treated with Interleukin‐2 Therapy and Chemotherapy: A Case Report

We report a case of angiosarcoma of the vagina in a 61‐year‐old woman who had undergone radical hysterectomy and pelvic irradiation for uterine cervical adenocarcinoma 14 years previously. Combination chemotherapy (cyclophosphamide, vincristine, doxorubicin and dacarbazine) and interleukin‐2 induced complete remission of the tumor. The patient remained free from disease for 15 months.

Sclerosing stromal tumor of the ovary treated with 2-incision total laparoscopic cystectomy.

Highlights • Sclerosing stromal tumor (SST) is an extremely rare benign tumor of the ovary and preoperative diagnosis of SST is difficult as it often mimics a malignant tumor.• SST occurs in young women.• Many cases of SST were treated by abdominal oophorectomy and laparoscopic surgery is seldom performed in SST cases.• We report a case of SST of the ovary in an 18-year-old girl who was diagnosed by preoperative imaging and underwent laparoscopic cystectomy.

Evaluation of anticancer agents using patient-derived tumor organoids characteristically similar to source tissues

Patient-derived tumor xenograft models represent a promising preclinical cancer model that better replicates disease, compared with traditional cell culture; however, their use is low-throughput and costly. To overcome this limitation, patient-derived tumor organoids (PDOs) were established from human lung, ovarian and uterine tumor tissues, among others, to accurately and efficiently recapitulate the tissue architecture and function. PDOs were able to be cultured for >6 months, and formed cell clusters with similar morphologies to their source tumors. Comparative histological and comprehensive gene expression analyses proved that the characteristics of PDOs were similar to those of their source tumors, even following long-term expansion in culture. At present, 53 PDOs have been established by the Fukushima Translational Research Project, and were designated as Fukushima PDOs (F-PDOs). In addition, the in vivo tumorigenesis of certain F-PDOs was confirmed using a xenograft model. The present study represents a detailed analysis of three F-PDOs (termed REME9, 11 and 16) established from endometrial cancer tissues. These were used for cell growth inhibition experiments using anticancer agents. A suitable high-throughput assay system, with 96- or 384-well plates, was designed for each F-PDO, and the efficacy of the anticancer agents was subsequently evaluated. REME9 and 11 exhibited distinct responses and increased resistance to the drugs, as compared with conventional cancer cell lines (AN3 CA and RL95-2). REME9 and 11, which were established from tumors that originated in patients who did not respond to paclitaxel and carboplatin (the standard chemotherapy for endometrial cancer), exhibited high resistance (half-maximal inhibitory concentration >10 µM) to the two agents. Therefore, assay systems using F-PDOs may be utilized to evaluate anticancer agents using conditions that better reflect clinical conditions, compared with conventional methods using cancer cell lines, and to discover markers that identify the pharmacological effects of anticancer agents.

Unique Learning System for Uterine Artery Embolization for Symptomatic Myoma and Adenomyosis for Obstetrician-Gynecologists in Cooperation with Interventional Radiologists: Evaluation of UAE From the Point of View of Gynecologists Who Perform UAE

STUDY OBJECTIVE To evaluate a unique learning system for uterine artery embolization (UAE) and examine its feasibility and clinical outcomes for the treatment of symptomatic uterine leiomyomas and adenomyosis when performed by obstetrician-gynecologists in cooperation with interventional radiologists (IVRs). DESIGN Retrospective study (Canadian Task Force classification II-2). SETTING University hospital. PATIENTS One hundred seventy-three patients who underwent UAE for symptomatic leiomyomas and adenomyosis. INTERVENTIONS We examined the medical records of patients who underwent UAE for symptomatic uterine leiomyomas and adenomyosis at our department between 2003 and 2012 using our learning system for UAE for obstetrician-gynecologists in cooperation with IVRs. The charts of all patients were reviewed, and data on etiologic factors, past medical history of leiomyomas and adenomyosis, symptoms, details of UAE, and clinical outcomes after UAE were extracted. MEASUREMENTS AND MAIN RESULTS A total of 173 patients who underwent 177 UAEs were identified, including 4 patients who underwent embolization twice because of primary treatment failure or symptom recurrence. During the study period, 2 gynecologists successfully acquired endovascular skills. The technical success rate was 97.7% (174 of 177). The duration of fluoroscopy in procedures performed by obstetrician-gynecologists who acquired endovascular skills was not significantly different from that in procedures performed by IVRs at our institution; however, this duration was significantly longer in procedures performed by obstetrician-gynecologists who did not have sufficient experience with our learning protocol for UAE because of inadequate live observation of UAEs performed by skilled IVRs. Complications that necessitated discontinuation of the procedure occurred in 2.3% of cases (4 of 177). The clinical outcomes were similar to those reported in previous studies. Adverse events after UAE included myeloid passages in 7.0% (11 of 158), infections in 2.5% (4 of 158), vaginal discharge in 2.5% of patients with leiomyomas (4 of 158), and vaginal discharge in 7.1% of patients with adenomyosis (1 of 14). All the adverse events were adequately treated by the obstetrician-gynecologists themselves. The timing of hysterectomy due to complications or recurrence of symptoms after UAE varied widely. CONCLUSION UAE performed by obstetrician-gynecologists in cooperation with radiologists can be achieved safely and successfully with acceptable clinical outcomes. Live observation of the procedure performed by skilled IVRs is essential to improving the skills and reducing the fluoroscopic time of obstetrician-gynecologists.

Mild phenotypes associated with an unbalanced X-autosome translocation, 46,X,der(X)t(X;8)(q28;q13)

Unbalanced X‐autosome translocation can result in various phenotypic manifestations. We present the first case of 46,X,der(X)t(X;8)(q28;q13) in a 34‐year‐old female with relatively mild manifestations, including congenital heart disease, epicanthal fold, mild intellectual disability, and menstrual irregularity. Our findings expand the known spectrum of unbalanced X‐autosome translocations, for improved clinical management.