Sexually dimorphic dynamics of the microtubule network in medaka (Oryzias latipes) germ cells.

Gametogenesis is the process through which germ cells differentiate into sexually dimorphic gametes, eggs and sperm. In the teleost fish medaka (Oryzias latipes), a germ cell-intrinsic sex determinant, foxl3, triggers germline feminization by activating two genetic pathways that regulate folliculogenesis and meiosis. Here, we identified a pathway involving a dome-shaped microtubule structure that may be the basis of oocyte polarity. This structure was first established in primordial germ cells in both sexes, but was maintained only during oogenesis and was destabilized in differentiating spermatogonia under the influence of Sertoli cells expressing dmrt1. Although foxl3 was dispensable for this pathway, dazl was involved in the persistence of the microtubule dome at the time of gonocyte development. In addition, disruption of the microtubule dome caused dispersal of bucky ball RNA, suggesting the structure may be prerequisite for the Balbiani body. Collectively, the present findings provide mechanistic insight into the establishment of sex-specific polarity through the formation of a microtubule structure in germ cells, as well as clarifying the genetic pathways implementing oocyte-specific characteristics.

Medaka Terb1 Mutant Displays Defects of Synaptonemal Complex Formation and Sexual Difference in Gametogenesis.

Formation of the synaptonemal complex (SC) is a prerequisite for proper recombination and chromosomal segregation during meiotic prophase I. One mechanism that ensures SC formation is chromosomal movement, which is driven by the force derived from cytoskeletal motors. Here, we report the phenotype of medaka mutants lacking the telomere repeat binding bouquet formation protein 1 (TERB1), which, in combination with the SUN/KASH protein, mediates chromosomal movement by connecting telomeres and cytoskeletal motors. Mutations in the terb1 gene exhibit defects in SC formation in medaka. Although SC formation was initiated, as seen by the punctate lateral elements and fragmented transverse filaments, it was not completed in the terb1 mutant meiocytes. The mutant phenotype further revealed that the introduction of double strand breaks was independent of synapsis completion. In association with these phenotypes, meiocytes in both the ovaries and testes exhibited an aberrant arrangement of homologous chromosomes. Interestingly, although oogenesis halted at the zygotene-like stage in terb1 mutant, testes continued to produce sperm-like cells with aberrant DNA content. This indicates that the mechanism of meiotic checkpoint is sexually different in medaka, similar to the mammalian checkpoint in which oogenesis proceeds while spermatogenesis is arrested. Moreover, our results suggest that spermatogenesis is mechanistically dissociable from meiosis.

Pembrolizumab with external radiation therapy effectively controlled TMB-high unresectable recurrent parathyroid cancer: a case report with review of literature.

Parathyroid cancer (PC) is extremely resistant to chemotherapy and radiotherapy (RT), but hormonally functional by producing excessive parathyroid hormone (PTH), causing remarkable hypercalcemia even in biochemical disease recurrence. Accordingly, management of hypercalcemia by calcimimetics and bisphosphonates has been main treatment for unresectable PC. Here, we report a case of unresectable tumor mutational burden (TMB)-high recurrent PC that has been effectively controlled by pembrolizumab (PEM) with RT. A 48-year-old male patient, with previous history of left single parathyroidectomy for primary hyperparathyroidism, underwent surgeries for recurrent hyperparathyroidism at 47 and 48 years of age, and was pathologically diagnosed with PC. He was referred to our hospital due to persistent hypercalcemia and elevated PTH. The recurrent tumors were identified in the superior mediastinum and radically resected, then the hyperparathyroidism was improved. A FoundationOne® CDx of the specimen called TMB-high. He demonstrated recurrent hyperparathyroidism at 49 years of age, and underwent a gross curative resection. However, hyperparathyroidism achieved only insufficient improvement, indicating biochemical residual cancer cells. PEM treatment was initiated in combination with RT to the left central-lateral neck and superior mediastinum. He successfully achieved evocalcet and zoledronate withdrawal, and the PTH level improvement was continuously observed for 8 months at present, with only grade 2 subclinical hypothyroidism. Interestingly, leukocyte fraction ratios were reversed corresponding to disease improvement. A combination of PEM and RT is a promising treatment of unresectable TMB-high PC. Recent evidence on the immunomodulatory effect of RT provides the rationale for the combination of RT and PEM.

foxl3, a sexual switch in germ cells, initiates two independent molecular pathways for commitment to oogenesis in medaka.

Germ cells have the ability to differentiate into eggs and sperm and must determine their sexual fate. In vertebrates, the mechanism of commitment to oogenesis following the sexual fate decision in germ cells remains unknown. Forkhead-box protein L3 (foxl3) is a switch gene involved in the germline sexual fate decision in the teleost fish medaka (Oryzias latipes). Here, we show that foxl3 organizes two independent pathways of oogenesis regulated by REC8 meiotic recombination protein a (rec8a), a cohesin component, and F-box protein (FBP) 47 (fbxo47), a subunit of E3 ubiquitin ligase. In mutants of either gene, germ cells failed to undergo oogenesis but developed normally into sperm in testes. Disruption of rec8a resulted in arrest at a meiotic pachytenelike stage specifically in females, revealing a sexual difference in meiotic progression. Analyses of fbxo47 mutants showed that this gene regulates transcription factors that facilitate folliculogenesis: LIM homeobox 8 (lhx8b), factor in the germline α (figla), and newborn ovary homeobox (nobox). Interestingly, we found that the fbxo47 pathway ensures that germ cells do not deviate from an oogenic pathway until they reach diplotene stage. The mutant phenotypes together with the timing of their expression imply that germline feminization is established during early meiotic prophase I.

The effectiveness of pretreatment video-based psychoeducation for patients with breast cancer.

OBJECTIVES: This study confirms the effectiveness of pretreatment video-based psychoeducation on stress management and relaxation in reducing depression, anxiety, and uncertainty among patients with breast cancer. METHODS: We conducted a nonrandomized trial with 86 pretreatment patients with breast cancer who were divided equally into intervention and control groups, and stratified according to cancer stages and patient ages. Omitting the excluded participants, 35 intervention group and 36 control group participants were asked to complete the Hospital Anxiety and Depression Scale and Universal Uncertainty in Illness Scale (UUIS) before the psychoeducational intervention (baseline, hereafter "BL ") as well as 1 and 3 months later. Then, a 2 group (intervention and control groups) × 3 time points (BL and 1 and 3 months post-intervention) mixed models repeated measures (MMRM) analysis was implemented. RESULTS: Analysis confirmed interaction between 2 group × 3 time points for depression, anxiety, and UUIS. Multiple comparisons revealed that each score in the intervention group was significantly lower 1 and 3 months post-intervention compared to BL. Meanwhile, in the control group, the depression score was significantly higher at 3 months post-intervention compared to pre-intervention. The anxiety scores and UUIS of the same group were not significantly different between 1 and 3 months post-intervention. The effect size values 3 months post-intervention were -0.57 for depression, -0.25 for anxiety, and 0.05 for uncertainty. SIGNIFICANCE OF RESULTS: Pretreatment psychoeducation reduced depression, anxiety, and uncertainty in the intervention group of patients with breast cancer compared to the control group. The effect sizes at 3 months post-intervention were moderate for depression and small for anxiety. These results suggest the effectiveness of psychoeducation for patients with breast cancer, using videos on stress management and relaxation, early at the pretreatment stage.

Germ cells in the teleost fish medaka have an inherent feminizing effect.

AUTHOR SUMMARY: Germ cells are the only cells that can transfer genetic materials to the next generation via the sperm or egg. However, recent analyses in teleosts revealed another essential role of germ cells: feminizing the gonads. In our study, medaka mutants in which gametogenesis was blocked at specific stages provides the novel view that the feminizing effect of germ cells occurs in parallel with other reproductive elements, such as meiosis, the sexual fate decision of germ cells, and gametogenesis. Germ cells in medaka may have a potential to feminize gonads at the moment they have developed.

Novel components of germline sex determination acting downstream of foxl3 in medaka.

Germline sex determination is an essential process for the production of sexually dimorphic gametes. In medaka, Forkhead box L3 (foxl3) was previously identified as a germ cell-intrinsic regulator of sex determination that suppresses the initiation of spermatogenesis in female germ cells. To reveal the molecular mechanism of germline sex determination by foxl3, we conducted the following four analyses: Comparison of transcriptomes between wild-type and foxl3-mutant germ cells; epistatic analysis; identification of the FOXL3-binding motif; and ChIP-qPCR assay using a FOXL3-monoclonal antibody. We identified two candidate genes acting downstream of foxl3: Rec8a and fbxo47. It has been known that Rec8 regulates sister chromatid cohesion and Fbxo47 acts as a ubiquitin E3 ligase. These functions have not been, however, associated with sexual differentiation in germ cells. Our results uncover novel components acting downstream of foxl3, providing insights into the mechanism of germline sex determination.

Lymphocyte-Monocyte Ratio Significantly Predicts Recurrence in Papillary Thyroid Cancer.

BACKGROUND: A growing body of evidences shows that systemic inflammatory responses are involved in patient prognosis in multiple cancers. Combinations of peripheral leukocyte fractions have been shown to be useful markers for the inflammatory responses. However, significance of such systemic inflammatory responses is still unknown in thyroid cancer. Accordingly, we aimed to clarify clinical impact of peripheral leukocyte fractions in papillary thyroid cancer (PTC). METHODS: Clinicopathological analyses were performed including preoperative leukocyte fractions in 570 patients with curatively resected PTC. Receiver operating characteristic curves were used to determine cutoffs of leukocyte fraction or inflammation indexes such as lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio. A Kaplan-Meier analysis and a Cox's proportional hazard model were used to conduct prognostic analysis. A multivariable logistic regression analysis was performed for correlation assay. RESULTS: Preoperative low LMR predicted recurrence with high sensitivity (63.3%) and specificity (68.7%) (P = 0.002). The multivariable prognostic analyses revealed that preoperative low LMR (P = 0.025), pathological N1b (P = 0.019), high metastatic lymph node ratio (node density) (P = 0.014), and high thyroglobulin level (P = 0.002) independently predicted worse prognosis. The combination of these independent parameters clearly enriched high-risk patients (P < 0.001). Of note, low LMR was dramatically associated with recurrence especially in patients with advanced PTC. CONCLUSIONS: Preoperative low LMR dramatically predicts high-risk patients for recurrences. The results in this study give rational to focusing on immune cell profiles to tackle advanced PTC.

[In Situ Ductal Carcinoma with Hereditary Breast and Ovarian Cancer Syndrome in a Patient Who Received Contralateral Risk-Reducing Mastectomy-A Case Report].

A woman in her 30s presented to our hospital with the chief complaint of a right breast mass after the birth of her first child. She was diagnosed as having right invasive ductal carcinoma of Luminal-B type and T3N3cM0, stage Ⅲc. While undergoing neoadjuvant chemotherapy, she received genetic counseling and underwent genetic testing and was determined to have deleterious BRCA1 and BRCA2 mutations. After completing chemotherapy, she underwent a right total mastectomy and axillary lymph node dissection. Two years postoperatively, she requested to undergo a contralateral risk-reducing mastectomy( CRRM)of her left breast. Therefore, CT and breast MRI were performed to confirm the absence of contralateral lesions and distant metastases, and subsequently, CRRM was performed. Postoperative pathology results showed non-invasive ductal carcinoma lesions at 5 sites. In the case of hereditary breast and ovarian cancer syndrome such as in this study, lesions may be discovered at an early stage by performing risk-reducing mastectomy.

Dysregulation of Intestinal Microbiota Elicited by Food Allergy Induces IgA-Mediated Oral Dysbiosis.

Food allergy is a life-threatening response to specific foods, and microbiota imbalance (dysbiosis) in gut is considered a cause of this disease. Meanwhile, the host immune response also plays an important role in the disease. Notably, interleukin 33 (IL-33) released from damaged or necrotic intestinal epithelial cells facilitates IL-2-producing CD4 helper T (Th2) responses. However, causal relationships between the gut and oral dysbiosis and food allergy remain unknown. In this study, we analyzed effects of gut and oral dysbiosis on development of food allergy. A murine model of food allergy was established via ovalbumin (OVA) injection in BALB/c mice. Viable fecal bacteria were identified using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). il33 expression in colon-26 mouse colon cells stimulated by isolated fecal bacteria was quantified by real-time PCR. Intestinal T cells from the mice were analyzed by flow cytometry. Salivary IgA levels were quantified by enzyme-linked immunosorbent assay (ELISA), and IgA-bound oral bacteria were detected by flow cytometry. Among fecal bacteria, the abundance of Citrobacter sp. increased in the feces of allergic mice and induced il33 expression in colon-26 cells. Orally administered Citrobacter koseri JCM1658 exacerbated systemic allergic symptoms and reduced intestinal Th17 cells. Salivary IgA and IgA-bound oral bacteria increased in the allergic mice. Based on the results described above, food allergy induced both gut and oral dysbiosis. Citrobacter sp. aggravated allergy symptoms by inducing IL-33 release from intestinal epithelial cells.

Comprehensive Genetic Search to Clarify the Molecular Mechanism of Drug Resistance Identifies ASCL2-LEF1/TSPAN8 Axis in Colorectal Cancer.

BACKGROUND: Treatment-resistance genes limiting anticancer therapy have not been well clarified in colorectal cancer (CRC). We explored gene expression profiles to identify biomarkers for predicting treatment resistance to an anticancer drug in CRC. METHODS: Six CRC cell lines were treated with phenylbutyrate (PB). The gene expression profiles were then compared using microarrays (harboring 54,675 genes), and genes associated with PB resistance were identified. Candidate genes were functionally examined in cell lines and clinically validated for treatment resistance in clinical samples. RESULTS: Both DLD1 and HCT15 cells were PB resistant, while HCT116 cells were identified as PB sensitive. On microarray analysis, among the PB resistance-related genes, the expression of the genes ASCL2, LEF1, and TSPAN8 was clearly associated with PB resistance. PB-sensitive cells transfected with one of these three genes exhibited significant (P < 0.001) augmentation of PB resistance; ASCL2 induced expression of both LEF1 and TSPAN8, while neither LEF1 nor TSPAN8 induced ASCL2. RNA interference via ASCL2 knockdown made PB-resistant cells sensitive to PB and inhibited both genes. ASCL2 knockdown also played a critical role in sensitivity to treatment by 5-fluorouracil and radiotherapy in addition to PB. Finally, ASCL2 expression was significantly correlated with histological grade of rectal cancer with preoperative chemoradiation therapy. CONCLUSIONS: ASCL2 was identified as a causative gene involved in therapeutic resistance against anticancer treatments in CRC.

Increase of cortisol levels after temperature stress activates dmrt1a causing female-to-male sex reversal and reduced germ cell number in medaka.

In vertebrates, there is accumulating evidence that environmental factors as triggers for sex determination and genetic sex determination are not two opposing alternatives but that a continuum of mechanisms bridge those extremes. One prominent example is the model fish species Oryzias latipes which has a stable XX/XY genetic sex determination system, but still responds to environmental cues, where high temperatures lead to female-to-male sex reversal. However, the mechanisms behind are still unknown. We show that high temperatures increase primordial germ cells (PGC) numbers before they reach the genital ridge, which, in turn, regulates the germ cell proliferation. Complete ablation of PGCs led to XX males with germ cell less testis, whereas experimentally increased PGC numbers did not reverse XY genotypes to female. For the underlying molecular mechanism, we provide support for the explanation that activation of the dmrt1a gene by cortisol during early development of XX embryos enables this autosomal gene to take over the role of the male determining Y-chromosomal dmrt1bY.

DNA diagnosis of peritoneal fluid cytology test by CDO1 promoter DNA hypermethylation in gastric cancer.

BACKGROUND: Minimal residual disease of the peritoneum is challenging for early cancer detection in gastric cancer (GC). Utility of PCR amplification of cancer-derived DNA has been considered feasible due to its molecular stability, however such markers have never been available in GC clinics. We recently discovered cancer-specific methylation of CDO1 gene in GC, and investigated the clinical potential to detect the minimal residual disease. METHODS: One hundred and two GC patients were investigated for peritoneal fluid cytology test (CY), and detection level of the promoter DNA methylation of CDO1 gene was assessed by quantitative methylation specific PCR (Q-MSP) in the sediments (DNA CY). RESULTS: (1) CY1 was pathologically confirmed in 8 cases, while DNA CY1 was detected in 18 cases. All 8 CY1 were DNA CY1. (2) DNA CY1 was recognized in 14.3, 25.0, 20.0, and 42.9%, in macroscopic Type II, small type III, large type III, and type IV, respectively, while it was not recognized in Type 0/I/V. (3) DNA CY1 was prognostic relevance in gastric cancer (p = 0.0004), and its significance was robust among Type III/IV gastric cancer (p = 0.006 for overall survival and p = 0.0006 for peritoneal recurrence free survival). (4) The peritoneal recurrence was hardly seen in GC patients with potent perioperative chemotherapy among those with DNA CY1. CONCLUSIONS: DNA CY1 detected by Q-MSP for CDO1 gene promoter DNA methylation has a great potential to detect minimal residual disease of the peritoneum in GC clinics as a novel DNA marker.

Promoter DNA methylation of CDO1 gene and its clinical significance in esophageal squamous cell carcinoma.

We have demonstrated that CDO1 methylation is frequently found in various cancers, including esophageal squamous cell carcinoma (ESCC), but its clinical relevance has remained elusive. CDO1 methylation was investigated in 169 ESCC patients who underwent esophagectomy between 1996 and 2007. CDO1 methylation was assessed by Q-MSP (quantitative methylation specific PCR), and its clinical significance, including its relationship to prognosis, was analyzed. (i) The median TaqMeth value of CDO1 methylation was 9.4, ranging from 0 to 279.5. CDO1 methylation was significantly different between cStage I and cStage II/III (P = 0.02). (ii) On the log-rank plot, the optimal cut-off value was determined to be 8.9; ESCC patients with high CDO1 methylation showed a significantly worse prognosis than those with low CDO1 methylation (P = 0.02). (iii) A multivariate Cox proportional hazards model identified only CDO1 hypermethylation as an independent prognostic factor (HR 2.00, CI 1.09-3.78, P = 0.03). (iv) CDO1 hypermethylation stratified ESCC patients' prognosis in cStage II/III for both neoadjuvant chemo(radio)therapy (NAC)-positive and NAC-negative cases. Moreover, the CDO1 methylation level was significantly lower in cases with Grade 2/3 than in those with Grade 0/1 (P = 0.02) among cStage II/III ESCC patients with NAC. Promoter DNA hypermethylation of CDO1 could be an independent prognostic factor in ESCC; it may also reflect NAC eradication of tumor cells in the primary tumors.

Phase II randomized, controlled trial of 1 day versus 3 days of dexamethasone combined with palonosetron and aprepitant to prevent nausea and vomiting in Japanese breast cancer patients receiving anthracycline-based chemotherapy.

PURPOSE: Dexamethasone, plus a 5-HT3 receptor antagonist and an NK-1 receptor antagonist are recommended for controlling the chemotherapy-induced nausea and vomiting (CINV) of highly emetogenic chemotherapy. Several days of dexamethasone are effective for CINV; however, dexamethasone also has side effects. The purpose of this trial was to investigate whether the use of a second-generation 5-HT3 receptor antagonist and an NK-1 receptor antagonist could allow a reduced dose of dexamethasone for breast cancer patients receiving highly emetogenic chemotherapy. METHODS: Eighty breast cancer patients who received an anthracycline-cyclophosphamide combination regimen were enrolled. The patients were randomized to arm A (dexamethasone days 1-3) and arm B (dexamethasone day 1). The primary endpoint was complete response (CR) (no emetic episodes and no rescue medication) during the overall phase (days 1-5). The secondary endpoints were the CR during the delayed phase (days 2-5), complete control (CC) (no emetic episodes, no rescue medication, and no more than mild nausea) during the overall phase, and the safety of this antiemetic therapy. RESULTS: There were no significant differences in the rates of CR and CC between arm A and B as follows: CR overall phase--arm A: 82.9%, 90% confidence interval [CI] 71.3-90.5% vs arm B: 82.1%, 90% CI 70.0-90.0%; p = 1.00; CR delayed phase--arm A: 87.8%, 90% CI 77.0-93.9% vs arm B: 94.9%, 90% CI 85.6-98.3%; p = 0.43; CC overall phase--arm A: 48.8%, 90% CI 36.4-61.3% vs arm B: 61.5%, 90% CI 48.4-73.2%; p = 0.27. There were very few adverse events and no severe adverse events associated with this antiemetic therapy. CONCLUSIONS: The results suggest that the antiemetic effect provided by dexamethasone administered for 3 days can be obtained by dexamethasone administered for 1 day.

Immunohistochemical analysis of RTKs expression identified HER3 as a prognostic indicator of gastric cancer.

Standard treatment in Japan for the 13th Japanese Gastric Cancer Association stage II/III advanced gastric cancer is postoperative adjuvant S-1 administration after curative surgery. High expression of receptor type tyrosine kinases (RTKs) has repeatedly represented poor prognosis for cancers. However it has not been demonstrated whether RTKs have prognostic relevance for stage II/III gastric cancer with standard treatment. Tumor tissues were obtained from 167 stage II/III advanced gastric cancer patients who underwent curative surgery and received postoperative S-1 chemotherapy from 2000 to 2010. Expression of the RTKs including EGFR, HER2, HER3, IGF-1R, and EphA2 was analyzed using immunohistochemistry (IHC). Analysis using a multivariate proportional hazard model identified the most significant RTKs that represented independent prognostic relevance. When tumor HER3 expression was classified into IHC 1+/2+ (n = 98) and IHC 0 (n = 69), the cumulative 5-year Relapse Free Survival (5y-RFS) was 56.5 and 82.9%, respectively (P = 0.0034). Significant prognostic relevance was similarly confirmed for IGF-1R (P = 0.014), and EGFR (P = 0.030), but not for EphA2 or HER2 expression. Intriguingly, HER3 expression was closely correlated with IGF-1R (P < 0.0001, R = 0.41), and EphA2 (P < 0.0001, R = 0.34) expression. Multivariate proportional hazard model analysis identified HER3 (IHC 1+/2+) (HR; 1.53, 95% CI, 1.11-2.16, P = 0.0078) as the sole RTK that was a poor prognostic factor independent of stage. Of the 53 patients who recurred, 40 patients (75.5%) were HER3-positive. Thus, of the RTKs studied, HER3 was the only RTK identified as an independent prognostic indicator of stage II/III advanced gastric cancer with standard treatment.

The safety of concentrated trastuzumab in 100 ml of saline solution for administration to patients with HER2-positive breast cancer: a phase 1 study.

BACKGROUND: It is recommended that administration of trastuzumab should be carried out in a volume of 250 ml of saline solution over 90 min. Since 2011, recommendations have allowed a shortening of the administration time to 30 min at the second administration. However, the volume to be administered is still 250 ml. The purpose of this study was to evaluate the safety of trastuzumab administered in 100 ml of saline solution over 30 min. METHODS: This study enrolled patients with HER2-positive breast cancer. Three dose levels of trastuzumab, each in 100 ml of saline solution, were used (2, 6 and 8 mg/kg). The primary end point was the determination of safety. RESULTS: Nine patients were enrolled. Since no adverse events were observed, the 8 mg/kg/100 ml saline solution dose level was the recommended dose. CONCLUSIONS: A 30-min administration of trastuzumab in 100 ml of saline solution is safe in patients with HER2-positive breast cancer.

Takotsubo cardiomyopathy after cesarean: a case report and published work review of pregnancy-related cases.

Takotsubo cardiomyopathy (TCM) primarily affects postmenopausal women and is an important differential diagnosis of acute coronary syndrome. We describe a rare case of post-partum TCM, and present a published work review of the cases of pregnancy-associated TCM. A 24-year-old Japanese woman pregnant with twins suffered from premature membrane rupture at 31 gestational weeks. Following emergency cesarean delivery, she complained of sudden dyspnea. Transthoracic echocardiography revealed an inverted Takotsubo pattern (ejection fraction, 46%). On post-delivery day 8, wall motion abnormalities subsided, and she was discharged on post-delivery day 16. We reviewed 18 relevant cases of peripartum TCM from the published work. Among them, 16 cases were post-partum and two cases occurred during pregnancy. Most women (81%) underwent cesarean delivery, and the first symptoms of TCM appeared during surgery in 38% of the cases. The dominant symptoms were chest pain (44%) and dyspnea (28%). Most cases (94%) exhibited electrocardiogram abnormalities, including ST changes and T-wave inversion. Serum levels of cardiac enzymes were abnormally high in 92% of the cases. Repeated echocardiography documented normalized left ventricular systolic function within 6 months in all cases. This case and review emphasize that TCM may be concealed in post-partum women by symptoms undistinguishable from acute coronary syndrome, peripartum cardiomyopathy or pulmonary thromboembolism, and that echocardiography may be a useful tool to distinguish them.

Correction: The Usefulness of AirSeal™ Intelligent Flow System in Gas Insufflation Total Endoscopic Thyroidectomy.

[This corrects the article DOI: 10.1007/s12070-022-03257-0.].

Fibrinogen concentrate substitution therapy for obstetric hemorrhage complicated by coagulopathy.

AIM: The aim of this study was to assess the efficacy and safety of fibrinogen concentrate therapy for women with obstetric hemorrhage complicated by dilutional or consumptive coagulopathy by retrospectively reviewing the medical records of relevant patients from a single tertiary center. MATERIAL AND METHODS: Eighteen cases of coagulopathy (8 dilutional, 10 consumptive) administered fibrinogen concentrate at our center over the past 5 years for treating hypofibrinogenemia were identified. Hemoglobin levels, platelet counts, fibrinogen levels, prothrombin time, activated partial thromboplastin time, and D-dimer levels were examined before and after fibrinogen substitution. Units of red blood cells, fresh frozen plasma, and pooled platelet concentrates transfused; blood loss volume; patient outcomes; and adverse events were obtained from medical and laboratory records. RESULTS: The overall response to fibrinogen concentrate was considered good in 12 cases, moderate in four, and poor in two. The response rate was good or moderate in 88% (7/8) of dilutional coagulopathy cases and 89% (9/10) of consumptive coagulopathy cases. Fibrinogen levels significantly increased after fibrinogen substitution therapy (approximately 40 mg/L per g fibrinogen concentrate) in both groups. Although prothrombin time and activated partial thromboplastin time improved after substitution, hemoglobin levels, platelet counts, and D-dimer levels remained unchanged. No serious adverse event was causally associated with fibrinogen substitution therapy. CONCLUSION: Fibrinogen concentrate substitution therapy for obstetric hemorrhage increases fibrinogen levels and appears to be effective in managing dilutional or consumptive coagulopathy.