Creation and Validation of Patient-Derived Cancer Model Using Peritoneal and Pleural Effusion in Patients with Advanced Ovarian Cancer: An Early Experience.

Background: The application of personalized cancer treatment based on genetic information and surgical samples has begun in the field of cancer medicine. However, a biopsy may be painful for patients with advanced diseases that do not qualify for surgical resection. Patient-derived xenografts (PDXs) are cancer models in which patient samples are transplanted into immunodeficient mice. PDXs are expected to be useful for personalized medicine. The aim of this study was to establish a PDX from body fluid (PDX-BF), such as peritoneal and pleural effusion samples, to provide personalized medicine without surgery. Methods: PDXs-BF were created from patients with ovarian cancer who had positive cytology findings based on peritoneal and pleural effusion samples. PDXs were also prepared from each primary tumor. The pathological findings based on immunohistochemistry were compared between the primary tumor, PDX, and PDX-BF. Further, genomic profiles and gene expression were evaluated using DNA and RNA sequencing to compare primary tumors, PDXs, and PDX-BF. Results: Among the 15 patients, PDX-BF was established for 8 patients (5 high-grade serous carcinoma, 1 carcinosarcoma, 1 low-grade serous carcinoma, and 1 clear cell carcinoma); the success rate was 53%. Histologically, PDXs-BF have features similar to those of primary tumors and PDXs. In particular, PDXs-BF had similar gene mutations and expression patterns to primary tumors and PDXs. Conclusions: PDX-BF reproduced primary tumors in terms of pathological features and genomic profiles, including gene mutation and expression. Thus, PDX-BF may be a potential alternative to surgical resection for patients with advanced disease.

Consistency between Primary Uterine Corpus Malignancies and Their Corresponding Patient-Derived Xenograft Models.

Patient-derived xenograft (PDX) models retain the characteristics of tumors and are useful tools for personalized therapy and translational research. In this study, we aimed to establish PDX models for uterine corpus malignancies (UC-PDX) and analyze their similarities. Tissue fragments obtained from 92 patients with uterine corpus malignancies were transplanted subcutaneously into immunodeficient mice. Histological and immunohistochemical analyses were performed to compare tumors of patients with PDX tumors. DNA and RNA sequencing were performed to validate the genetic profile. Furthermore, the RNA in extracellular vesicles (EVs) extracted from primary and PDX tumors was analyzed. Among the 92 cases, 52 UC-PDX models were established, with a success rate of 56.5%. The success rate depended on tumor histology and staging. The pathological and immunohistochemical features of primary and PDX tumors were similar. DNA sequencing revealed similarities in gene mutations between the primary and PDX tumors. RNA sequencing showed similarities in gene expressions between primary and PDX tumors. Furthermore, the RNA profiles of the EVs obtained from primary and PDX tumors were similar. As UC-PDX retained the pathological and immunohistochemical features and gene profiles of primary tumors, they may provide a platform for developing personalized medicine and translational research.

Triple repeated fetal congenital heart disease linked to PLD1 mutation: a case report.

BACKGROUND: Congenital heart disease occurs in approximately 1 in 100 cases. Although sibling occurrence is high (3-9%), the causative genes for this disease are still being elucidated. PLD1 (Phospholipase D1) is a recently discovered gene; however, few case reports have been published on it. In this report, we describe a case of triplicate fetal congenital heart disease that was diagnosed as a PDL1 mutation. Our objective is to explore the clinical manifestations of PLD1 mutations in this particular case. CASE PRESENTATION: A 32-year-old Japanese woman (gravida, para 0) was introduced since fetus four chamber view was not clear and was diagnosed with ductus arteriosus-dependent left ventricular single ventricle and pulmonary atresia at 21 weeks and 1 day of gestation during her first pregnancy. Artificial abortion using Gemeprost was performed at 21 weeks and 5 days of gestation. The second pregnancy was diagnosed as pulmonary atresia with intact ventricular septum with cardiomegaly, a cardiothoracic area ratio of more than 35%, and a circulatory shunt at 13 weeks and 3 days of gestation. Subsequently, intrauterine fetal death was confirmed at 14 weeks and 3 days of gestation. Regarding the third pregnancy, fetal ultrasonography at 11 weeks and 5 days of gestation showed mild fetal hydrops and moderate tricuspid valve regurgitation. At 16 weeks and 5 days of gestation, the fetus was suspected to have a left ventricular-type single ventricle, trace right ventricle, pulmonary atresia with intact ventricular septum, or cardiomyopathy. Cardiac function gradually declined at 26 weeks of gestation, and intrauterine fetal death was confirmed at 27 weeks and 5 days of gestation. The fourth pregnancy resulted in a normal heart with good progression and no abnormal baby. We submitted the first and second fetuses' umbilical cord, third fetus' placenta, and the fourth fetus' blood to genetic testing using whole exome analysis with next generation sequencing. Genetic analysis identified hemizygous PLD1 mutations in the first, second, and third fetuses. The fourth fetus was heterozygous. In addition, the parents were heterozygous for PLD1. This case is based on three consecutive cases of homozygosity for the PLD1 gene in the sibling cases and the fetuses with recurrent right ventricular valve dysplasia. This will elucidate the cause of recurrent congenital heart disease and intrauterine fetal death and may serve as an indicator for screening the next fetus. To date, homozygous mutations in PLD1 that repeat three times in a row are not reported, only up to two times. The novelty of this report is that it was repeated three times, followed by a heterozygous live birth. CONCLUSIONS: This report is consistent with previous reports that mutations in PLD1 cause right ventricular valve dysplasia. However, there have been few case reports of PLD1 mutations, and we hope that this report will contribute to elucidate the causes of congenital heart disease, especially right ventricular valve dysplasia, and that the accumulation of such information will provide more detailed information on PLD1 mutations in heart disease.

Lymphatic Complications Following Sentinel Node Biopsy or Pelvic Lymphadenectomy for Endometrial Cancer.

Sentinel node biopsy (SNB) is performed worldwide in patients with endometrial cancer (EC). The aim of this study was to evaluate and compare the occurrence rate of lymphatic complications between SNB and pelvic lymphadenectomy (LND) for EC. The medical records of women who underwent SNB or pelvic LND for EC between September 2012 and April 2022 were assessed. A total of 388 patients were enrolled in the current study. Among them, 201 patients underwent SNB and 187 patients underwent pelvic LND. The occurrence rates of lower-extremity lymphedema (LEL) and pelvic lymphocele (PL) were compared between the patients who underwent SNB and those who underwent pelvic LND. The SNB group had a significantly lower occurrence rate of lower-extremity LEL than the pelvic LND group (2.0% vs. 21.3%, p < 0.01). There were no patients who had PL in the SNB group; however, 4 (2.1%) patients in the pelvic LND group had PL. The occurrence rates of lower-extremity LEL and PL were significantly lower in patients who underwent SNB than those who underwent pelvic LND. SNB for EC has a lower risk of lymphatic complications compared to systemic LND.

Cancer-Specific miRNAs Extracted from Tissue-Exudative Extracellular Vesicles in Ovarian Clear Cell Carcinoma.

Ovarian clear cell carcinomas (OCCs) arise from endometriotic cysts that many women develop. Biomarkers for early OCC detection need to be identified. Extracellular vesicles have attracted attention as biomarker carriers. This study aims to identify cancer-specific miRNAs as novel OCC biomarkers using tissue-exudative extracellular vesicles (Te-EVs). Te-EVs were collected from four patients with OCC on one side and a normal ovary on the other side. Microarray analysis was performed to identify cancer-specific miRNAs in Te-EVs. Serum samples obtained before and after surgery from patients with OCC and atypical endometrial hyperplasia (AEH) (controls) were compared using real-time PCR to examine changes in the detected EV miRNA levels. Thirty-seven miRNAs were >2-fold upregulated on the OCC side compared with the normal ovarian side. We selected 17 miRNAs and created specific primers for 12 of these miRNAs. The levels of six EV miRNAs were significantly decreased in postoperative OCC serum compared to those in preoperative OCC serum. In contrast, no significant change was observed between the pre and postoperative values in the control group. We identified OCC tissue-specific miRNAs in the EVs secreted by OCC tissues. These EV miRNAs have potential for use as biomarkers for the early diagnosis and detection of OCC.

The Effect of Maternal Coagulation Parameters on Fetal Acidemia in Placental Abruption.

This study aimed to identify factors predicting the probability of serious fetal acidemia at delivery in placental abruption. We identified 5769 women who delivered at >22 weeks' gestation at two institutions in a tertiary referral unit specializing in neonatal infant care between January 2007 and December 2011. Ninety-one abruption cases were identified based on clinical and histological diagnoses. Serious fetal acidemia was defined as a pH < 7.0 in the umbilical arterial blood at delivery. Using a linear discriminant function, we calculated the score to determine the probability of serious fetal acidemia. Serious fetal acidemia was observed in 34 patients (37.4%). A logistic regression model showed that abnormal fetal heart rate patterns (bradycardia and late decelerations), uterine spasm, and maternal plasma concentration of fibrinogen less than 288 ng/dL were significantly associated with the occurrence of serious fetal acidemia. We suggest that the implementation of maternal fibrinogen in patients with placental abruption is a prognostic factor for serious fetal acidemia at delivery.

Efficacy of Hydroxychloroquine for Improving Pregnancy Outcomes in a Female with Systemic Lupus Erythematosus and Antiphospholipid Syndrome.

The use of heparin and low-dose aspirin is the current conventional treatment for pregnant females with antiphospholipid syndrome (APS). However, there is no additional treatment recommended for cases where the standard treatment cannot prevent obstetric complications such as fetal loss and placental insufficiency. Recently, the addition of a novel antimalarial, hydroxychloroquine (HCQ), to the conventional treatment has shown the potential to prevent obstetric complications. Herein, we report a case in which the addition of HCQ improved adverse pregnancy outcomes in a pregnant female with systemic lupus erythematosus and aspirin-heparin-resistant APS.

Pelvic Abscess after Cesarean Section Treated with Laparoscopic Drainage.

Cesarean section (CS), the rate of which is increasing worldwide, may be associated with complications. Although pelvic abscess after CS is rare, it is difficult to treat. We herein report two cases of pelvic abscess treated laparoscopically after CS. The abscesses of the patients were located in the pouch of Douglas and the uterine scar after CS, respectively. Several days after CS, the patients presented with lower abdominal pain and fever. Laparoscopic drainage was performed because imaging revealed a pelvic abscess that was not amenable to drainage through interventional radiology. The patients recovered from infection and were discharged four days after drainage.

Hemoperitoneum associated with uterine fibroids: A case report.

INTRODUCTION: Uterine fibroids, which are common benign tumors, rarely cause acute complications. We herein report a case of hemoperitoneum associated with uterine fibroid that could be diagnosed preoperatively with contrast-enhanced computerized tomography (CT). PATIENT CONCERNS: A 48-year-old woman with uterine fibroid developed extremely severe lower abdominal pain on the first day of her menstrual period. DIAGNOSIS: Ultrasonography and contrast-enhanced CT revealed a uterine fibroid and extravasation from the dilated vessels of the uterine fibroid. INTERVENTION: Emergent abdominal hysterectomy was performed. OUTCOMES: The total amount of bleeding was 4,600 mL. Intraoperative blood salvage (1,357 mL), 6 units of red blood cells, 4 units of fresh frozen plasma, and 20 units of platelet concentrates were transfused. The postoperative course was uneventful. Pathological examination confirmed a benign uterine fibroid. CONCLUSION: CT could be useful to determine a diagnosis for bleeding from ruptured subserosal uterine fibroid.

Possible prevention of post-partum depression by intake of omega-3 polyunsaturated fatty acids and its relationship with interleukin 6.

AIM: This study examined whether the intake of omega-3 polyunsaturated fatty acids (PUFA) prevented post-partum depression and if interleukin 6 (IL-6) was involved in this effect. We hypothesized that omega-3 supplementation has a protective effect against post-partum depression. METHODS: We measured eicosapentaenoic acid (EPA), the arachidonic acid (AA)/EPA ratio, and IL-6 in 80 singleton pregnant women during the first and second trimesters, and post-partum. The women also completed a dietary questionnaire, and post-partum depression was measured using the Edinburgh Postnatal Depression Scale (EPDS). We examined the correlations between the frequency of eating fish and EPA, the AA/EPA ratio and IL-6 in the first and second trimesters, and post-partum. We also investigated the correlation between the EPDS and the EPA, the AA/EPA ratio and IL-6. RESULTS: The frequency of eating fish was significantly correlated with EPA in the second trimester and post-partum and with the AA/EPA ratio in the second trimester. There was no correlation between IL-6 levels and the frequency of eating fish. Post-partum levels of EPA and the AA/EPA ratio were higher in the EPDS >7 group than in the EPDS ≤7 group. In the second trimester, a higher AA/EPA ratio was associated with EPDS >7. IL-6 levels did not differ between the two groups. CONCLUSION: In conclusion, a low dietary intake of omega-3 PUFA during pregnancy was correlated with lower EPA levels, which tended to lead to post-partum depression. The relationship between the IL-6 level and the pathogenesis of post-partum depression was unclear from the results of this study.

Intravenously Injected Pluripotent Stem Cell-derived Cells Form Fetomaternal Vasculature and Prevent Miscarriage in Mouse.

Miscarriage is the most common complication of pregnancy, and about 1% of pregnant women suffer a recurrence. Using a widely used mouse miscarriage model, we previously showed that intravenous injection of bone marrow (BM)-derived endothelial progenitor cells (EPCs) may prevent miscarriage. However, preparing enough BM-derived EPCs to treat a patient might be problematic. Here, we demonstrated the generation of mouse pluripotent stem cells (PSCs), propagation of sufficient PSC-derived cells with endothelial potential (PSC-EPs), and intravenous injection of the PSC-EPs into the mouse miscarriage model. We found that the injection prevented miscarriage. Three-dimensional reconstruction images of the decidua after tissue cleaning revealed robust fetomaternal neovascularization induced by the PSC-EP injection. Additionally, the injected PSC-EPs directly formed spiral arteries. These findings suggest that intravenous injection of PSC-EPs could become a promising remedy for recurrent miscarriage.

Ritodrine-Induced Agranulocytosis: A Case Report and Literature Review.

Ritodrine hydrochloride is used for preterm labor, although serious side effects, including agranulocytosis, are reported. We report a case of ritodrine hydrochloride-induced agranulocytosis accompanied by bacteremia due to catheter infection. At 24 weeks of gestation, a female patient presented due to threatened premature labor and was administered continuous intravenous infusion of ritodrine hydrochloride. On day 36 after starting intravenous ritodrine hydrochloride, she was diagnosed with agranulocytosis. The white blood cell and granulocyte count nadirs were 1,660/µl and 438/µl. The cumulative dose of ritodrine hydrochloride was 2,610 mg. Ritodrine therapy was immediately stopped, and she was given an intravenous injection of antibiotics and granulocyte colony-stimulating factor. From her blood culture, methicillin-sensitive Staphylococcus aureus was detected. However, she started vaginal delivery two days after we stopped the ritodrine infusion. When using ritodrine hydrochloride, it is necessary to frequently check the white blood cell count, regardless of the total dose and treatment period.

A rare case of ovarian carcinosarcoma with squamous cell carcinoma.

BACKGROUND: Ovarian carcinosarcoma, which contains sarcomatous and carcinomatous components, is a very rare tumor. The carcinomatous component is often adenocarcinoma, and squamous cell carcinoma is extremely rare. We herein report a case of ovarian carcinosarcoma in which the carcinomatous component was squamous cell carcinoma. CASE PRESENTATION: A 68-year-old woman presented with a huge ovarian tumor with a clinical diagnosis of malignant tumor of the ovary. She underwent hysterectomy, bilateral adnexectomy, omentectomy and lymphadenectomy. Histologically, the tumor cells showed undifferentiated pleomorphic sarcoma as the sarcomatous component and squamous cell carcinoma as the carcinomatous component. The final diagnosis was ovarian carcinosarcoma with squamous cell carcinoma in the carcinomatous component, stage IIIA1. Postoperatively, the patient was treated with six cycles of combination chemotherapy with paclitaxel and carboplatin as adjuvant therapy. The patient was free of disease at 45 months' follow-up consultation. CONCLUSION: This is a rare report of ovarian carcinosarcoma with an epithelial component composed of squamous cell carcinoma. Combination chemotherapy with paclitaxel and carboplatin may be an effective choice as adjuvant chemotherapy in cases of ovarian carcinosarcoma including squamous cell carcinoma.

Recombinant human soluble thrombomodulin as an anticoagulation therapy improves recurrent miscarriage and fetal growth restriction due to placental insufficiency - The leading cause of preeclampsia.

INTRODUCTION: Placental insufficiency is one of the major risk factors for growth restriction and preeclampsia. The aim of this study is to investigate whether recombinant human Thrombomodulin(r-TM) improves fetal conditions and physiological outcomes. METHODS: We used CBA/J × BALB/C mice as a control and CBA/J × DBA/2 mice - a well-studied model of recurrent spontaneous miscarriage. Pregnant mice received daily subcutaneous injections of r-TM or saline from day 0-15. The fetal resorption rate, fetal weight, and litter size were calculated at day 15. Additionally, we analyzed the mRNA expression of angiogenic factors and the concentration of soluble Flt-1 (sFlt-1) using the ELISA kit. RESULTS: The rate of fetal resorption in CBA/J × DBA/2 mice treated with r-TM was significantly lower compared with mice without r-TM treatment. Additionally, fetal weight and litter size were also significantly higher in the r-TM treated mice. Fibrinogen deposition in the labyrinth area of the CBA/J × DBA/2 mice treated with r-TM was significantly lower compared with deposits in the mice untreated with r-TM. As well, r-TM significantly increased the gene expression level of VEGF and Flt-1 mRNA in the placentas of the CBA/J × DBA/2 mice. r-TM treatment also significantly decreased the production of sFlt-1 protein in the placentas of preeclampsia-like diseased mice. CONCLUSION: r-TM as an anticoagulation therapy has the potential for the medical treatment of recurrent miscarriage and fetal growth restriction due to improved angiogenic factors. Additionally, r-TM treatment has the potential for the recovery of preeclampsia.

Utility of Fluid Assessment Based on the Intrathoracic Impedance Monitoring in a Peripartum Woman with Heart Disease.

Recently, implantable cardioverter-defibrillators (ICD) have become capable of monitoring intrathoracic impedance to detect an increased fluid volume and heart failure. Pregnancy is a well-known cause of an increased body fluid volume; however, it is not clear whether the measurement of intrathoracic impedance by ICD is clinically useful for precisely detecting heart failure in pregnant women. We herein report the case of a 39-year-old woman with an ICD that had been implanted after an event of ventricular fibrillation due to severe aortic regurgitation with a bicuspid aortic valve. Elevated right ventricular pressure and brain natriuretic peptide levels were detected at 37 weeks of gestation and postpartum. At the same time, the ICD's stored fluid index gradually increased and exceeded the threshold on the 10th day after delivery. She was treated with diuretics and recovered from postpartum heart failure. The physiological volume changed in the perinatal period, but we were still able to detect heart failure by ICD. Intrathoracic impedance monitoring is effective in the perinatal field.

Management of pulmonary vasodilator therapy in three pregnancies with pulmonary arterial hypertension.

Pregnancy with pulmonary arterial hypertension (PAH) has a significantly high risk of maternal death and women with PAH are basically advised to avoid pregnancy. Recently, several reports have described pregnant women with PAH who were treated with pulmonary vasodilators during pregnancy and delivered safely. However, the efficacy of this treatment during pregnancy is still not clear. Here we report on the short-term outcomes of three primiparous women with PAH who were prescribed pulmonary vasodilator therapy during their pregnancies. All women delivered preterm due to cardiac and/or obstetric reasons and were discharged without any complication. Pulmonary vasodilator therapy can be used safely during the pregnancies of PAH patients and may contribute to improved maternal and fetal prognoses.

A Case of Intestinal Obstruction in Pregnancy Diagnosed by MRI and Treated by Intravenous Hyperalimentation.

Intestinal obstruction in pregnancy is rare and is mainly caused by prior pelvic surgery. We herein report a case of intestinal obstruction in a pregnant female with a history of laparoscopic myomectomy, who presented with hypogastric pain, abdominal distension, and vomiting at 26 weeks of gestation. A simple intestinal obstruction was diagnosed by MRI. Conservative treatments, including intravenous hyperalimentation and the placement of an ileus tube, were provided and her abdominal symptoms improved for 14 days. After restarting oral intake, she had no abdominal symptoms. She gave birth to a 2,146 g female infant by caesarean section at 37 weeks and 1 day of gestation. Although an area of cicatrization, which was thought to have been the starting point of the occlusion that caused the intestinal obstruction, was found, the excision of the small intestine was not necessary. Her postoperative course was uneventful. Intestinal obstruction requires a prompt diagnosis and aggressive intervention may be necessary to minimize the morbidity and mortality associated with this rare complication of pregnancy. MRI can be safely used during pregnancy to diagnose intestinal obstruction and intravenous hyperalimentation may improve the maternal and fetal prognoses.

Mitotically active cellular fibroma of the ovary: a case report and literature review.

BACKGROUND: The ovarian cellular fibrous tumor with mitotic figure >4 per 10 high power field without moderate to severe atypia is defined as mitotically active cellular fibroma according to the 2014 World Health Organization classification. As this category is new and rare now, we described here a case of MACF and reviewed the literature. CASE: We present a case of mitotically active cellular fibroma of the ovary with 10-year history that was treated with laparoscopic surgery. METHODS: We reviewed the relevant literature using PubMed search system and analyzed the previous cases. RESULTS: To date, only 5 cases of mitotically active cellular fibroma have been reported. Our patient is the first case of mitotically active cellular fibroma of the ovary treated with laparoscopic surgery. CONCLUSION: MACF of the ovary is a newly defined category and few cases have been reported, while prognostic factors have also not yet been fully characterized. Long-term clinical follow-up is necessary.