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Background and Aim: Portopulmonary hypertension (PoPH) is a complication associated with portal hypertension. Since the epidemiological study in Japan was limited, this study aimed to investigate the characteristics, treatment patterns, and prognosis of PoPH patients in real‐world data. Methods: The characteristics and treatment patterns of PoPH (n = 386) and portal hypertension without pulmonary arterial hypertension (portal hypertension w/o PAH) (n = 96 463) were analyzed based on the Medical Data Vision (MDV) dataset from April 2008 to September 2020. Survival‐time analyses of emergency hospitalization and mortality were also conducted between matched pair cohorts of PoPH (n = 210) and portal hypertension w/o PAH (n = 840). Results: Among 386 PoPH patients, the Child–Pugh classification of PoPH group comprised patients with Class A (59 [15.3%]), B (109 [28.2%]), and C (42 [10.9%]), and missing (176 [45.6%]). Regarding the feature of PoPH group, the proportion of primary biliary cholangitis (PBC) (13.7%) and splenomegaly (9.8%) was higher compared with portal hypertension w/o PAH group. The survival time of all‐cause hospitalization in PoPH group was shorter than portal hypertension w/o PAH group in matched pair cohort (P < 0.001 by log‐rank test). Of PoPH patients, the frequency of PAH‐specific medicine usage within 90 days was monotherapy of 79 patients (20.5%), combination therapy of 64 patients (16.6%), and PAH‐specific medicine usage of 243 patients (63.0%). Conclusion: This was the first study demonstrating that high proportion of PBC and splenomegaly and a greater risk of hospitalization were observed in PoPH patients based on the analysis using administrative claim database. [ABSTRACT FROM AUTHOR]

Background: The clinical significance of CD8‐positive (CD8+) lymphocytes on tumor cell clusters of ascites cell blocks in patients with ovarian high‐grade serous carcinoma (HGSC) was investigated. Methods: Among HGSC patients who underwent surgery from January 2014 to December 2019, 38 patients with ascites cell block were selected. Using these cell blocks and primary ovarian tumor tissue, the presence of CD8+ lymphocytes and the expression of PD‐L1 were examined immunohistochemically. Tumor cell clusters were defined as cell clumps consisting of more than 10 malignant cells in cell block. Cases with at least one CD8+ lymphocyte in tumor cell cluster were defined as positive CD8+ lymphocytes (Group A); others were defined as negative CD8+ lymphocytes (Group B). The tumor tissue CD8+ lymphocytes were counted mechanically. Clinicopathological features were retrospectively compared between the two groups. Results: In total, 38 cases were identified: 25 (65.8%) in Group A and 13 (34.2%) in Group B. More cases in Group A were positive for CD4 (p < 0.01), PD‐L1 (p = 0.02), FoxP3 (p = 0.02) and had a higher number of CD8+ lymphocytes in the tissue (p = 0.03). Patients in Group A had better progression‐free survival (p < 0.01) and overall survival (p = 0.04). In multivariate analysis, Group A was an independent prognostic factor for both progression‐free survival (hazard ratio, 0.24; p < 0.01) and overall survival (hazard ratio, 0.21; p = 0.03). Conclusion: The presence of CD8+ lymphocytes in tumor cell clusters of ascites was associated with the status of immune reaction in the tissue and prognosis in patients with HGSC and might be useful information of the immune‐associated therapy. [ABSTRACT FROM AUTHOR]

Introduction: Placenta previa with placenta accreta spectrum (PAS) is a life-threatening disease that results in massive hemorrhage. The clinical and histologic criteria of PAS were adopted according to the International Federation of Gynaecology and Obstetrics (FIGO) classification. We aimed to investigate whether FIGO criteria and topography were associated with maternal complications in patients with placenta previa.Material and Methods: Patients with placenta previa who underwent cesarean section at our institution between January 2003 and December 2019 were identified. First, they were divided based on FIGO classification, as follows: Group A, with clinical criteria; Group B, with histologic criteria; and Group C: without clinical or histologic criteria. Next, cases with PAS were classified according to the topographic invasion area, as follows: type 1, upper posterior bladder; type 2, lower posterior bladder; type 3, parametrium; type 4, posterior lower uterine segment. Predictive factors for massive hemorrhage were retrospectively analyzed.Results: Among the 350 patients, 24 (6.9%) were classified as Group A, 16 (4.6%) as Group B and 310 (88.5%) as Group C. Regarding maternal history and hemostatic procedures, there were no significant factors other than hysterectomy (p < .01) in Groups A and B. The volume of blood loss in both Groups A and B was greater than in Group C (p < .01). The rates of uterine artery embolization and blood transfusion were higher in Groups A and B than in Group C (p < .01). In addition, there were no significant factors other than hysterectomy between Groups A and B. In the multivariate analysis for massive hemorrhage, Group A (odds ratio: 2.73, p = .04) and Group B (odds ratio: 12.69, p < .01) were identified as independent predictive factors. In addition, massive hemorrhage was closely related to the lower posterior bladder and parametrial invasion in both Groups A and B.Conclusions: Both clinical and histologic criteria for PAS in the FIGO classification were associated with massive hemorrhage. Diagnosing clinical PAS using the FIGO classification, additional hemostatic procedures might be necessary according to the topographic invasion area. [ABSTRACT FROM AUTHOR]

Aim: To investigate the differences in epithelial‐mesenchymal transition (EMT)‐ and matrix metalloproteinases (MMP)‐related factors among placenta previa with and without placenta accreta spectrum (PAS) (n = 69), and normal placenta (n = 51). Methods: The women diagnosed with placenta previa with or without PAS, and normal placentas, who delivered at our institution between 2006 and 2016, were enrolled. The difference of EMT‐related factors' expression by immunochemical analysis in chorionic villi and decidual cells between the normal placenta and placenta previa with or without PAS were evaluated. Results: In chorionic villi of placenta previa with and without PAS, E‐cadherin expression decreased, while that of ZEB1, SNAIL2 and MMP‐9 increased than that in normal placenta. In decidual cells of placenta previa with and without PAS, expression of vimentin, ZEB1 and MMP‐9 increased than that in normal placenta. In placenta previa with and without PAS, there was strong co‐expression of ZEB1 and vimentin in chorionic villi, of ZEB1 and MMP‐2 or MMP‐9 in decidual cells, and of SNAIL2 and vimentin or MMP‐9 in both chorionic villi and decidual cell. Vimentin expression in both chorionic villi and decidual cells was higher in placenta previa with PAS (n = 18) than in placenta previa without PAS (n = 51). MMP‐2 expression in decidual cells was higher in placenta previa with PAS than in placenta previa without PAS. Conclusion: This study revealed that EMT‐ and MMP‐associated factors may be related to placenta previa with and without PAS. Furthermore, placenta previa without PAS may acquire invasive nature. [ABSTRACT FROM AUTHOR]

Introduction: Massive hemorrhage due to placenta previa with placenta accreta spectrum is associated with high maternal mortality and morbidity. Therefore, accurate prediction of placenta previa with placenta accreta spectrum is essential; magnetic resonance imaging (MRI) is a useful tool for this purpose. This study investigated novel predictors of anterior and posterior placenta previa with placenta accreta spectrum using MRI. Material and methods: This was a retrospective study at a tertiary obstetrics hospital in Japan. The singleton patients with placenta previa who were scanned with MRI prenatally and had a cesarean section at our institution between 2007 and 2018 were included. The prediction of anterior and posterior placenta previa with placenta accreta spectrum was evaluated using four MRI findings: heterogeneous signals in the placenta, dark T2‐weighted intraplacental bands, myometrial thinning or interruption, and focal uterine bulging. The prediction of posterior placenta previa with placenta accreta spectrum was performed using the quantification of cervical varicosities, which were defined as the ratio of the distance between the minimum distance from the most dorsal cervical varicosities (a) to the deciduous and amniotic placenta (b) on a sagittal image. Results: Among 202 patients, 14 (6.9%) patients were pathologically diagnosed as having placenta accreta spectrum. Further, 38 (18.8%) patients had anterior placenta previa and 164 (81.2%) patients had posterior placenta previa. When anterior placenta previa with placenta accreta spectrum was predicted using at least one of the four MRI findings, the sensitivity and specificity of the anterior placenta previa with placenta accreta spectrum were 87.5% and 86.7%, respectively. In contrast, the sensitivity and specificity of posterior placenta previa with placenta accreta spectrum were 42.9% and 96.2%, respectively. But when the A/B ratio was set at 0.20, the sensitivity and specificity of the prediction for posterior placenta previa with placenta accreta spectrum using cervical varicosities were 100.0% and 89.2%, respectively. Conclusions: The findings of MRI to predict the anterior placenta previa with placenta accreta spectrum were different from posterior placenta previa. The cervical varicosities may be useful in predicting posterior placenta previa with placenta accreta spectrum. [ABSTRACT FROM AUTHOR]

A placental surface cyst is a cystic mass arising from the surface of the placenta. It is seldom complicated by intracystic hemorrhaging and the clinical importance of this kind of case is unclear. Therefore, we present a case of a placental surface cyst with intracystic hemorrhaging. A 29-year-old multiparous woman was diagnosed with multiple placental surface cysts with threatened preterm birth and fetal growth restriction on ultrasonography at 26 gestational weeks (GW). At 31 GW, the hemorrhage was identified inside the cyst. At 32 GW, she presented with placental abruption, and emergency cesarean section was performed. Both the mother and her baby survived. Placental surface cysts up to 77 × 65 mm in diameter containing old hemorrhages were discovered, and pathological examination revealed hemosiderin and fibrin deposition. Pregnancy with a placental surface cyst with intracystic hemorrhaging may have the potential for severe obstetric complications. [ABSTRACT FROM AUTHOR]

Aim Irinotecan-induced severe toxicities are possibly related to UGT1A1*6 and *28 genotypes. However, the correlation between UGT1A1 polymorphisms and the risk of toxicities induced by low-dose irinotecan plus platinum combination therapy still remains controversial. This prospective observational study aimed to examine the correlation between UGT1A1 genotypes and clinical outcomes of low-dose irinotecan (median 60 mg/m2, range 25-115 mg/m2) plus platinum in Japanese patients with solid tumors. Methods Toxicity profiles were compared between UGT1A1 SNP heterozygotes (hetero-group) and patients with homozygous SNP profile (*6/*6, *28/*28 and *6/*28). Logistic regression models were used to identify independent risk factors for these toxicities. Results A total of 331 patients were enrolled: 84% with hetero-group and 16% with homo-group. Although the initial irinotecan dose was similar, the dose intensities during the three cycles were significantly lower in the homo-group ( P < 0.01). Grade 3/4 hematological toxicities were significantly more frequent in the homo-group. Multivariable analysis identified UGT1A1 genotype ( P < 0.01) as an independent factor for grade 4 hematological toxicity in the first treatment cycle. Conclusion UGT1A1 genotype has a major impact on the increased risk of severe hematological toxicities, even in low-dose irinotecan regimens. UGT1A1 genotypes are useful biomarkers for predicting severe hematological toxicities in patients treated with irinotecan plus platinum analog. [ABSTRACT FROM AUTHOR]

Clear cell carcinoma of the ovary has shown an exceedingly chemo-resistant phenotype, especially in cases that are recurrent or refractory to previous therapy. Also, progression-free survival was less than 6 months, even in the patients that achieved response when they were treated with conventional anti-cancer cytotoxic agents. We present a case with recurrent and refractory ovarian clear cell carcinoma that achieved complete remission using a combination of bevacizumab, trabectedin and oxaliplatin. The progression-free interval of the patient is over 30 months, and she is still receiving the combination therapy without toxicities of more than grade 2. [ABSTRACT FROM AUTHOR]

Yamamoto S, Tsuda H, Honda K, Takano M, Tamai S, Imoto I, Inazawa J, Yamada T & Matsubara O (2012) Histopathology 60,1073-1083 ACTN4 gene amplification and actinin-4 protein overexpression drive tumour development and histological progression in a high-grade subset of ovarian clear-cell adenocarcinomas Aims: Actinin-4, encoded by the ACTN4 gene located on chromosome 19q13.2, enhances cell motility by bundling the actin cytoskeleton. We assessed how ACTN4/actinin-4 alterations contribute to the tumorigenesis of ovarian clear-cell adenocarcinomas (CCAs). Methods and results: Fluorescence in-situ hybridization analysis demonstrated that ACTN4 amplification (≥4 ACTN4 copies in ≥40% of cells) occurred in 27 (33%) of 81 CCAs and genomic gains of ACTN4 were associated strongly with immunohistochemical actinin-4 overexpression, poorly differentiated tumour histology and shorter patient survival (all P < 0.05). From the 27 ACTN4-amplified CCAs, 23 tumours with adjacent putative precursor lesions were selected and examined for ACTN4/actinin-4 alterations with respect to their intratumoral heterogeneity. In this selected cohort, none of the precursors lacking cytological atypia exhibited gains of ACTN4 or actinin-4 overexpression; 50% of the atypical endometrioses and 75% of the borderline CCAFs showed low-level gains of ACTN4 and actinin-4 overexpression, respectively. In 12 of 23 ACTN4-amplified CCAs, intratumoral heterogeneity for ACTN4 alterations was documented in carcinomatous components; the better differentiated carcinoma components exhibited fewer alterations than those with poorly differentiated histology. Conclusion: Accumulative genomic gains of ACTN4, causing actinin-4 protein overexpression, drive the development and progression of ovarian CCAs with high-grade histology. [ABSTRACT FROM AUTHOR]

Clear cell adenocarcinoma (CCA), a highly lethal histological subtype of ovarian carcinoma, is a type of human cancer with a high frequency of activating mutations in the PIK3CA gene. In this study, we aimed to determine how these mutations contribute to tumour development of CCAs. Exons 9 and 20 of the PIK3CA gene were analysed by direct genomic DNA sequencing of 23 CCAs with synchronous putative precursor lesions (ie endometriosis adjacent to carcinoma, with or without cytological atypia) and their mutational statuses were compared. Somatic mutations of the PIK3CA gene were detected in 10/23 (43%) carcinomas and in all cases the type of mutation was H1047R in the kinase domain. The identical H1047R mutation was also detected in the coexisting endometriotic epithelium, adjacent to the CCAs, in nine of ten (90%) cases. Moreover, in six of the nine lesions, the H1047R mutation was identified even in the endometrioses lacking cytological atypia. These findings provide evidence that mutations of the PIK3CA gene occur in the putative precursor lesions of CCA, strongly suggesting that they are very early events in tumourigenesis, probably initiating the malignant transformation of endometriosis. A specific kinase inhibitor to mutated PIK3CA may potentially be an effective therapeutic reagent against these carcinomas. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aim: To evaluate toxicity, response and progression-free survival of single nedaplatin chemotherapy in women with platinum/taxane-resistant/refractory epithelial ovarian, tubal and peritoneal cancer. Methods: Seventeen patients with platinum/taxane-resistant/refractory epithelial ovarian, fallopian tube or primary peritoneal cancer who were treated with a single nedaplatin regimen at 90 mg/m [ABSTRACT FROM AUTHOR]

Survival of the conceptus is dependent on continuous progesterone signaling in the maternal decidua but how this is achieved under conditions of oxidative stress that characterize early pregnancy is unknown. Using primary cultures, we show that modest levels of reactive oxygen species (ROS) increase sumoylation in human endometrial stromal cells (HESCs), leading to enhanced modification and transcriptional inhibition of the progesterone receptor (PR). The ability of ROS to induce a sustained hypersumoylation response, or interfere with PR activity, was lost upon differentiation of HESCs into decidual cells. Hypersumoylation in response to modest levels of ROS requires activation of the JNK pathway. Although ROS-dependent JNK signaling is disabled on decidualization, the cells continue to mount a transcriptional response, albeit distinct from that observed in undifferentiated HESCs. We further show that attenuated JNK signaling in decidual cells is a direct consequence of altered expression of key pathway modulators, including induction of MAP kinase phosphatase 1 (MKP1). Overexpression of MKP1 dampens JNK signaling, prevents hypersumoylation, and maintains PR activity in undifferentiated HESCs exposed to ROS. Thus, JNK silencing uncouples ROS signaling from the SUMO conjugation pathway and maintains progesterone responses and cellular homeostasis in decidual cells under oxidative stress conditions imposed by pregnancy. [ABSTRACT FROM AUTHOR]

Yamamoto S, Tsuda H, Miyai K, Takano M, Tamai S & Matsubara O (2010) Histopathology 56, 740–749 Cumulative alterations of p27 Kip1 -related cell-cycle regulators in the development of endometriosis-associated ovarian clear cell adenocarcinoma Aims: To identify the key cell-cycle dysregulations in the development of endometriosis-associated ovarian clear cell adenocarcinoma (CCA). Methods and results: Expression of p27Kip1-interacting cell-cycle regulators, such as p27Kip1 itself, Skp2, cyclin-dependent kinase subunit 1 (Cks1), cyclin A and cyclin E, and Ki67 labelling index (LI), were analysed by immunohistochemistry in 23 CCAs with 36 endometriotic or atypical endometriotic lesions adjacent to CCA from a cohort of 23 patients, and in 31 cases of solitary endometriosis. The cell-cycle regulators examined were overexpressed (Skp2, Cks1, cyclin A and cyclin E; P < 0.01, each) or down-regulated (p27Kip1, P = 0.044) significantly more frequently in the CCAs than in the adjacent endometriosis. The frequency of Skp2 overexpression was significantly higher in atypical endometriosis than in endometriosis, and the frequency of Skp2 and cyclin A overexpression was significantly higher in CCA than in atypical endometriosis ( P < 0.01, each). Mean Ki67 LI increased from endometriosis (8.4%) through atypical endometriosis (21.4%) to CCA (46.9%), with statistical significance between each component ( P < 0.01, each). The frequency of cell-cycle regulator expression and mean Ki67 LIs were not significantly different between solitary endometriosis and endometriosis adjacent to CCA. Conclusions: Alteration of the p27Kip1-interacting cell-cycle regulators appeared strongly involved in the progression of endometriosis-associated ovarian clear cell carcinogenesis through increasing cell proliferative activity. [ABSTRACT FROM AUTHOR]