A Case Report of Anti-TIF1-γAntibody-Positive Dermatomyositis Concomitant with Small Cell Neuroendocrine Carcinoma of the Urinary Bladder.

Small cell neuroendocrine carcinoma is rare among urinary bladder cancer types, and to date, there are no case reports of concurrent antitranscriptional intermediary factor 1-γantibody-positive dermatomyositis. We describe the case of a 69-year-old Japanese man who presented with elevated creatine kinase levels and haematuria on medical examination. Approximately one month later, he developed dysphagia. Laryngoscopy confirmed laryngeal dysfunction. He also presented with muscle weakness and a skin rash. Magnetic resonance imaging of the upper extremities suggested bilateral brachial muscle myositis. He was diagnosed as having dermatomyositis and was later found to be positive for antitranscriptional intermediary factor 1-γ antibody. Computed tomography revealed an intravesical space-occupying lesion and right iliac lymphadenopathy, suggesting urinary bladder cancer. The patient was admitted to our hospital for treatment. Urinary bladder biopsy confirmed small cell neuroendocrine carcinoma because tumour cells were positive for synaptophysin, CD56, and chromogranin A. Thus, the patient was diagnosed as having an antitranscriptional intermediary factor 1-γantibody-positive dermatomyositis concomitant with urinary bladder small cell neuroendocrine carcinoma. The patient was treated with glucocorticoid and intravenous immune globulin therapy for dermatomyositis. Radiotherapy was selected for the carcinoma. Although muscle weakness and skin symptoms improved with treatment, dysphagia persisted. Furthermore, expression of the transcriptional intermediary factor 1-γ protein in tumour cells was also confirmed by immunohistochemistry, but the significance is unknown. It should be noted that antitranscriptional intermediary factor 1-γantibody-positive dermatomyositis can occur concomitantly with such a rare malignancy.

Thrombotic thrombocytopenic purpura that developed 3 years after systemic lupus erythematosus had remitted with rituximab therapy.

Patients with systemic lupus erythematosus (SLE) occasionally develop thrombotic thrombocytopenic purpura (TTP), which can be fatal. Here, we report a case of TTP developing 3 years after SLE remitted with rituximab (RTX) therapy. A 50-year-old woman was treated with RTX for marked immune thrombocytopenic purpura and autoimmune haemolytic anaemia due to SLE relapse. After induction of remission, she was treated with prednisolone alone without maintenance therapy with RTX. Approximately 3 years later, she was readmitted with marked thrombocytopenia and severe renal dysfunction. On admission, she was diagnosed with TTP for the first time based on severe reduction in a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity and detection of ADAMTS13 inhibitors. CD19+ B cells in the patient's serum increased to 34%, suggesting that B cells had reactivated once the effect of RTX had subsided. The patient was successfully treated with plasmapheresis, glucocorticoid pulse therapy, and RTX. There are no previous reports of newly diagnosed TTP with ADAMTS13 inhibitor production after having achieved remission of SLE with RTX. Therefore, our report also discusses the potential mechanisms of production of new autoantibodies after B-cell depletion therapy.

MED12 mutations in uterine leiomyomas: prediction of volume reduction by gonadotropin-releasing hormone agonists.

BACKGROUND: Gonadotropin-releasing hormone agonists are used to treat premenopausal uterine leiomyomas; however, leiomyoma volume reduction is not always achieved. The reduction rate after this treatment varies for each leiomyoma, even in the same patient. Therefore, an effective method for predicting uterine leiomyoma volume reduction is required to reduce the adverse hypoestrogenic effects and drug-related economic burden related to gonadotropin-releasing hormone agonists. OBJECTIVE: This study aimed to determine the predictive use of MED12 mutations for evaluating the effect of gonadotropin-releasing hormone agonist treatment concerning reducing uterine leiomyoma volume and to predict the MED12 mutation status based on the findings of magnetic resonance imaging performed before treatment. STUDY DESIGN: MED12 exon 2 mutation and erythropoietin expression in uterine leiomyomas were evaluated concerning volume reduction, as measured using magnetic resonance imaging. We developed a system for classifying leiomyomas according to T2-weighted magnetic resonance imaging signals to noninvasively predict the presence or absence of MED12 mutations in leiomyomas. Leiomyoma samples (>5 cm) were obtained from 168 patients during surgery (hysterectomy or myomectomy) between 2005 and 2021 at Yokohama City University Hospital. To analyze the rate of leiomyoma volume reduction, 41 patients had been preoperatively administered the gonadotropin-releasing hormone agonist (leuprorelin acetate 3.75 mg, monthly subcutaneous injection) for 3 months; magnetic resonance imaging was performed before and after treatment without contrast material. RESULTS: Patients with MED12 exon 2 mutations had smaller volume reduction after treatment with the gonadotropin-releasing hormone agonist (P<.001, Mann-Whitney U test) and displayed lower signal intensity on T2-weighted images than those with leiomyomas expressing wild-type MED12 exon 2. The newly proposed magnetic resonance imaging-based classification system showed that MED12 exon 2 mutations were more frequent in the low-signal group than in the high-signal group, with nearly equal proportions of mutated and wild-type MED12 exon 2 leiomyomas noted in the intermediate group. The low-signal group had significantly lower erythropoietin expression levels than the high-signal group (P<.001, Kruskal-Wallis test with the Dunn posthoc analysis). CONCLUSION: MED12 mutation status can be a candidate marker for predicting the effect of gonadotropin-releasing hormone agonists on uterine leiomyoma reduction. Magnetic resonance imaging findings can be used to determine MED12 mutation status as a noninvasive strategy to select patients who will most likely benefit from gonadotropin-releasing hormone agonist treatment.

Possible significance of degeneration and decreased expression of progesterone receptor in postmenopausal uterine leiomyoma.

BACKGROUND: The growth of uterine leiomyomas is dependent on the levels of sex steroid hormones, and they usually shrink after menopause. However, there are cases in which leiomyomas continue to grow and/or surgery is required after menopause. In addition to estrogen, progesterone has recently been implicated in leiomyoma enlargement, but its relevance to postmenopausal leiomyoma remains unknown. Therefore, we investigated whether hormone receptor expression is associated with postmenopausal leiomyoma enlargement and characterized pathological findings of postmenopausal leiomyoma, which have not been clarified yet. METHODS: Nine cases that required total hysterectomy for leiomyomas after menopause were examined. Surgeries were conducted because of pelvic pressure, pelvic pain, suspected malignancy, or growing leiomyoma. Six cases of leiomyomas being incidentally found during total hysterectomy for postmenopausal uterine prolapse, and six patients who underwent hysterectomy for leiomyomas before menopause, were examined as controls. We evaluated the expression of estrogen receptor, progesterone receptor B, and progesterone receptor AB by immunohistochemical staining among the cases. We also analyzed the pathological findings of leiomyomas. RESULTS: In postmenopausal leiomyomas, the expression of progesterone receptor was higher than that in the adjacent myometrium. Compared with premenopausal leiomyomas, the expression of progesterone receptor decreased. Postmenopausal leiomyomas that required surgery did not show elevated sex steroid hormone receptor expression, compared with the leiomyomas that did not require surgery. The degeneration frequency of leiomyomas was 92% in the group that underwent surgery for postmenopausal leiomyomas, 65% in the group that underwent surgery for reasons other than the presence of leiomyomas after menopause, and 47% in the group operated for leiomyomas before menopause. CONCLUSIONS: These results suggest that sex steroid hormones are unlikely to be associated with the growth of leiomyomas after menopause. Since leiomyoma degeneration with increased extracellular matrix is likely to occur in postmenopausal women, the degeneration of leiomyomas may be the main mechanism for the growth of postmenopausal leiomyomas.

A rare case of gestational ovarian choriocarcinoma coexistent with intrauterine pregnancy.

OBJECTIVE: To report the rare case of gestational primary ovarian choriocarcinoma coexistent with intrauterine pregnancy, successfully treated with surgery and systemic chemotherapy. We also describe the utility of short tandem repeat (STR) genotyping in the diagnosis of choriocarcinoma. CASE REPORT: A 38-year-old woman at 17 gestational weeks presented with an ovarian tumor rupture in the left ovary. Left salpingo-oophorectomy was performed and the patient was diagnosed with gestational ovarian choriocarcinoma via histopathology and STR genotyping. After artificial abortion, the patient underwent 8 cycles of chemotherapy. Abdominal hysterectomy was performed because of the presence of low levels of human chorionic gonadotropin and the tumor that developed behind the uterus. However, no viable choriocarcinoma cells were found in the residual tumor, suggesting that the patient achieved full remission. CONCLUSIONS: Early detection is crucial in treating choriocarcinomas; thus, clinicians should consider the possibility of choriocarcinoma at the presence of an ovarian tumor during pregnancy. Gestational and non-gestational choriocarcinomas differ in prognosis and sensitivity to chemotherapy due to their different etiologies. Therefore, STR genotyping may be beneficial in predicting the patient's prognosis or selecting the appropriate regimen.

A Case of Granulomatosis with Polyangiitis with Various Breast Lesions as the Initial Symptoms: A Case-Based Review.

A 44-year-old woman presenting with pus-like discharge from the nipples visited our hospital for scleritis. Subcutaneous induration and ulceration were found on her breast. She was diagnosed with granulomatosis with polyangiitis (GPA) considering scleritis, sinusitis, cutaneous granuloma formation, and antiproteinase 3-antineutrophil cytoplasmic antibodies and was successfully treated with glucocorticoids. Fifteen months later, she developed pulmonary consolidation and a right breast nodule. Biopsies of the breast nodule showed granulomatous vasculitis, and she was treated with rituximab. While breast involvement in GPA is rare, unilateral breast mass is a typical clinical feature; thus, GPA should be considered in such cases.

Pretreatment maximum standardized uptake value in 18F-fluorodeoxyglucose positron emission tomography-computed tomography as a prognostic factor for ovarian clear cell carcinoma and low-grade serous carcinoma.

OBJECTIVE: The maximum standardized uptake value (SUVmax) derived by positron emission tomography-computed tomography (PET/CT) can be an index of biological tumor aggressiveness, which is assessed using noninvasive tools before the treatment of epithelial ovarian cancer (EOC). This study aimed to evaluate the prognostic value of the pretreatment SUVmax in patients with EOC. MATERIALS AND METHODS: We reviewed the data of patients with EOC who underwent pretreatment 18F-FDG PET/CT between June 2006 and September 2016. The relationships between pretreatment SUVmax and histological subtypes of EOC were determined. Moreover, progression-free survival (PFS) and overall survival (OS) were evaluated according to the pretreatment SUVmax. Risk factors associated with progression or death were also analyzed. RESULTS: Of 148 patients, 66 (44.6%), 11 (7.4%), 34 (23.0%), 19 (12.8%), 15 (10.1%), and three (2.0%) were diagnosed with high-grade serous carcinoma (HGSC), low-grade serous carcinoma (LGSC), clear cell carcinoma (CCC), endometrioid carcinoma, mucinous carcinoma, and others, respectively. The median SUVmax was marginally lower in LGSC (6.80 vs. 10.5; P = 0.059) and significantly lower in CCC (5.92 vs. 10.5; P = 0.001) than in HGSC. A high pretreatment SUVmax (≥9.30) was a prognostic factor for OS in patients with LGSC (P = 0.046). Furthermore, multivariate analysis revealed that a high SUVmax (≥5.85) was an independent prognostic factor for OS (P = 0.046) in patients with CCC. However, a high SUVmax (≥7.77) was a poor predictor of PFS and OS in patients with EOC (P = 0.156 and P = 0.158, respectively). CONCLUSION: Our findings suggest that the pretreatment SUVmax is not only an independent predictor of survival in patients with CCC but also a significant predictor of survival in patients with LGSC.

Evaluating the safety of dienogest in women with adenomyosis: A retrospective analysis.

AIM: Dienogest (DNG) is highly effective for relieving pain caused by endometriosis and adenomyosis. However, women with severe uterine swelling due to adenomyosis who take DNG usually experience metrorrhagia. This study aimed to examine the safety of DNG usage in women with adenomyosis. METHODS: This study included 20 women who were prescribed DNG for adenomyosis in our hospital from January 2016 to December 2016. We retrospectively analyzed women's clinical background characteristics (age, the use of the gonadotropin-releasing hormone agonist as pre-treatment of DNG, the uterus size [major axis, minor axis, maximum thickness in the myometrium, and length of the uterine body] by transvaginal ultrasonography [TVUS], hemoglobin level, and the presence of metrorrhagia during treatment). These variables were compared between the DNG continuation and discontinuation groups using the Mann-Whitney U test. RESULTS: Thirteen women continued DNG, and seven discontinued DNG within 12 months because of metrorrhagia. The uterine size was significantly larger in the discontinuation group than in the continuation group. All uterine measurements had high Spearman rank correlation coefficients (ρ > 0.8, P < 0.05). In six of seven cases in the discontinuation group, adenomyosis was in the anterior wall. Measuring the uterus size and locating adenomyosis by TVUS are simple methods of predicting DNG discontinuation. CONCLUSION: We consider that DNG can be safely administered in women with adenomyosis if the uterine size is <6 cm in the minor axis and the main lesion of adenomyosis is located in the posterior uterine wall.

Expression of erythropoietin messenger ribonucleic acid in wild-type MED12 uterine leiomyomas under estrogenic influence: new insights into related growth disparities.

OBJECTIVE: To determine factors that impact erythropoietin (EPO) production in leiomyomas. We have previously implicated EPO production in promoting the growth of some leiomyomas. DESIGN: The relationship between EPO messenger RNA (mRNA) expression and MED12 gene mutations or mRNA expression levels of high-mobility group AT-hook (HMGA) 1 and HMGA2 were analyzed. Effects of 10-8 M 17ß-E2 on EPO mRNA expression were evaluated using leiomyoma cells grown in primary cultures. SETTING: Graduate school of medicine. PATIENT(S): Patients with leiomyoma. INTERVENTION(S): We used tissue samples and clinical data of 108 patients with leiomyomas to analyze the relation between EPO mRNA expression and MED12 mutation. Tissue samples from another 10 patients with leiomyomas were collected for in vitro experimentation using primary cultures of leiomyoma and myometrial cells. MAIN OUTCOME MEASURE(S): Relations between EPO mRNA expression, MED12 exon 2 mutation, and HMGA1/HMGA2 mRNA expression levels in leiomyoma samplings, in addition to effects of estrogen (E) on EPO mRNA expression in cultures of leiomyoma cells. RESULT(S): The EPO mRNA level was threefold higher in leiomyomas with wild-type (vs. mutated) MED12 genes. There was no correlation between EPO and HMGA1 or HMGA2 mRNA expression levels. In wild-type MED12 leiomyomas only, E2 treatment produced a twofold increase in EPO mRNA expression, whereas mutated MED12 leiomyomas were unaffected. CONCLUSION(S): The EPO mRNA expression increased significantly after E2 treatment only in leiomyomas lacking MED12 mutations. In conjunction with prior evidence linking EPO mRNA expression levels and tumor size, E2-stimulated EPO mRNA expression may explain the marked growth disparities seen in these tumors.

Magnetic Resonance Imaging Grading System for Preoperative Diagnosis of Leiomyomas and Uterine Smooth Muscle Tumors.

STUDY OBJECTIVE: To evaluate a new magnetic resonance imaging (MRI) grading system for preoperative differentiation between benign and variant-type uterine leiomyomas including smooth muscle tumors of uncertain malignant potential (STUMPs). DESIGN: Retrospective analysis (Canadian Task Force classification III). SETTING: Teaching hospital (Teine Keijinkai Hospital). PATIENTS: Three-hundred thirteen patient medical records were retrospectively reviewed if treated for uterine myomas and diagnosed with variant type leiomyomas or STUMPs (n = 27) or benign, typical leiomyomas (n = 286) and treated between January 2012 and December 2014. INTERVENTION: Uterine myoma classifications using MRI findings according to a 5-grade system (grades I-V) based on 3 elements. MEASUREMENTS AND MAIN RESULTS: Uterine myoma MRI classifications were based on 3 elements: T2-weighted imaging (high or low), diffusion-weighted imaging (high or low), and apparent diffusion coefficient values (high or low; apparent diffusion coefficient < 1.5 × 10-3 mm2/sec was considered low). Grades I to II were designated as typical or benign leiomyomas, grade III as degenerated leiomyomas, and grades IV to V as variant type leiomyomas or STUMPs. Accuracy levels were 98.9%, 100%, 94.3%, 58.8%, and 41.9% for grades I through V lesions, respectively. The grades were divided into 2 groups to discriminate benign leiomyomas and STUMPs (grades I-III were considered negative and grades IV-V positive). Grades IV to V scored 85.2% for sensitivity, 91.3% for specificity, 47.9% positive predictive value, 98.5% negative predictive value, a 9.745 positive likelihood ratio, and a .162 negative likelihood ratio. CONCLUSION: This novel MRI grading system for uterine myomas may be beneficial in differentiating benign leiomyomas from STUMPs or variant type leiomyomas and could be a future effective presurgical assessment tool.

Teriparatide and denosumab treatment for pregnancy and lactation-associated osteoporosis with multiple vertebral fractures: A case study.

OBJECTIVE: Pregnancy and lactation-associated osteoporosis (PLO) is a rare disease, which can lead to vertebral fractures in women of reproductive age. No treatment strategy for PLO has been established. Here we report a case of PLO treated with teriparatide followed by denosumab, in which remarkable improvement in bone mineral density (BMD) was achieved. CASE REPORT: A 27-year-old woman experienced severe back pain two weeks after her first delivery. PLO was diagnosed from her low BMD and multiple vertebral compression fractures. She was treated with teriparatide for 6 months, followed by denosumab. After 1 year, her BMD increase from baseline was 16.5% in L2∼4 and her pain had been relieved. CONCLUSION: In addition to weaning, administration of teriparatide followed by denosumab led to remarkable improvement in the patient's symptoms and BMD. Therefore, we regard this method as a promising choice for the treatment of PLO.

Aberrant Expression of the Cell Polarity Regulator aPKCλ/ι is Associated With Disease Progression in Cervical Intraepithelial Neoplasia (CIN): A Possible Marker for Predicting CIN Prognosis.

Atypical protein kinase C λ/ι (aPKCλ/ι) is a regulator of epithelial cellular polarity. It is also overexpressed in several cancers and functions in cell proliferation and invasion. Therefore, we hypothesized that aPKCλ/ι may be involved in development and progression of cervical intraepithelial neoplasia (CIN), the precancerous disease of cervical cancer induced by human papillomavirus. To do this, we investigated the relationship between aPKCλ/ι expression and CIN. aPKCλ/ι expression level and subcellular localization were assessed in 192 CIN biopsy samples and 13 normal epithelial samples using immunohistochemistry. aPKCλ/ι overexpression (normal epithelium, 7.7%; CIN1, 41.7%; CIN2/3, 76.4%) and aPKCλ/ι nuclear localization (normal epithelium, 0.0%; CIN1, 36.9%; CIN2/3, 78.7%) were higher in CIN samples than normal samples (P<0.05), suggesting that CIN grade is related to aPKCλ/ι overexpression and nuclear localization. Then, 140 CIN cases were retrospectively analyzed for 4-yr cumulative disease progression and regression rates using the Cox proportional hazards model. CIN1 cases with aPKCλ/ι overexpression or aPKCλ/ι nuclear localization had a higher progression rate than CIN1 cases with normal aPKCλ/ι expression levels or cytoplasmic localization (62.5% vs. 9.7% and 63.1% vs. 9.4%, respectively; P<0.001). Multivariate analysis indicated that human papillomavirus types 16 and 18, aPKCλ/ι overexpression (hazard ratio=4.26; 95% confidence interval, 1.50-12.1; P=0.007), and aPKCλ/ι nuclear localization (hazard ratio=3.59; 95% confidence interval, 1.24-10.4; P=0.019) were independent risk factors for CIN1 progression. In conclusion, aPKCλ/ι could be useful for the therapeutic management of patients with CIN, particularly those with non-human papillomavirus 16/18 types.

Increasing trends in cervical cancer mortality among young Japanese women below the age of 50 years: an analysis using the Kanagawa population-based Cancer Registry, 1975-2012.

BACKGROUND: In Japan, cervical cancer (CC) deaths among women aged <50 years have doubled over the last three decades. Obtaining age-specific CC mortality rates among young women is important for taking measures against CC. Age-adjusted CC mortality rates for all ages are inadequate because of the classification of 'uterine cancer, not otherwise specified' (NOS uterine cancer) and CC mortality rates among elderly women. The aim of the present study was to calculate exact age-specific CC mortality rates in women aged <50 years in Kanagawa, taking into account the impact of NOS uterine cancer. METHODS: Using the Kanagawa Cancer Registry, CC deaths (1975-2012) were analyzed and CC mortality rates (age-adjusted, 20-29, 30-49, and ≥50 years) were calculated. In addition, hospitals were surveyed to reclassify cases of NOS uterine cancer. After reclassification, chronological trends were also analyzed. RESULTS: Age-specific CC mortality rates in Kanagawa and Japan overall showed increasing trends for ages 20-29 (P for trend<0.001) and 30-49 (P for trend<0.001). Rates of NOS uterine cancer death were significantly lower in Kanagawa than in Japan overall (P<0.05), except for patients aged <50 years in 2005-2009 (P=0.159). CONCLUSIONS: The present study revealed concern for CC among Japanese women younger than 50 years. Well-organized CC screening and HPV vaccination should be provided to reduce CC mortality rates for these young women.

Aberrant expression of erythropoietin in uterine leiomyoma: implications in tumor growth.

OBJECTIVE: Myomatous erythrocytosis syndrome is a rare complication of uterine leiomyoma caused by erythropoietin (EPO) that is produced by tumor cells. We assessed the EPO expression in leiomyomas and investigated the effects of EPO on the tumor growth. STUDY DESIGN: Tissue samples were collected from 114 patients with uterine leiomyomas who underwent myomectomy or hysterectomy in Yokohama City University Hospital. From 17 patients, the corresponding normal myometrium was also collected. All samples were analyzed for EPO messenger RNA (mRNA) expression by real-time reverse transcription-polymerase chain reaction. EPO protein expression was determined by an enzyme-linked immunosorbent assay. The relationships between EPO expression and clinicopathological features were retrospectively analyzed using the patients' charts. Blood vessel density and maturity were assessed using hematoxylin-eosin staining and CD34 immunohistochemistry. RESULTS: EPO mRNA expression was detected in 108 of 114, or 95%, of the leiomyomas. The mean EPO mRNA expression in the leiomyoma was higher than the corresponding normal myometrium (3836 ± 4122 vs 1455 ± 2141; P = .025 by Wilcoxon rank test). The EPO mRNA expression in the leiomyomas varied extensively among samples, ranging from undetectable levels to 18-fold above the mean EPO mRNA of normal myometrium. EPO protein production was observed concomitant with mRNA expression. A positive correlation of leiomyoma size and EPO mRNA expression was shown by Spearman rank correlation coefficient (ρ = 0.294; P = .001), suggesting the involvement of EPO in leiomyoma growth. The blood vessel maturity was also significantly increased in EPO-producing leiomyomas (high vessel maturity in high vs low EPO group: 67% vs 20%; P = .013 by Fisher exact test). CONCLUSION: This report demonstrates that EPO is produced in most of conventional leiomyomas and supports a model in which EPO accelerates tumor growth, possibly by inducing vessel maturity. Our study suggests one possible mechanism by which some uterine leiomyomas reach a large size, and the understanding of EPO expression patterns in these tumors may be useful for management of the patients with leiomyomas.

Dienogest was effective in treating hemorrhagic ascites caused by endometriosis: a case report.

Hemorrhagic ascites caused by endometriosis is extremely rare, and its treatment is under discussion. We report a case of recurrent endometriosis-related ascites treated with dienogest (DNG). A 35-year-old nulliparous Japanese woman with a history of infertility presented with worsening dysmenorrhea and abdominal distention caused by massive ascites. The patient underwent exploratory laparotomy, and hemorrhagic ascites (5500 mL) was drained. She had a normal-sized uterus, and the bilateral ovaries could not be observed because of extensive adhesion in the abdominal cavity. Endometriosis was diagnosed by histopathological evaluation of the omental biopsy, and this was considered to be the cause of ascites. After laparotomy, she had recurrence of ascites. For the next 8 years, the patient was treated conservatively with gonadotropin-releasing hormone agonist therapy and drainage during the intermittent periods followed by DNG administration. She has been treated continuously with DNG for 1 year with no recurrence of ascites. DNG could be an effective treatment for recurrent ascites associated with endometriosis, especially when surgical therapy is undesirable.