Educational results of the Japan Maternal Emergency Life-Saving (J-MELS) simulation training organized by Japan Council for the Implementation of the Maternal Emergency Life-Saving System (J-CIMELS): a 12-month longitudinal follow-up study in Japan.

AIMS: This study aimed to evaluate the long-term results of Japan Maternal Emergency Life-Saving (J-MELS) simulation training on obstetric healthcare providers, over a 12-month follow-up period. METHODS: A total of 273 trainees from 17 J-MELS Basic courses conducted between August 2021 and October 2023 were included. The trainees' responses to the pre- and post-tests, questionnaires, and self-reports on the usefulness of the J-MELS scenarios in actual clinical settings at 1, 6, and 12 months after the training were analyzed. Multivariate logistic regression analysis was also conducted to identify the factors influencing knowledge retention. RESULTS: We found an overall improvement in clinical knowledge acquisition after J-MELS training and a significant retention of this improvement at least until 12 months later. However, these scores gradually declined over. Trainees reported increased usefulness of J-MELS scenarios in actual clinical practice at 1, 6, and 12 months after training, particularly in managing obstetric emergencies such as atonic postpartum hemorrhage. Knowledge retention was influenced by several specific factors, such as years of clinical experience, affiliated institutions, qualifications, and especially pre-test scores. CONCLUSION: Our longitudinal follow-up study demonstrated, for the first time, the long-term results of J-MELS simulation training using post-tests and self-report data. Our findings provide valuable insight into the impact of J-MELS simulation training on maternal emergency care. By elucidating the factors influencing knowledge retention and practical utility, the findings offer actionable recommendations for optimizing training strategies and improving maternal outcomes in actual clinical practice.

Prevalence, Risk Factors, and Perinatal Outcomes of Velamentous Umbilical Cord Insertion in Twin Pregnancies: A Single-Center Retrospective Study.

BACKGROUND: The effect of velamentous cord insertion (VCI) on perinatal outcomes in twin pregnancies is unclear due to conflicting findings. This retrospective study aimed to examine VCI prevalence and related risk factors in twin pregnancies and its association with adverse perinatal outcomes. METHODS: Women with twin pregnancies who delivered between January 2012 and December 2021 in a single tertiary hospital were included. The participants were divided into dichorionic (DC) and monochorionic diamniotic (MCDA) groups, and their maternal and fetal characteristics and VCI rates were compared. Logistic regression models were used to identify risk factors for VCI and VCI-related perinatal outcomes. RESULTS: Among the 694 twin pregnancies included in this study, the VCI rate was significantly higher in MCDA than in DC twins. Body mass index and MCDA twins were significant risk factors for VCI, whereas assisted reproductive technology pregnancy was a significant protective factor against VCI. In DC twins, VCI did not affect perinatal outcomes. In MCDA twins, VCI was a significant risk factor for fetal growth restriction, twin-to-twin transfusion syndrome, and preterm birth at <36 weeks. CONCLUSIONS: VCI was a prominent risk factor for adverse perinatal outcomes only in MCDA twins. Antenatal sonographic assessment of the umbilical cord insertion site would be beneficial.

NECTIN4-targeted antibody-drug conjugate is a potential therapeutic option for extramammary Paget disease.

Extramammary Paget disease (EMPD) is a rare skin cancer mainly found in areas rich in apocrine sweat glands. Since the effective treatments for advanced and/or metastasized EMPD are limited, there is an urgent need to develop novel therapeutic approaches. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed in cancers and considered to be a promising therapeutic target. NECTIN4 is also expressed in EMPD, but its role and the efficacy of NECTIN4-targeted therapy in EMPD remain unclear. This study investigated the potential of NECTIN4 as a novel therapeutic target for EMPD. NECTIN4 expression was immunohistochemically analysed in EMPD patients' primary (118 samples) and metastatic (21 samples) lesions. Using an EMPD cell line, KS-EMPD-1, the effects of NECTIN4 inhibition on cell proliferation and migration were investigated. NECTIN4 was expressed in primary and metastatic EMPD lesions, and the H-score of NECTIN4 staining was significantly higher in metastatic lesions than in primary ones. Knockdown of NECTIN4 significantly inhibited cell proliferation and affected cell migration. The cytotoxic effects of NECTIN4-targeted antibody-drug conjugate (ADC) were further evaluated, revealing a significant decrease in EMPD cell viability. In conclusion, NECTIN4 is a potential therapeutic target and NECTIN4-targeted ADC is promising as a therapeutic option for EMPD.

FOXM1: a new therapeutic target of extramammary Paget disease.

Extramammary Paget disease (EMPD) is a rare skin cancer that primarily affects older individuals predominantly in areas with apocrine sweat glands. Although most early EMPD lesions are indolent, patients with metastatic EMPD have a poor prognosis due to the lack of effective systemic treatment. In this study, we investigated the role of forkhead box M1 (FOXM1), a potent transcription factor, in EMPD and assessed the potential of FOXM1 as a therapeutic target. Immunohistochemistry of 112 primary and 17 metastatic EMPD samples revealed that FOXM1 expression increased with tumor progression. Patients in whom FOXM1 was expressed in more than 10% of tumor cells had significantly shorter disease-specific survival than the other patients (p = 0.0397). In in vitro studies using our newly established EMPD cell line, KS-EMPD-1, we found high expression of FOXM1. Knockdown of FOXM1 impaired tumor cell viability, migration, and invasion. Inhibition of FOXM1 using thiostrepton also reduced tumor cell viability in a dose-dependent manner. These findings suggest that FOXM1 is a promising therapeutic target for patients with EMPD.

A real-world study on the safety profile of extended-interval dosing of immune checkpoint inhibitors for melanoma: a single-center analysis in Japan.

Background: Anti-programmed death-1 (PD-1) antibodies are the mainstay for the treatment of unresectable or high-risk melanoma. However, real-world data on the safety profile of their extended-interval doses (EDs) are limited, particularly in Asian patients with melanoma. Materials and methods: In this single-center retrospective study, we analyzed the risks of immune-related adverse events (irAEs) among 71 Japanese patients (36 males; mean age, 65.0 years) who received anti-PD-1 monotherapy for melanoma at our institute. Patients who were administered ipilimumab prior to anti-PD-1 monotherapy were excluded. Patients were divided into three groups: canonical-interval dose (CD) group (n = 50, body weight-based dosing or 240 mg Q2W for nivolumab and body weight-based dosing or 200 mg Q3W for pembrolizumab), ED group (n = 14, 480 mg Q4W for nivolumab and 400 mg Q6W for pembrolizumab), and dose-switch (DS) group (n = 7, upfront CD followed by ED). Results: The CD group received nivolumab more frequently in the metastatic setting. There were no significant differences in baseline characteristics among the three groups, including in sex, age, primary tumor site, tumor subtype, and follow-up period. irAEs occurred in 36.6% (26 patients) of all patients (32.0% of the CD group, 35.7% of the ED group, and 71.4% of the DS group), while severe (grade ≥ 3) irAEs occurred in only two patients, both of whom were in the CD group. Most of the irAEs occurred during the first 6 months of anti-PD-1 therapy and, interestingly, all of the irAEs in the DS group occurred before the switch (during the CD). There was no significant difference among the three groups in the probability of irAE estimated by the Kaplan-Meier method. Conclusion: These findings may highlight the safety of ED of anti-PD-1 monotherapy in the treatment of Asian patients with melanoma.

KS-EMPD-1: a novel cell line of primary extramammary Paget's disease.

Extramammary Paget's disease (EMPD) is a rare skin cancer that mainly occurs in apocrine sweat gland-rich areas in elderly people. The prognosis of metastatic EMPD is unfavorable because of the lack of fully effective systemic therapies. However, the difficulty in establishing a model of EMPD has hampered basic research for exploring its pathogenesis and optimal treatments. Here, we established for the first time an EMPD cell line (named KS-EMPD-1) from a primary tumor on the left inguinal region of an 86-year-old Japanese male. The cells were successfully maintained for more than 1 year, with a doubling time of 31.2 ± 0.471 h. KS-EMPD-1 exhibited constant growth, spheroid formation, and invasiveness, and was confirmed to be identical to the original tumor by short tandem repeat analyses, whole exome sequencing, and immunohistochemistry (CK7+CK20-GCDFP15+). Western blotting of the cells revealed the protein expression of HER2, NECTIN4, and TROP2, which have recently attracted attention as potential therapeutic targets for EMPD. KS-EMPD-1 was highly sensitive to docetaxel and paclitaxel on chemosensitivity test. The KS-EMPD-1 cell line is a promising resource for basic and preclinical research on EMPD to better define the tumor characteristics and treatment strategy of this rare cancer.

Nail Apparatus Melanoma: Current Management and Future Perspectives.

Nail apparatus melanoma (NAM) is a rare type of cutaneous melanoma that belongs to the acral melanoma subtype. NAM is managed principally in accordance with the general treatment for cutaneous melanoma, but there is scarce evidence in support of this in the literature. Acral melanoma is genetically different from non-acral cutaneous melanoma, while recently accumulated data suggest that NAM also has a different genetic background from acral melanoma. In this review, we focus on recent advances in the management of NAM. Localized NAM should be surgically removed; amputation of the digit and digit-preserving surgery have been reported. Sentinel lymph node biopsy can be considered for invasive NAM for the purpose of accurate staging. However, it is yet to be clarified whether patients with metastatic sentinel lymph nodes can be safely spared completion lymph node dissection. Similar to cutaneous melanoma, immune checkpoint inhibitors and BRAF/MEK inhibitors are used as the first-line treatment for metastatic NAM, but data on the efficacy of these therapies remain scarce. The therapeutic effects of immune checkpoint inhibitors could be lower for NAM than for cutaneous melanoma. This review highlights the urgent need to accumulate data to better define the optimal management of this rare melanoma.

Human epidermal growth factor receptor 3 serves as a novel therapeutic target for acral melanoma.

Acral melanoma (AM) is a rare, life-threatening skin cancer. Since AM bears unique features, existing therapies for other types of malignant melanomas have limited effects and the establishment of effective treatments for AM is strongly desired. Human epidermal growth factor receptor 3 (HER3) is a receptor tyrosine kinase that is frequently elevated in tumors and contributes to tumor progression, so it is considered a promising therapeutic target for tumors. This study was established to evaluate the potential of HER3-targeted therapy to treat AM by investigating the expression and function of HER3. HER3 expression was immunohistochemically analyzed in AM lesions of 72 patients and in AM cell lines. To investigate function of HER3, effects of HER3 inhibition on cell proliferation, apoptosis/survival, anchorage-independent growth, and underlying signals were assessed. HER3 was expressed in patients' AM tissues with various intensities and HER3 expression was significantly correlated with patient's disease-free survival. In vitro analyses revealed that HER3 is more highly expressed in AM cells than in normal epidermal melanocytes. AM cells were also shown to be sensitive to the cytotoxic part of a HER3-targeted antibody-drug conjugate. Inhibition of HER3 did not affect cell proliferation, whereas it decreased the anchorage-independent growth of AM cells likely through affecting the nuclear translocation of Yes-associated protein. It is implied that HER3 may serve as a novel therapeutic target for AM.

Impact of the interpregnancy interval after cesarean delivery on subsequent perinatal risks: a retrospective study.

PURPOSE: To assess the impact of the interpregnancy interval (IPI) after cesarean delivery on the risks of adverse perinatal events during subsequent pregnancies. METHODS: We retrospectively examined perinatal outcomes of subsequent pregnancies of women whose most recent birth experience involved cesarean delivery at our hospital between January 2014 and December 2019. IPI was defined as the time between live birth and subsequent conception. Three IPI groups: < 18 months, 18-60 months, and > 60 months, were assessed. The risks of preterm birth, preeclampsia, placenta previa, placental abruption, fetal growth restriction, and successful vaginal birth were compared among the three IPI groups using uni- and multivariate analyses. RESULTS: We registered 592 births after cesarean delivery: 178, 288, and 126 in the IPI < 18 months, 18-60 months, and > 60 months groups, respectively. The groups did not differ significantly regarding perinatal outcomes. The multivariate analysis revealed no significant differences in the risks of adverse perinatal outcomes among all groups. The odds ratios (ORs) for preterm birth at < 37 weeks of gestation were 1.24 and 1.64 for those in the < 18 months and > 60 months groups, respectively (P = 0.362 and P = 0.055, respectively). The groups did not differ significantly regarding vaginal birth success rate (ORs 1.72 for the < 18 months group, 0.49 for the > 60 months group; P = 0.486 and P = 0.446, respectively). CONCLUSION: After cesarean delivery, IPIs shorter than 18 months and longer than 60 months do not significantly impact the risks of adverse perinatal outcomes or successful vaginal birth compared with IPIs of 18-60 months.

TRPM1 promotes tumor progression in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway.

INTRODUCTION: Acral melanoma is a predominant and aggressive subtype of melanoma in non-Caucasian populations. There is a lack of genotype-driven therapies for over 50% of patients. TRPM1 (transient receptor potential melastatin 1), a nonspecific cation channel, is mainly expressed in retinal bipolar neurons and skin. Nonetheless, the function of TRPM1 in melanoma progression is poorly understood. OBJECTIVES: We investigated the association between TRPM1 and acral melanoma progression and revealed the molecular mechanisms by which TRPM1 promotes tumor progression and malignancy. METHODS: TRPM1 expression and CaMKII phosphorylation in tumor specimens were tested by immunohistochemistry analysis and scored by two independent investigators. The functions of TRPM1 and CaMKII were assessed using loss-of-function and gain-of-function approaches and examined by western blotting, colony formation, cell migration and invasion, and xenograft tumor growth assays. The effects of a CaMKII inhibitor, KN93, were evaluated using both in vitro cell and in vivo xenograft mouse models. RESULTS: We revealed that TRPM1 protein expression was positively associated with tumor progression and shorter survival in patients with acral melanoma. TRPM1 promoted AKT activation and the colony formation, cell mobility, and xenograft tumor growth of melanoma cells. TRPM1 elevated cytosolic Ca2+ levels and activated CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) to promote the CaMKIIδ/AKT interaction and AKT activation. The functions of TRPM1 in melanoma cells were suppressed by a CaMKII inhibitor, KN93. Significant upregulation of phospho-CaMKII levels in acral melanomas was related to increased expression of TRPM1. An acral melanoma cell line with high expression of TRPM1, CA11, was isolated from a patient to show the anti-tumor activity of KN93 in vitro and in vivo. CONCLUSIONS: TRPM1 promotes tumor progression and malignancy in acral melanoma by activating the Ca2+/CaMKIIδ/AKT pathway. CaMKII inhibition may be a potential therapeutic strategy for treating acral melanomas with high expression of TRPM1.

Prenatal diagnosis of distal 13q deletion syndrome in a fetus with esophageal atresia: a case report and review of the literature.

BACKGROUND: Chromosome 13q deletion syndrome shows variable clinical features related to the different potential breakpoints in chromosome 13q. The severely malformed phenotype is known to be associated with the deletion of a critical region in 13q32. However, esophageal atresia is a rare symptom and the relevant region is unknown. Thus, determining the association between accurate breakpoints and new clinical features is essential. CASE PRESENTATION: A 28-year-old Japanese primigravid woman was referred for fetal growth restriction, absence of a gastric bubble, cerebellar hypoplasia, overlapping fingers, and polyhydramnios at 31 weeks gestation. At 38 + 0 weeks, she delivered a 1774 g female infant. The infant presented with isolated esophageal atresia (Gross type A), Dandy-Walker malformation, right microphthalmia, left coloboma, overlapping fingers, pleurocentrum in the thoracic vertebrae, reduced anogenital distance, and hearing loss. Her karyotype was diagnosed as 46,XX,del(13)(q32.1-qter) by amniocentesis, but array comparative genomic hybridization after birth revealed the deletion of 13q31.3-qter. At 48 days after birth, the infant underwent surgery for esophageal atresia and was later discharged from the hospital at 7 months of age. CONCLUSION: This case report and the literature reviews supports the previous findings on the pathological roles of haploinsufficiency of the ZIC2/ZIC5 in Dandy-Walker malformation and the EFBN2 haploinsufficiency in eye malformation and hearing loss. Furthermore, the possible involvement of IRS2, COLA1, and COLA2 in eye malformation were identified. This is the first case of 13q deletion syndrome with esophageal atresia (Gross A), but it may be a symptom of VATER/VACTER association (vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects), as in the previous cases. These symptoms might also be associated with EFBN2 haploinsufficiency, although further research is required.

NECTIN4 expression in sebaceous and sweat gland carcinoma

Background: Sebaceous carcinoma and sweat gland carcinoma (malignant tumours with apocrine and eccrine differentiation) are rare malignant adnexal tumours that differentiate toward sebaceous glands and eccrine and apocrine glands, respectively. Because of the rarity of these malignancies, standard treatments for advanced disease have yet to be established. The outcomes of patients with systemic metastasis remain poor, highlighting the need for novel treatment strategies. Nectin cell adhesion molecule 4 (NECTIN4) and its antibody-drug conjugate, enfortumab vedotin, have attracted attention as potential treatments for solid tumours. Objectives: To examine the potential use of NECTIN4-target therapy for sebaceous and sweat gland carcinoma. Materials & Methods: We immunohistochemically investigated NECTIN4 expression in 14 sebaceous carcinoma samples and 18 sweat gland carcinoma samples, and examined whether NECTIN4-targeted therapy could be applied to these cancers. Results: We found strong and frequent expression of NECTIN4 in both cancers. All tumours exhibited positive staining at least in a part of the lesion, and the mean H-score, a semiquantitative score ranging from 0 to 300, was 259.4 for sebaceous carcinoma and 253.1 for sweat gland carcinoma. Conclusion: Our results suggest that both sebaceous carcinoma and sweat gland carcinoma could be potentially treated with NECTIN4-targeted antibody-drug conjugates, such as enfortumab vedotin.

TROP2 Expression in Sebaceous and Sweat Gland Carcinoma.

Sebaceous carcinoma and sweat gland carcinoma (malignant tumors with apocrine and eccrine differentiation) are rare malignant skin adnexal tumors that differentiate toward sebaceous gland and eccrine and apocrine glands, respectively. Owing to the rarity of these carcinomas, standard treatments for advanced disease have not been established. Because the prognosis of patients with systemic metastasis is poor, a new treatment for these diseases is eagerly desired. Trophoblast cell surface antigen 2 (TROP2) and sacituzumab govitecan, an antibody-drug conjugate of TROP2, have attracted attention in the treatment of various solid tumors. In the current study, we immunohistochemically investigated TROP2 expression in 14 sebaceous carcinoma and 18 sweat gland carcinoma samples and found strong and relatively homogeneous TROP2 staining in both cancer types. The mean Histoscore, a semi-quantitative scoring ranging from 0 (negative) to 300, was 265.5 in sebaceous carcinoma and 260.0 in sweat gland carcinoma. These observations directly suggest that both sebaceous carcinoma and sweat gland carcinoma could be potentially treated with TROP2-targeted antibody-drug conjugates such as sacituzumab govitecan.

Maternal Renal Dysfunction in Late Pregnancy in Twin and Singleton Pregnancies: Retrospective Study.

This study aimed to evaluate the differences in the impact on maternal renal function between singleton and twin pregnancies in the second half of pregnancy. It retrospectively enrolled 1711 pregnant women consisting of 1547 singleton pregnancies and 164 twin pregnancies from Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital from January 2019 to June 2021. Patients underwent renal function tests (serum blood urea nitrogen, creatinine, and estimated glomerular filtration rate (eGFR)) at least one month before delivery. The main outcome measure was maternal renal dysfunction, defined as a serum creatinine level above 0.8 mg/dL. The serum creatinine level was significantly higher and the eGFR was significantly lower in twin than in singleton pregnancies (p < 0.001). In addition, the rate of renal dysfunction was significantly higher in twin than in singleton pregnancies (7.9% vs. 2.6%; p < 0.01). Multivariate analysis revealed that twin pregnancy (odds ratio (OR) 3.38), nulliparity (OR 2.31), and preeclampsia (OR 3.64) were significant risk factors for maternal renal dysfunction. Maternal renal dysfunction was observed in 13 twin pregnancies, all of which recovered to within normal limits during the early months of the postpartum period. Twin pregnancy is a significant risk factor for maternal renal dysfunction; renal function should be carefully monitored in twin pregnancies.

Evaluation of the risk factors for antepartum hemorrhage in cases of placenta previa: a retrospective cohort study.

OBJECTIVE: The aim of this study was to examine the risk factors for antepartum hemorrhage (APH) in women with placenta previa. METHODS: In this retrospective cohort study, we analyzed the medical records of 233 women with singleton pregnancies presenting with placenta previa whose deliveries were performed at our hospital between January 2009 and July 2018. RESULTS: Of the 233 women included in this study, 130 (55.8%) had APH. In the APH group, the gestational age and neonatal birth weight were significantly lower compared with the no hemorrhage group. Maternal age <30 years and multiparity were identified as significant risk factors for APH in both the univariate and multivariate analyses. Focusing on the previous route of delivery in multiparous women, the risk of APH was significantly higher in multiparous women who had experienced at least one vaginal delivery compared with nulliparous women (adjusted odds ratio (OR): 3.42 [95% confidence interval: 1.83-6.38]). CONCLUSION: We showed that women with placenta previa who were under 30 years old and who had a history of vaginal delivery may be at significant risk of experiencing APH.

Prenatal Molecular Hydrogen Administration Ameliorates Several Findings in Nitrofen-Induced Congenital Diaphragmatic Hernia.

Oxidative stress plays a pathological role in pulmonary hypoplasia and pulmonary hypertension in congenital diaphragmatic hernia (CDH). This study investigated the effect of molecular hydrogen (H2), an antioxidant, on CDH pathology induced by nitrofen. Sprague-Dawley rats were divided into three groups: control, CDH, and CDH + hydrogen-rich water (HW). Pregnant dams of CDH + HW pups were orally administered HW from embryonic day 10 until parturition. Gasometric evaluation and histological, immunohistochemical, and real-time polymerase chain reaction analyses were performed. Gasometric results (pH, pO2, and pCO2 levels) were better in the CDH + HW group than in the CDH group. The CDH + HW group showed amelioration of alveolarization and pulmonary artery remodeling compared with the CDH group. Oxidative stress (8-hydroxy-2'-deoxyguanosine-positive-cell score) in the pulmonary arteries and mRNA levels of protein-containing pulmonary surfactant that protects against pulmonary collapse (surfactant protein A) were significantly attenuated in the CDH + HW group compared with the CDH group. Overall, prenatal H2 administration improved respiratory function by attenuating lung morphology and pulmonary artery thickening in CDH rat models. Thus, H2 administration in pregnant women with diagnosed fetal CDH might be a novel antenatal intervention strategy to reduce newborn mortality due to CDH.

CDK4: A Novel Therapeutic Target for Extramammary Paget's Disease.

BACKGROUND: The outcome of extramammary Paget's disease (EMPD) is poor when it progresses to metastasis because of the lack of effective systemic therapies. Recently, CDK4-targeted therapy has attracted attention as a potential therapeutic target for some cancers. The aim of this study was to analyze the impact of CDK4 expression on the survival of patients with EMPD. METHODS: We retrospectively reviewed 110 patients with EMPD. We conducted immunohistochemical analysis of CDK4 and cyclin D1 expression, and assessed the association between their expression and survival. RESULTS: Most EMPD lesions (108/110, 98.2%) were positive for CDK4 staining and there was a positive correlation between CDK4 expression and cyclin D1 expression (r = 0.54, p < 0.001). Tumor thickness (p = 0.0003) and the presence of regional lymph node metastasis (p = 0.015) were significantly associated with high CDK4 expression. Regarding invasive EMPD, the multivariate analysis did not show the correlation between the expression of CDK4/cyclin D1 and survival outcomes (HR: 3.14, p = 0.14). CONCLUSION: The overexpression of CDK4 was identified as a major risk factor for disease progression. CDK4-targeted therapy could thus be a novel treatment option for unresectable EMPD.

Trop2 Expression in Extramammary Paget's Disease and Normal Skin.

Extramammary Paget's disease (EMPD) is a rare skin cancer arising in the apocrine gland-rich areas. Most EMPD tumors are dormant, but metastatic lesions are associated with poor outcomes owing to the lack of effective systemic therapies. Trophoblast cell surface antigen 2 (Trop2), a surface glycoprotein, has drawn attention as a potential therapeutic target for solid tumors. Sacituzumab govitecan, an antibody-drug conjugate of Trop2, has recently entered clinical use for the treatment of various solid cancers. However, little is known about the role of Trop2 in EMPD. In this study, we immunohistochemically examined Trop2 expression in 116 EMPD tissue samples and 10 normal skin tissues. In normal skin, Trop2 was expressed in the epidermal keratinocytes, inner root sheaths, and infundibulum/isthmus epithelium of hair follicles, eccrine/apocrine glands, and sebaceous glands. Most EMPD tissues exhibited homogeneous and strong Trop2 expression, and high Trop2 expression was significantly associated with worse disease-free survival (p = 0.0343). These results suggest the potential use of Trop2-targeted therapy for EMPD and improve our understanding of the skin-related adverse effects of current Trop2-targeted therapies such as sacituzumab govitecan.

Mucosal Invasion, but Not Incomplete Excision, Has Negative Impact on Long-Term Survival in Patients With Extramammary Paget's Disease.

BACKGROUND: Extramammary Paget's disease (EMPD) sometimes spreads from the skin to mucosal areas, and curative surgical excision of these areas is challenging. The aim of this study is to analyze the impact of mucosal involvement and surgical treatment on the survival of patients with EMPD. METHODS: We conducted a retrospective review of 217 patients with EMPD. We also assessed the associations between tumor involvement in boundary areas (anal canal, external urethral meatus, vaginal introitus), prognostic factors, and survival in 198 patients treated with curative surgery. RESULTS: Of 217 patients, 75 (34.6%) had mucosal boundary area involvement. Lesions in these areas were associated with frequent lymphovascular invasion (p = 0.042), lymph node metastasis (p = 0.0002), incomplete excision (p < 0.0001), and locoregional recurrence (p < 0.0001). Boundary area involvement was an independent prognostic factor associated with disease-specific survival, per multivariate analysis (HR: 11.87, p = 0.027). Incomplete excision was not significantly correlated with disease-specific survival (HR: 1.05, p = 0.96). CONCLUSION: Boundary area tumor involvement was a major risk factor for incomplete excision, local recurrence, and poor survival outcomes. However, incomplete removal of primary tumors was not significantly associated with poor prognosis. A less invasive surgical approach for preserving anogenital and urinary functions may be acceptable as the first-line treatment for resectable EMPD.

The Outcome of Chemotherapy for Metastatic Extramammary Paget's Disease.

The efficacy and survival impact of conventional chemotherapies for metastatic extramammary Paget's disease (EMPD) have not been fully elucidated. This study examined the long-term outcome of chemotherapy for this indication. We conducted a retrospective review of 21 patients with distant metastatic EMPD (14 patients treated with chemotherapy and 7 patients treated without chemotherapy). The response rate of chemotherapy and patient survival were statistically analyzed. Among the 14 patients treated with chemotherapy, 12, 1, and 1 patient received docetaxel, paclitaxel, and low-dose 5-fluorouracil plus cisplatin, respectively, as the first-line treatment. The response rate was 50.0% (7/14), and the disease control rate was 64.3% (9/14). The median progression-free survival (PFS) and overall survival (OS) were 16.8 and 27.9 months, respectively. Multivariate analyses revealed that chemotherapy was a significant factor for prolonged PFS (hazard ratio (HR) 0.22, p = 0.038) but not for OS (HR = 1.71, p = 0.54). Ten patients (71.4%) had severe (grade 3 or 4) hematological adverse events. Although conventional chemotherapy improved PFS, we failed to show a significantly improved OS. Considering the frequent adverse events of conventional chemotherapy, targeted therapy may become a mainstay for the treatment of metastatic EMPD.