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Lymphatic ascites following pelvic and para-aortic lymphadenectomy is a well-known complication. Surgical treatment and interventional radiology are required in a few cases. To determine the appropriate treatment strategy, it is important to preoperatively detect the presence and location of lymphatic leakage. However, the methods have yet to be established.We report a case in which lymphoscintigraphy with single-photon emission computerized tomography/computed tomography (SPECT/CT) was performed to evaluate pelvic lymphorrhea that occurred following total hysterectomy with pelvic and para-aortic lymphadenectomy for stage IIIA uterine sarcoma. Lymphoscintigraphy with SPECT/CT showed leakage of radioisotopes into the pelvic space, and intranodal lymphangiography was performed based on these findings. Following the procedure, the pelvic lymphorrhea improved, and no radioisotope leakage was confirmed by re-evaluation with lymphoscintigraphy with SPECT/CT.Our case indicates that lymphoscintigraphy with SPECT/CT may be useful for detecting the precise site of lymphatic leakage before interventional radiology or surgery.

The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a principal regulator of calcium homeostasis through activation of the vitamin D receptor (VDR). Previous studies have shown that 2α-(3-hydroxypropyl)-1,25D3 (O1C3) and 2α-(3-hydroxypropoxy)-1,25D3 (O2C3), vitamin D derivatives resistant to inactivation enzymes, can activate VDR, induce leukemic cell differentiation, and increase blood calcium levels in rats more effectively than 1,25(OH)2D3. In this study, to further investigate the usefulness of 2α-substituted vitamin D derivatives, we examined the effects of O2C3, O1C3, and their derivatives on VDR activity in cells and mouse tissues and on osteoblast differentiation of dedifferentiated fat (DFAT) cells, a cell type with potential therapeutic application in regenerative medicine. In cell culture experiments using kidney-derived HEK293 cells, intestinal mucosa-derived CaCO2 cells, and osteoblast-derived MG63 cells, and in mouse experiments, O2C2, O2C3, O1C3, and O1C4 had a weaker effect than or equivalent effect to 1,25(OH)2D3 in VDR transactivation and induction of the VDR target gene CYP24A1, but they enhanced osteoblast differentiation in DFAT cells equally to or more effectively than 1,25(OH)2D3. In long-term treatment with the compound without the medium change (7 days), the derivatives enhanced osteoblast differentiation more effectively than 1,25(OH)2D3. O2C3 and O1C3 were more stable than 1,25(OH)2D3 in DFAT cell culture. These results indicate that 2α-substituted vitamin D derivatives, such as inactivation-resistant O2C3 and O1C3, are more effective than 1,25(OH)2D3 in osteoblast differentiation of DFAT cells, suggesting potential roles in regenerative medicine with DFAT cells and other multipotent cells.

Abstract Background Retained products of conception (RPOC) often cause severe postpartum hemorrhage (PPH) but the clinical significance of RPOC in placenta previa is unclear. This study aimed to investigate the clinical significance of RPOC in women with placenta previa. The primary outcome was to evaluate risk factors of RPOC and the secondary outcome was to consider risk factors of severe PPH. Methods Singleton pregnant women with placenta previa who underwent cesarean section (CS) and placenta removal during the operation at the National Defense Medical College Hospital between January 2004 and December 2021 were identified. A retrospective analysis was performed to examine the frequency and risk factors of RPOC and the association of RPOC with severe PPH in pregnant women with placenta previa. Results This study included 335 pregnant women. Among these, 24 (7.2%) pregnant women developed RPOC. Pregnant women with prior CS (Odds Ratio (OR) 5.98; 95% Confidence Interval (CI) 2.35–15.20, p

Abstract Background Mucinous carcinoma (MC) is a histological subtype of ovarian cancer that has a worse prognosis at advanced stages than the most prevalent histological subtype, high-grade serous carcinomas. Invasive patterns have been recognized as prognostic factors for MCs. MCs with infiltrative invasion were more aggressive than those with expansile invasion. MC with an expansile pattern exhibited behavior similar to mucinous borderline tumors (MBT). However, genomic analysis of invasive patterns is insufficient. This study aimed to compare genetic information between groups with MC and infiltrative invasion (Group A) and those with MC with expansile invasion or MBT (Group B). Methods Ten cases each of MC with infiltrative invasion, MC with expansile invasion, and MBT between 2005 and 2020 were identified. Deoxyribonucleic acid (DNA) extraction from formalin-fixed paraffin-embedded tissues was performed, and cases with DNA fragmentation or the possibility of DNA fragmentation were excluded. Mutant base candidates and tumor mutation burden (TMB) values (mutations/megabase) were calculated. Results After assessing the quality of purified DNA, seven cases of MC with infiltrative invasion, five cases of MC with expansile invasion, and three cases of MBT were included. More patients in group A experienced recurrence or progression (p

Abstract 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

Abstract Pulmonary arterial hypertension (PAH) is a fatal disease that often occurs at an early age. In recent years, aggressive treatment with multiple drugs from the early‐stage diagnosis is expected to improve the prognosis. Indeed, a high rate of initial combination therapy and excellent treatment outcomes have been reported from specialized centers for PAH in Japan. However, information on PAH epidemiology, including non‐PAH specialized centers in Japan, is unclear. To address the above, we conducted a retrospective observational cohort study from April 2008 to September 2020 using real‐world evidence from a large‐scale administrative database (Medical Data Vision) to examine baseline characteristics, comorbidities, and treatment profiles of Japanese patients with PAH. Five hundred and eighteen patients with PAH (treatment‐naive PAH, age 67.2 ± 15.9) were identified through our comprehensive approach which combined PAH disease codes, medications, and diagnostic procedures. Moreover, we showed that a larger proportion of patients received monotherapy in their initial treatment (66%) compared to those receiving combination therapy (34%). During the 1‐year follow‐up after PAH diagnosis, 13% of patients increased their PAH medications while other patients either decreased their PAH medications (6%) or discontinued PAH treatment (27%). The 3‐ and 5‐year event‐free survival rates of all‐cause death were 72% and 64%, respectively. This is the first large‐scale administrative database study that provides insights into real‐world PAH management in Japan. This study highlighted a different PAH clinical landscape which included a larger portion of the elderly population, higher initial monotherapy treatment, and lower survival rates than previous studies.

Abstract Active vitamin D form 1α,25-dihydroxtvitamin D3 (1,25(OH)2D3) plays pivotal roles in calcium homeostasis and osteogenesis via its transcription regulation effect via binding to vitamin D receptor (VDR). Mutated VDR often causes hereditary vitamin D-dependent rickets (VDDR) type II, and patients with VDDR-II are hardly responsive to physiological doses of 1,25(OH)D3. Current therapeutic approaches, including high doses of oral calcium and supraphysiologic doses of 1,25(OH)2D3, have limited success and fail to improve the quality of life of affected patients. Thus, various vitamin D analogues have been developed as therapeutic options. In our previous study, we generated genetically modified rats with mutated Vdr(R270L), an ortholog of human VDR(R274L) isolated from the patients with VDDR-II. The significant reduced affinity toward 1,25(OH)2D3 of rat Vdr(R270L) enabled us to evaluate biological activities of exogenous VDR ligand without 1α-hydroxy group such as 25(OH)D3. In this study, 2α-[2-(tetrazol-2-yl)ethyl]-1α,25(OH)2D3 (AH-1) exerted much higher affinity for Vdr(R270L) in in vitro ligand binding assay than both 25(OH)D3 and 1,25(OH)2D3. A robust osteogenic activity of AH-1 was observed in Vdr(R270L) rats. Only a 40-fold lower dose of AH-1 than that of 25(OH)D3 was effective in ameliorating rickets symptoms in Vdr(R270L) rats. Therefore, AH-1 may be promising for the therapy of VDDR-II with VDR(R274L).

Abstract 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

Abstract Background Tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) may be useful prognostic indicators in endometrial cancer. However, standardized assessment methods and the prognostic roles of these cells in different stage groups are unclear. Methods Formalin-fixed paraffin-embedded tissue samples of 107 endometrioid-type endometrial carcinomas (EECs) comprising 60 stage IB and 47 stage IIIC or IVB cases were evaluated. CD3+ TILs, CD8+ TILs, CD68+ TAMs, and CD163+ TAMs were detected by immunohistochemistry, and their densities were evaluated by semiquantitative and quantitative methods. TILs within tumor epithelial cell nests (E-TILs) and those within the stroma at the invasive front (S-TILs) were evaluated separately for CD3+ and CD8+ cells. The “TIL score” was defined as the sum of semiquantitative scores of CD3+ E-TILs, CD3+ S-TILs, CD8+ E-TILs, and CD8+ S-TILs. For TAMs, the area of CD68+ and CD163+ cells in the invasive margin were semiquantitatively and quantitatively evaluated. Clinicopathological and prognostic implications of TILs and TAMs in stage IB and IIIC/IVB EECs were examined by Cox univariate and multivariate analyses. Results By Cox univariate analyses, semiquantitatively low CD3+ E-TILs, low CD8+ E-TILs, and low “TIL score” were significantly correlated with worse prognosis in stage IB patients (P = 0.011, 0.040, and 0.039, respectively). Likewise, low CD3+ E-TILs and low CD8+ E-TILs, by both semiquantitative (P = 0.011 and 0.0051) and quantitative evaluations (P

Abstract Background Bevacizumab (Bev) plays the central role of the adjuvant therapy for patients with ovarian carcinoma. The aim of our study was to examine whether differences in the administration of Bev influence the prognosis of patients. Methods Patients with ovarian carcinoma who received treatment at two hospitals between 1999 and 2020 were identified. Patients treated with weekly low-dose administration of Bev (100 mg Bev on days 1 and 8 and 200 mg Bev on day 15, monthly) at one hospital (group A) and those with monthly high-dose administration of Bev (15 mg/kg of Bev on day 1, monthly) at another hospital (group B) were retrospectively compared. Results Among the total patients, 44 were assigned to group A and 33 were assigned to group B. More patients in group A had advanced disease (p = 0.03) and a lower dose of Bev at the first time during the first cycle administration (p

Abstract Background The aim of this study was to evaluate the clinicopathological factors and prognosis of mucinous carcinoma (MC) with infiltrative invasion, MC with expansile invasion, and high-grade serous carcinoma (HGSC). Methods Cases of MC and HGSC between 1984 and 2019 were identified. The clinicopathological factors and prognosis of MC with infiltrative invasion or expansile invasion and HGSC were retrospectively compared. Although our present study included cases in our previous studies, we extended observational period when analysis was performed. Accordingly, our study added increased cases and survival analysis was newly conducted. Results After pathological review, 27 cases of MC with infiltrative invasion, 25 cases of MC with expansile invasion, and 219 cases of HGSC were included. MC had a better prognosis in terms of progression-free survival (PFS, p < 0.01) and overall survival (OS, p < 0.01) than HGSC for all International Federation of Gynecology and Obstetrics (FIGO) stages; however, multivariate analysis did not show statistical differences in PFS and OS. There were no statistically significant differences in PFS and OS for all FIGO stages between MC with infiltrative invasion and HGSC. However, in cases with FIGO stages II to IV, MC with infiltrative invasion had worse PFS (p < 0.01) and OS (p < 0.01) than HGSC. In univariate analysis, MC with infiltrative invasion was a worse prognostic factor for PFS (hazard ratio [HR] 2.83, p < 0.01) and OS (HR 3.83, p < 0.01) than HGSC. Compared with HGSC, MC with expansile invasion had better PFS (p < 0.01) and OS (p < 0.01). Multivariate analysis demonstrated that MC with expansile invasion was a better prognostic factor for PFS (HR 0.17, p < 0.01) and OS (HR 0.18, p = 0.03) than HGSC. Conclusions Compared to the prognosis of HGSC, that of MC was different according to the invasive pattern and FIGO stage. Therefore, future study may be needed to consider this association.

Abstract We aimed to investigate the resuscitative efficacy of hemoglobin vesicles (HbVs) as a red blood cell (RBC) substitute for the initial treatment of severe postpartum hemorrhage (PPH). Twenty-five pregnant rabbits underwent cesarean section; uncontrolled hemorrhage was induced by transecting the right uterine artery to establish a severe PPH model. During the first 30 min, all rabbits were administered 6% hydroxyethyl starch (HES) of an equivalent volume to the hemorrhage every 5 min. Thereafter, they received any of the following three isovolemic fluids for resuscitation every 5 min: RBCs with platelet-poor plasma (RBC/PPP) (n = 8), 6% HES (n = 7), or HbVs with 25% human serum albumin (n = 10). After surgical hemostasis at 60 min, survival was monitored until 12 h. No rabbits receiving only HES infusion survived beyond 6 h, whereas all rabbits receiving RBC/PPP transfusion survived. The rabbits receiving HbV infusion showed significantly higher mean arterial pressure and hemoglobin levels than the HES-receiving rabbits, and 8 of 10 rabbits survived for 6 h. The HbV group showed significantly higher survival than the HES group but worse survival than the RBC/PPP group. In conclusion, HbV infusion for severe PPH effectively prevents lethal hemorrhagic shock in a pregnant rabbit model.

Abstract Background This study aimed to investigate the association between clinicopathologic factors, mesothelin, and cancer antigen (CA) 125 in endometrial carcinoma. Methods Between 1989 and 2017, patients with endometrial carcinoma who underwent total hysterectomy and bilateral salpingo-oophorectomy at our hospital were identified. The association between either or both immunochemical expression of mesothelin and CA125 and clinicopathological features were retrospectively examined. Results Among 485 patients, 171 were positive for mesothelin, 368 were positive for CA125, and 167 were positive for mesothelin and CA125. The expression of mesothelin and CA125 was positively correlated (p

Abstract Background In ovarian mucinous carcinoma, invasive pattern is the important factor but there were less reposts to investigate it. The aim of this study was to examine the association between prognosis and invasive patterns of ovarian mucinous carcinoma and to investigate the biomarkers of the diagnosis and prognosis immunochemically. Patients with ovarian mucinous carcinoma at our institution between 1984 and 2018 were identified. A pathological review was conducted using the 2020 World Health Organization criteria. The prognosis of infiltrative invasion and expansile invasion of ovarian mucinous carcinoma were retrospectively compared. In addition, immunohistochemical staining was conducted for all cases, and the immunohistochemical differences between the two invasive patterns were compared. Results After the pathological review, 25 cases with infiltrative invasion and 24 cases with expansile invasion were included. Ovarian mucinous carcinoma with infiltrative invasion showed significantly worse progression-free survival (PFS, p

Objective: In Japan, perioperative prophylaxis of pulmonary embolism (PE) in gynecologic cancer patients with preoperative asymptomatic venous thromboembolism (VTE) has not been well established yet. The GOTIC-VTE trial was a prospective, multi-center, single-arm clinical trial to investigate the prevention of postoperative symptomatic PE onset by seamless anticoagulant therapy from the preoperative period to 4 weeks after surgery instead of using intermittent pneumatic compression. Methods: Anticoagulant therapy was started immediately after asymptomatic VTE diagnosis and stopped preoperatively according to the rules of each institution. Unfractionated heparin administration was resumed within 12 hours postoperatively, and this was followed by the switch to low-molecular-weight heparin and subsequently, edoxaban; this cycle was continued for 28 days. Primary outcome was the occurrence of symptomatic PE in 28 days postoperatively. Secondary outcomes were the incidence of VTE-related events in 28 days and 6 months postoperatively and protocol-related adverse events. Results: Between February 2018 and September 2020, 99 patients were enrolled; of these, 82 patients were assessed as the full analysis set, including 58 for ovarian cancer, fallopian tube, or peritoneal cancer; 21 for endometrial cancer; and 3 for cervical cancer. No symptomatic PE was observed within 28 days postoperatively; two patients had bleeding events (major bleeding and clinically relevant nonmajor bleeding) and three had grade 3 adverse events (increased alanine transaminase, aspartate aminotransferase, or gamma-glutamyl transferase). Conclusion: The multifaceted perioperative management for gynecologic malignancies with asymptomatic VTE effectively prevented postoperative symptomatic PE. [ABSTRACT FROM AUTHOR]

Chemosensitivity to cisplatin derivatives varies among individual patients with intractable malignancies including ovarian cancer, while how to unlock the resistance remain unknown. Ovarian cancer tissues were collected the debulking surgery in discovery- (n = 135) and validation- (n = 47) cohorts, to be analyzed with high-throughput automated immunohistochemistry which identified cystathionine γ-lyase (CSE) as an independent marker distinguishing non-responders from responders to post-operative platinum-based chemotherapy. We aimed to identify CSE-derived metabolites responsible for chemoresistant mechanisms: gold-nanoparticle (AuN)-based surface-enhanced Raman spectroscopy (SERS) was used to enhance electromagnetic fields which enabled to visualize multiple sulfur-containing metabolites through detecting scattering light from Au–S vibration two-dimensionally. Clear cell carcinoma (CCC) who turned out less sensitive to cisplatin than serous adenocarcinoma was classified into two groups by the intensities of SERS intensities at 480 cm−1; patients with greater intensities displayed the shorter overall survival after the debulking surgery. The SERS signals were eliminated by topically applied monobromobimane that breaks sulfane-sulfur bonds of polysulfides to result in formation of sulfodibimane which was detected at 580 cm−1, manifesting the presence of polysulfides in cancer tissues. CCC-derived cancer cell lines in culture were resistant against cisplatin, but treatment with ambroxol, an expectorant degrading polysulfides, renders the cells CDDP-susceptible. Co-administration of ambroxol with cisplatin significantly suppressed growth of cancer xenografts in nude mice. Furthermore, polysulfides, but neither glutathione nor hypotaurine, attenuated cisplatin-induced disturbance of DNA supercoiling. Polysulfide detection by on-tissue SERS thus enables to predict prognosis of cisplatin-based chemotherapy. The current findings suggest polysulfide degradation as a stratagem unlocking cisplatin chemoresistance.

Objective: Recently, Bakri balloon (BBT) was effective for women with placenta previa to reduce hemorrhage. However, about 10% of women needed to receive an invasive strategy. Thus, the identification of risk factors and the development of additional measurements for BBT failure was needed. The aim of our study is to investigate the cause and measurements of failing prophylactic BBT in women with placenta previa. Materials and methods: Women with placenta previa who underwent cesarean section and had a prophylactic BBT inserted during the operation at our institution between January 2015 and December 2017 were enrolled. Patients requiring additional procedures after cesarean section for massive hemorrhage were defined as BBT failures. Additionally, the patterns and risk factors of BBT failure were retrospectively evaluated. Results: Seventy women met the inclusion criteria. Of them, 9 (13%) were in the balloon failure group and 61 (87%), in the balloon success group. Between two groups, the median of postoperative blood loss was 1153 g vs. 70 g (p

Objective: The current definition of placenta previa does not include whether the placental edge is parenchyma or marginal sinus defined as placenta previa in which the placental marginal sinus just reached the internal os and/or in which the placental parenchyma might be located at > 2 cm from internal os. Materials and Methods: Cases with placenta previa were identified through the review of magnetic resonance imaging (MRI) from among 210 cases at our institution between 2007 and 2016. The clinical outcomes of patients with marginal sinus placenta previa (Group A) were compared with patients with low-lying placenta and marginal placenta (Group B) and patients with partial placenta and total placenta previa (Group C), respectively. This study was a retrospective analysis. Results: Twenty-seven (12.7%) cases were included in Group A. The patients in Group B and Group C were 72 and 108 cases, respectively. First, Group A more frequently underwent emergency cesarean section than Group B (p = 0.02). There was no statistical significance with other maternal history, post–or pre-operative hemorrhage, and/or additional treatment for hemorrhage between the two groups. Additionally, Group A delivered at a later gestational age (p

We have developed an in vitro system to easily examine the affinity for vitamin D receptor (VDR) and CYP24A1-mediated metabolism as two methods of assessing vitamin D derivatives. Vitamin D derivatives with high VDR affinity and resistance to CYP24A1-mediated metabolism could be good therapeutic agents. This system can effectively select vitamin D derivatives with these useful properties. We have also developed an in vivo system including a Cyp27b1-gene-deficient rat (a type I rickets model), a Vdr-gene-deficient rat (a type II rickets model), and a rat with a mutant Vdr (R270L) (another type II rickets model) using a genome editing method. For Cyp27b1-gene-deficient and Vdr mutant (R270L) rats, amelioration of rickets symptoms can be used as an index of the efficacy of vitamin D derivatives. Vdr-gene-deficient rats can be used to assess the activities of vitamin D derivatives specialized for actions not mediated by VDR. One of our original vitamin D derivatives, which displays high affinity VDR binding and resistance to CYP24A1-dependent metabolism, has shown good therapeutic effects in Vdr (R270L) rats, although further analysis is needed.

Objective: Uterine artery embolization has become an effective treatment for postpartum hemorrhage. The safety of pregnancy after uterine artery embolization for postpartum hemorrhage has been established. Case report: We present the case of a pregnant woman with asymptomatic uterine complete rupture who underwent uterine artery embolization for a previous placenta previa. She had not been diagnosed with uterine rupture until cesarean section was performed, and fortunately, we obtained the best maternal and neonatal outcomes. Conclusion: Many studies have been reported that uterine artery embolization for postpartum hemorrhage did not affect subsequent pregnancy outcomes. However, we report that this procedure contains a potential risk for asymptomatic uterine rupture in a subsequent pregnancy. Although it is difficult to diagnose uterine rupture without symptoms, the obstetrician should be aware of the possibility of uterine rupture.