Drug-induced interstitial lung disease caused by olaparib: three case reports and review of the Japanese Adverse Drug Event Report database and literature.

BACKGROUND: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has demonstrated effectiveness in treating ovarian, breast, and other cancers, particularly those with specific molecular subtypes including, but not limited to, BRCA1/2 mutations. Consequently, its utilization is expected to increase in the future. For this reason, it is important to acknowledge the potential for adverse events associated with olaparib, including the relatively rare but significant risk of drug-induced interstitial lung disease (DIILD). Since DIILD can lead to fatal outcomes, its early detection is crucial. The dissemination of knowledge regarding DIILD can be facilitated through case reports; however, specific reports of DIILD caused by olaparib have only been published in Japanese. To the best of our knowledge, this is the first report in English of our experience with three cases of DIILD caused by olaparib. CASE PRESENTATION: Cases 1, 2, and 3 involved Japanese women with ovarian cancer who had been receiving olaparib at a dose of 600 mg/day. Case 1, a 72-year-old woman who had been on olaparib for 4 months, and case 2, a 51-year-old woman who had been on olaparib for 8 months, reported fever and general malaise. Chest computed tomography (CT) revealed pale ground glass opacity (GGO) similar to hypersensitivity pneumonitis. The severity grade was 2 in both cases. Case 3, a 78-year-old woman who had been on olaparib for 3 weeks, presented with cough and reported dyspnea on exertion. Chest CT revealed non-specific interstitial pneumonia and organizing pneumonia-like shadows. The severity grade was 4. Olaparib was discontinued in all cases. Case 1 received 0.6 mg/kg of prednisolone due to mild hypoxia, while prednisolone was not administered in case 2 due to the absence of hypoxia. Case 3 received steroid pulse therapy due to severe hypoxia. Olaparib administration was not resumed in any patient. CONCLUSION: DIILD caused by olaparib in Japan, including the present three cases, commonly presents with GGO, similar to hypersensitivity pneumonitis on chest CT. The prognosis for the majority of patients is favorable; however, there have been instances of severe cases. Early recognition of drug-induced lung injury and further accumulation of cases is important.

AMH producing purely cystic virilizing adult granulosa cell tumor in 17 years old girl: a case report and review of literatures.

BACKGROUND: Androgen-producing granulosa cell tumor in adolescent girl is rare condition and clinical characteristics are not fully elucidated. CASE PRESENTATION: Seventeen years old girl complained of secondary amenorrhea was referred to our out-patient consultation. Markedly elevated serum testosterone, LH, and AMH levels were noted. Mild hirsutism and clitoromegaly were presented. Transabdominal ultrasonography and MRI revealed cystic mass occupied pelvic cavity probably originated from left ovary. Right ovary showed polycystic appearance. Laparoscopic left ovarian cystectomy was performed. After the surgery, her menstruation resumed along with normalized hormonal parameters, and clinical hyperandrogenism were improved. Since the scarcity of cellular lining of inner cyst wall, definitive pathological diagnosis was difficult. After the consultation with gynecological pathologist, the tumor was diagnosed as sex cord stromal tumor, highly suspicious for adult granulosa cell tumor. Residual left salpingo-oophorectomy was performed by additional laparoscopic surgery. Her serum testosterone and AMH levels were remained low with regular menstrual cycles and no evidence of recurrence. CONCLUSIONS: Androgen-producing cystic granulosa cell tumor is rare gynecological disorders, which need both gynecologic oncological and endocrinological approach. Its clinical manifestations may bring some clues to the pathogenesis of ovulatory dysfunctions, such as polycystic ovary syndrome.

Accumulation of fibrosis and altered perifollicular stromal differentiation in vitrified-thawed human ovarian tissue xenografted to nude mice.

Purpose: Ovarian tissue cryopreservation and its auto-transplantation is promising technique in fertility preservation. Longevity of grafted tissue is limited though mechanism of follicle reduction is not fully understood. We evaluated histological alteration of vitrified-thawed ovarian tissue that grafted to nude mice. Materials and Methods: Human ovarian tissue was cryopreserved by vitrification. After thawing, they were grafted to mesentery of nude mice. Twelve weeks after transplantation, the implants were removed and histologically examined. The presence of follicles, the degree of fibrosis, and TUNEL staining in surrounding cortex were evaluated. The stromal expressions of alpha-smooth muscle actin (aSMA) were determined. Results: Normal ovarian cortex was decreased, and fibrotic area were significantly increased after grafting. The distributions of developmental stage of follicles shifted toward activation of follicular growth. Stromal TUNEL staining was increased in frozen/thawed tissue. The expression of aSMA were found in perifollicular stroma of growing follicles, which were decreased in grafted tissue associated with reduction of cortical stroma. Conclusions: Fibrosis, reduced cortical stroma, and activation of dormant follicles were concomitantly observed in grafted ovarian cortex, which may relate to limited longevity. Perifollicular aSMA expression can be regarded as a marker of the competence of cortical stroma that regulate follicular development.

AMH Concentrations in Peritoneal Fluids of Women With and Without Endometriosis.

Background: As its name indicates, anti-Müllerian hormone (AMH) is primarily found as an inhibitor of the Müllerian duct in male fetus. On the other hand, AMH may act as a mediator of Müllerian duct-derived female tissue, such as endometrium in normal and pathological conditions. However, the role of AMH in the functional regulations of endometriosis is not well understood. It can be hypothesized that AMH in peritoneal fluids may affect the activity of peritoneal endometriosis. In this study, we investigated the levels of AMH in peritoneal fluids (PF) in women with and without endometriosis. Methods: PF were collected during laparoscopy from 90 women diagnosed as having advanced endometriosis (rASRM stage III, n = 30; stage IV, n = 60), and 32 women without endometriosis were served as control. Paired serum samples were also collected before the surgery. AMH in PF and serum were measured by ELISA. Individual clinical information was collected. AMH levels were compared according to the presence of endometriosis. The expression of AMHR2 in peritoneal endometriotic lesions obtained during laparoscopy was examined by immunohistochemistry. Results: AMH levels in PF were positively and significantly correlated with serum AMH levels in both women with and without endometriosis (R 2 = 0.17, P < 0.0001; R 2 = 0.30, P = 0.001, respectively). Serum AMH levels were inversely and significantly correlated with age in women with endometriosis (R 2 = 0.092, P = 0.004) and in control women without statistical significance (R 2 = 0.078, P = 0.12). AMH levels in PF were also inversely but not significantly correlated with age in women with and without endometriosis (R 2 = 0.029, P = 0.11 and R 2 = 0.027, P = 0.37, respectively). Mean age and serum AMH levels were not significantly different between two groups. On the other hand, AMH levels in PF were significantly lower in women with endometriosis compared to those of control women [2.15 ± 2.13 (mean ± SD) vs. 4.40 ± 4.77 ng/mL, P = 0.0001]. AMHR2 are localized at glandular epithelium and stromal cells in the ectopic endometrium of peritoneal endometriosis. Conclusions: Women with endometriosis may present lower PF AMH levels even if they retain serum levels similar to women without disease. As peritoneal endometriosis expresses a specific receptor for AMH, lower AMH levels in PF of women with advanced endometriosis may be involved in the pathophysiology of peritoneal endometriosis.

Ovarian reserve after three-step laparoscopic surgery for endometriomas utilizing dienogest: A pilot study.

PURPOSE: Surgery for endometriomas may cause detrimental effects on ovarian reserve. We evaluated the safety of three-step laparoscopic surgery for endometriomas utilizing dienogest in terms of post-surgical ovarian reserve. METHODS: Twelve women received first look laparoscopy (FLL) with fenestration and drainage. Immediately after the surgery, they took oral dienogest 2 mg for three months; then, they received second look laparoscopy (SLL) with cystectomy. We compared serum AMH levels between women had three-step management with dienogest, and another twelve women had conventional one-step surgery without medications. In women had three-step procedures, the changes in concentration of proinflammatory cytokines and chemokines in peritoneal fluids were evaluated. RESULTS: Serum AMH levels were significantly decreased after three months of dienogest following FLL. AMH levels were also significantly decreased 3-6 months both after SLL and after one-step surgery; however, recovery of serum AMH levels at 9-12 months after surgery was evident in women had three-step surgery comparing to those of one-step surgery. Proinflammatory cytokines and chemokines in peritoneal fluids were downregulated at the time of SLL comparing to those of FLL. CONCLUSIONS: Three-step surgery with dienogest may be a beneficial approach to protect ovarian reserve. Dienogest may exert its effects in part by lowering proinflammatory cytokines and chemokines.

Synthesis, Crystal Structure, and Photoluminescent Properties of 3,3',4,4'-Tetraethyl-5,5'-divinyl-2,2'-bipyrrole Derivatives.

Photoluminescent divinylbipyrroles were synthesized from 3,3',4,4'-tetraetyl-2,2'-bipyrrole-5,5'-dicarboxaldehyde and activated methylene compounds via aldol condensation. For mechanistic clarity, molecular structures of Meldrum's acid- and 1,3-dimethylbarbituric acid-derived divinylbipyrroles were determined by single-crystal X-ray diffraction. Photoluminescent properties of the synthesized divinylbipyrroles in dichloromethane were found to be dependent on the presence of electron withdrawing groups at the vinylic terminal. The divinylbipyrroles derived from malononitrile, Meldrum's acid, and 1,3-dimethylbarbituric acid showed fluorescent peaks at 553, 576, and 602 nm respectively. Computational studies indicated that the alkyl substituents on the bipyrrole 3 and 3' positions increased energy level of the highest occupied molecular orbital (HOMO) compared to the unsubstituted derivatives and provided rationale for the bathochromic shift of the ultraviolet-visible (UV-Vis) spectra compared to the previously reported analogs.

Long-term outcome of non-surgical treatment in patients with oral leukoplakia.

UNLABELLED: The standard treatments for oral leukoplakia range from careful observation to complete resection. No surgical intervention is chosen for several supposable reasons. Surgical treatment and no surgical treatment for oral leukoplakia have no defined basis for comparisons, and few studies have reported on the long-term outcomes of oral leukoplakia without surgery. OBJECTIVES: This study aimed to identify the important factors using a long-term wait-and-see policy in patients with oral leukoplakia. MATERIALS AND METHODS: In total, 237 lesions from 218 patients selected for non-surgical therapy between 2001 and 2010 were analyzed. On the basis of long-term follow-up data, lesions were classified as unchanged, reduced, disappeared, expanded, and malignantly transformed. RESULTS: In total, 135 (57.0%) lesions remained unchanged, 30 (12.7%) lesions were characterized by a reduction in size or clinical severity, and 44 (18.6%) lesions had disappeared. Another 17 (7.2%) lesions resulted in spread or clinical deterioration, and 11 (4.6%) lesions developed oral squamous cell carcinoma. CONCLUSIONS: We demonstrated a cumulative malignant transformation rate of 11.6% in 10years without resection. The lesions that were nonhomogeneous, and higher degree of epithelial dysplasia, located on the tongue were likely to progress into cancer. In addition, 32.5% of lesions without surgical treatment were reduced or disappeared. There is a possibility that removal of considerable irritation for a long time contributes to the treatment of this disease. The development of appropriate treatments for oral leukoplakia is required, which will enable successful differentiation between surgical and observation cases.

Sensory changes after tongue reduction for macroglossia.

We report sensory changes after tongue reduction by the Harada-Enomoto method for macroglossia in a 20-year-old woman with Beckwith-Wiedemann syndrome. Sensory tests were performed before surgery and 1 week and 2 months after surgery. We assessed the static tactile threshold, vibration sense, static 2-point discrimination, pain threshold, and taste. No sensory loss of any category tested was observed after tongue reduction.

[Detection of potentially malignant and malignant lesions of oral cavity using autofluorescence visualization device].

Light-based oral cancer screening aids have been developed in identifying potentially malignant and malignant lesions of oral cavity at their earliest stage. The VELscope system is a simple hand-held device that facilitates the direct visualization of oral-cavity fluorescence for the detection of precancerous and cancerous lesions. Some published reports have shown that this system can assist in the detection of precancerous and cancerous lesions, but there is no evidence that it can distinguish between them. We studied whether objective discrimination criteria can be set for this system when observing oral mucosal lesions. We examined 74 cases with biopsy-confirmed oral mucosal lesions; 37 squamous cell carcinoma lesions, 14 moderate to severe epithelial dysplasia lesions, 13 mild epithelial dysplasia lesions and 10 lichen planus lesions. Lesions were examined macroscopically under the conventional overhead light, and then, examined by this device. Each examination was recorded with a digital camera. We contrasted findings with histopathological manifestation, and calculated the attenuation score. It is found that several conditions and sites, such as keratinization and the degree of inflammatory cell infiltration, were associated with detection sensitivity using this device. Based on the attenuation scores, a significant difference was seen between squamous cell carcinoma and epithelial dysplasia. It is suggested that this device might be a valuable adjunct in the early detection of potentially malignant and malignant lesions of the oral cavity.

Chronic exposure to arsenite induces S100A8 and S100A9 expression in rat RBL-2H3 mast cells.

To investigate the effects of chronic exposure to arsenite on the gene expression profiles of mast cells, microarray analysis was performed on rat basophilic leukemia RBL-2H3 cells exposed to arsenite for 28 days. Upregulated genes include calcium-binding S100 proteins such as S100A9, S100A10, S100A6, and S100A13, and granzymes B and C. Among S100 proteins, S100A9 showed the highest expression (8.62-fold of untreated cells) after 4-weeks of exposure to arsenite. As S100A8 and S100A9 comprise a heterodimer called calprotectin, and are implicated in the development of atherosclerosis and cancer, mRNA levels of both S100A8 and S100A9 were analyzed. The results demonstrated that exposure of RBL-2H3 cells to arsenite for a few weeks induces marked increases in mRNA levels of S100A8 and S100A9.

DNA microarray analysis of the liver of mice treated with cobalt chloride.

To investigate the in vivo effects of cobalt chloride on gene expression at early time points, DNA microarray analysis was performed on the liver of mice injected subcutaneously with cobalt chloride. The liver tissue samples were taken 0.5, 1, and 3 hr after injection. Of the 14 genes up-regulated at 0.5 hr after injection, 7 are related to immunological responses, and 4 of the 7 were found to be involved in the activation of interferon.

Low-dose recombinant canine interferon-gamma for treatment of canine atopic dermatitis: an open randomized comparative trial of two doses.

The purpose of this study was to investigate the minimum effective dose of recombinant canine interferon-gamma (rCaIFN-gamma) for the treatment of dogs with atopic dermatitis (AD). Thirty-four dogs with AD from 17 animal hospitals in Japan were administered half or one-fifth of the approved rCaIFN-gamma dose of 10 000 units/kg, three times a week for 4 weeks, followed by once weekly for an additional 4 weeks. Pruritus, excoriation, erythema and alopecia were evaluated and scored by the investigators on weeks 2, 4, 6, 8 and 12. The efficacy rate (number of excellent cases + number of good cases/total number of cases) at week 8 in the 2000 units/kg group was 36.4% for pruritus, 36.4% for excoriation, 45.5% for erythema and 36.4% for alopecia. In contrast, in the 5000 units/kg group, the efficacy rate was 64.3% for pruritus, 57.1% for excoriation, 78.6% for erythema and 78.6% for alopecia. The efficacy rate of the 5000 units/kg group was high for all signs evaluated and comparable to that of the 10 000 units/kg group reported in a previous study. The results of this study showed that 2000 units/kg of rCaIFN-gamma is less effective than 5000 units/kg to treat dogs with AD, and the efficacy of the 5000 units/kg dose is comparable to that of 10 000 units/kg at week 8.

Androgen receptor expression in breast cancer: relationship with clinicopathological factors and biomarkers.

BACKGROUND: Breast cancer is a hormone-dependent tumor. Most breast cancer cells have an androgen receptor (AR), but the clinical value of AR expression is unclear. METHODS: AR expression was evaluated in 227 primary breast cancers using immunohistochemistry. The relation of AR expression to clinicopathological factors and biomarkers was analyzed. AR expression was assessed semiquantitatively, and tumors with more than 10% of stained cells were regarded as positive. RESULTS: The AR-positive rate was higher in smaller tumors (P=0.045), tumors with negative lymph node metastasis (P=0.045), scirrhous-type tumors (P<0.0001), tumors of low histological grade (P=0.0001), and p53-negative tumors (P = 0.0097). Although AR had no relation to menopausal status, 79% of cases of high AR expression (>50% stained cells) were in postmenopausal women. AR was related to estrogen receptor (ER; P=0.027) and progesterone receptor (PR; P=0.016) expression, but showed no relation to human epidermal growth factor receptor type 2 (Her2) expression. Regarding the coexpression of these receptors, 18 of the 42 cases of triple-negative (ER/PR/Her2-negative) tumors (43%) were AR-positive. CONCLUSION: AR expression is related to low malignancy in breast cancer. The assessment of AR expression may lead to new treatment strategies for breast cancer, especially in postmenopausal women and in women with tumors that show triple negativity for hormone receptors.

Fundamental study of expression-library immunization against Taenia taeniaeformis in rats.

Expression-library immunization has been proposed as an effective means to screen a large number of genes of the pathogen as candidate protective molecules. In this study, we examined the efficacy of expression-library immunization using a T. taeniaeformis rat model system. Total RNAs were isolated from the last 15 segments of adult T. taeniaeformis and poly A RNA was purified. cDNA library was produced using SuperScript Plasmid System, which contains a mammalian expression vector, pCMV*SPORT6. From about 3,500 clones examined, more than 800 clones were found to contain DNA fragments. About 200 clones were sequenced and the homology search was carried out. The blast search revealed that 29% of the expression genes were mitochondrial genes (rRNA; 17%, protein; 12%). Nuclear rRNA genes (10%), nuclear protein (9%) and genes from Escherichia coli were also detected. Forty-two percent of sequences did not show a significant similarity to any genes deposited in the public database. Rats were immunized with expression-library and injected orally with 1,000 T. taeniaeformis eggs. However the protective effect of expression-library vaccine was not confirmed.