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Supplementary Data from DNA Copy Numbers Profiles in Affinity-Purified Ovarian Clear Cell Carcinoma

Supplementary Figures, Tables and Methods from Analysis of DNA Copy Number Alterations in Ovarian Serous Tumors Identifies New Molecular Genetic Changes in Low-Grade and High-Grade Carcinomas

Ovarian serous carcinoma, the most common and lethal type of ovarian cancer, is thought to develop from two distinct molecular pathways. High-grade (HG) serous carcinomas contain frequent TP53 mutations, whereas low-grade (LG) carcinomas arise from serous borderline tumors (SBT) and harbor mutations in KRAS/BRAF/ERBB2 pathway. However, the molecular alterations involved in the progression from SBT to LG carcinoma remain unknown. In addition, the extent of deletion of tumor suppressors in ovarian serous carcinomas has not been well studied. To further address these two issues, we assessed DNA copy number changes among affinity-purified tumor cells from 37 ovarian serous neoplasms including SBT, LG, and HG tumors using high-density 250K single nucleotide polymorphism arrays. Chromosomal instability index as measured by changes in DNA copy number was significantly higher in HG than in LG serous carcinomas. Hemizygous ch1p36 deletion was common in LG serous carcinomas but was rarely seen in SBT. This region contains several candidate tumor suppressors including miR-34a. In contrast, in HG serous carcinomas, significant numbers of amplifications and deletions, including homozygous deletions, were identified. Among homozygous deletions, loci containing Rb1, CDKN2A/B, CSMD1, and DOCK4 were most common, being present in 10.6%, 6.4%, 6.4%, and 4.3%, respectively, in independent 47 affinity-purified HG serous carcinomas. Except for the CDKN2A/B region, these homozygous deletions were not present in either SBT or LG tumors. Our study provides a genome-wide homozygous deletion profile in HG serous carcinomas, which can serve as a molecular foundation to study tumor suppressors in ovarian cancer. [Cancer Res 2009;69(9):4036–42]

Low-grade ovarian serous carcinoma (LGSOC) has clinical features different from high-grade serous ovarian carcinoma (HGSOC) accounting for the majority of epithelial ovarian cancer. Because of its rarity, previous studies have only focused on the high-grade disease without considering the differences between the two subtypes. This study aimed to evaluate the effect of the clinical prognostic factors known for HGSOC on survival in patients with LGSOC. Based on the Federation of Gynecology and Obstetrics (FIGO) stage, progression-free survival (PFS) was markedly decreased in advanced disease compared with early disease. For stage I, patients with stage IC had poorer survival than those with stage IA and IB regardless of the number of cycles of adjuvant chemotherapy. For advanced disease, no gross residual disease after primary cytoreductive surgery was significantly associated with longer PFS when compared with gross residual disease. In multivariate analysis for PFS and overall survival (OS), age, preoperative CA-125, time interval from surgery to chemotherapy, and the number of cycles of adjuvant chemotherapy were not associated with prognosis. Complete cytoreduction was the only independent prognostic factor for PFS (HR 2.45, p = 0.045). Our study revealed that the known prognostic factors in HGSOC did not show any effect on the survival in LGSOC except for FIGO stage and complete cytoreduction.

Ovarian cancer has a high recurrence rate after platinum‐based chemotherapy. To improve the treatment of ovarian cancer and identify ovarian cancer‐specific antibodies, we immunized mice with the human ovarian carcinoma cell line, SKOV‐3, and generated hybridoma clones. Several rounds of screening yielded 30 monoclonal antibodies (mAbs) with no cross‐reactivity to normal cells. Among these mAbs, OV‐Ab 30‐7 was found to target integrin α3 and upregulate p53 and p21, while stimulating the apoptosis of cancer cells. We further found that binding of integrin α3 by OV‐Ab 30‐7 impaired laminin‐induced focal adhesion kinase phosphorylation. The mAb alone or in combination with carboplatin and paclitaxel inhibited tumor progression and prolonged survival of tumor‐bearing mice. Moreover, immunohistochemical staining of ovarian patient specimens revealed higher levels of integrin α3 in cancer cells compared with normal cells. By querying online clinical databases, we found that elevated ITGA3 expression in ovarian cancer is associated with poor prognosis. Taken together, our data suggest that the novel mAb, OV‐Ab 30‐7, may be considered as a potential therapeutic for ovarian cancer., The novel mAb, OV‐Ab 30‐7, can induce ovarian cancer cell apoptosis, and blockage integrin‐laminin signaling, and may be considered as a potential therapeutic for ovarian cancer.

Background DNA mismatch repair (MMR) proteins form 2 heterodimers-MutSα formed by MSH2 and MSH6, and MutLα by MLH1 and PMS2. In endometrial endometrioid adenocarcinomas, cases with MMR protein defect also usually harbor other recurrent genetic mutations of the neoplasm. However, it remains unknown whether defects of the 2 functionally different heterodimers are linked to mutations in different genes. We aimed to study the MMR protein expression, microsatellite instability (MSI), and other common genetic mutations of endometrial endometrioid adenocarcinoma. Materials and methods We investigated the MSI status of 107 endometrial endometrioid adenocarcinoma patients. MMR protein expression, and mutation of KRAS, CTNNB1, and PIK3CA were also evaluated by immunohistochemistry and sequencing. Results An overall 34.6% (37/107) of endometrial endometrioid adenocarcinomas were MSI-H. All MSI-H tumors exhibited loss of MMR protein expression (loss of MLH1, PMS2, MSH6, and MSH2 was noted in 22, 25, 12, and 7 cases, respectively). CTNNB1, PIK3CA, and KRAS mutation were present in 9, 7, and 7 MSI-H tumors. Compared with patients with loss of PMS2 and/or MLH1 expression, patients with loss of MSH6 and/or MSH2 expression were associated with higher frequencies of CTNNB1 mutation (P=0.036) and PIK3CA mutation (P=0.025). Conclusions In MSI-H endometrial endometrioid adenocarcinomas, different types of MMR protein deficiency indicate different molecular genetic alterations.

To assess deep convective parameterizations in a variety of GCMs and examine the fast-time-scale convective transition, a set of statistics characterizing the pickup of precipitation as a function of column water vapor (CWV), PDFs and joint PDFs of CWV and precipitation, and the dependence of the moisture–precipitation relation on tropospheric temperature is evaluated using the hourly output of two versions of the GFDL Atmospheric Model, version 4 (AM4), NCAR CAM5 and superparameterized CAM (SPCAM). The 6-hourly output from the MJO Task Force (MJOTF)/GEWEX Atmospheric System Study (GASS) project is also analyzed. Contrasting statistics produced from individual models that primarily differ in representations of moist convection suggest that convective transition statistics can substantially distinguish differences in convective representation and its interaction with the large-scale flow, while models that differ only in spatial–temporal resolution, microphysics, or ocean–atmosphere coupling result in similar statistics. Most of the models simulate some version of the observed sharp increase in precipitation as CWV exceeds a critical value, as well as that convective onset occurs at higher CWV but at lower column RH as temperature increases. While some models quantitatively capture these observed features and associated probability distributions, considerable intermodel spread and departures from observations in various aspects of the precipitation–CWV relationship are noted. For instance, in many of the models, the transition from the low-CWV, nonprecipitating regime to the moist regime for CWV around and above critical is less abrupt than in observations. Additionally, some models overproduce drizzle at low CWV, and some require CWV higher than observed for strong precipitation. For many of the models, it is particularly challenging to simulate the probability distributions of CWV at high temperature.

DNA damage response (DDR) is important for maintaining genomic integrity of the cell. Aberrant DDR pathways lead to accumulation of DNA damage, genomic instability and malignant transformations. Gene mutations have been proven to be associated with epithelial ovarian cancer, and the majority of the literature has focused on BRCA. In this study, we investigated the somatic mutation of DNA damage response genes in epithelial ovarian cancer patients using a multiple-gene panel with next-generation sequencing. In all, 69 serous, 39 endometrioid and 64 clear cell carcinoma patients were enrolled. Serous carcinoma patients (69.6%) had higher percentages of DDR gene mutations compared with patients with endometrioid (33.3%) and clear cell carcinoma (26.6%) (p &lt, 0.001, chi-squared test). The percentages of DDR gene mutations in patients with recurrence (53.9 vs. 32.9% p = 0.006, chi-squared test) or cancer-related death (59.2 vs. 34.4% p = 0.001, chi-squared test) were higher than those without recurrence or living patients. In endometrioid carcinoma, patients with ≥2 DDR gene mutations had shorter PFS (p = 0.0035, log-rank test) and OS (p = 0.015, log-rank test) than those with one mutation or none. In clear cell carcinoma, patients with ≥2 DDR gene mutations had significantly shorter PFS (p = 0.0056, log-rank test) and OS (p = 0.0046, log-rank test) than those with 1 DDR mutation or none. In the EOC patients, somatic DDR gene mutations were associated with advanced-stage tumor recurrence and tumor-related death. Type I EOC patients with DDR mutations had an unfavorable prognosis, especially for clear cell carcinoma.

Predicting human intention in vehicles, pedestrians and bicyclists interactions can help autonomous vehicles and human drivers to plan their routes in a safer manner and better optimise the use of road space. Several studies have studied human intention when interacting with other agents at crossroads using handcrafted features, motif analyses, and machine learning approaches. Yet, many of them are limited in accuracy due to relatively insufficient consideration of surrounding agents and limited observations (occlusions and inaccurate estimation of pose and location) confined by camera angles. This study utilised a multi-branch Gated Recurrent Unit encoder-decoder (MBGED) model to predict the intention of pedestrians and bicyclists when contenting with vehicles at intersections by analysing the properties of directly and indirectly involved road agents. This study identified decisive factors of human intention and constructed an encoder-decoder architecture based on those factors. The network was trained, validated, and tested on unsignalised and uncontrolled intersections. The system predicted the intention of vulnerable road users with 96% accuracy, 91% precision, and 93% recall at 2 seconds before the intersections happen, which could provide a reliable reference for autonomous vehicle navigation and advanced driver assistant systems.

In East Asia, the breast cancer incidence rate among women aged APOA1/C3/A4/A5, a lipid-metabolizing gene cluster (33 vs. 10%, P APOA1/C3/A4/A5 expressions than tumors of Western patients. These copy number loss related– and GE–related results were validated in another Taiwanese cohort and in two GE datasets, respectively. The copy number loss was significantly associated with poor survival among Western patients, but not among East Asian patients. Lower APOA1, APOC3, and APOA5 expressions were associated with higher ESTIMATE immune scores, indicating an abundance of tumor-infiltrating immune cells. In conclusion, APOA1/C3/A4/A5 copy number loss was more prevalent in luminal breast tumors among East Asian women aged

Uterine mesenchymal tumors are genetically heterogenous; those with uniform cytomorphology, best exemplified by endometrial stromal tumors, often contain various fusion genes. Novel fusions involving ESR1 and GREB1, key factors in sex hormone pathways, have been implicated in rare uterine mesenchymal tumors. Particularly, the fusions between 5'-ESR1/GREB1 and 3'-NCOA2/NCOA3 were recently identified in 4 uterine tumors resembling ovarian sex-cord tumor (UTROSCT). By RNA sequencing, pathology review, and FISH screening, we identified 4 uterine sarcomas harboring rearranged GREB1, including GREB1-NCOA2 and the novel GREB1-NR4A3, GREB1-SS18, and GREB1-NCOA1, validated by RT-PCR and/or FISH. They occurred in the myometrium of postmenopausal women and were pathologically similar despite minor differences. Tumor cells were generally uniform and epithelioid, with vesicular nuclei and distinct to prominent nucleoli. Growth patterns included solid sheets, trabeculae/cords, nests, and fascicles. Only 1 tumor showed small foci of definitive sex-cord components featuring well-formed tubules, retiform structures, Leydig-like cells, and lipid-laden cells and exhibiting convincing immunoreactivity to sex-cord markers (calretinin, α-inhibin, and Melan-A). In contrast, all the 4 classic UTROSCT we collected occurred in premenopausal patients, consisted predominantly of unequivocal sex-cord elements, prominently expressed multiple sex-cord markers, and harbored ESR1-NCOA3 fusion. Combined with previously reported cases, GREB1-rearranged tumors involved significantly older women (P=0.001), tended to be larger and more mitotically active, showed more variable and often inconspicuous sex-cord differentiation, and appeared to behave more aggressively than ESR1-rearranged UTROSCT. Therefore, these 2 groups of tumors might deserve separate consideration, despite some overlapping features and the possibility of belonging to the same disease spectrum.

Pancreatoblastoma is a rare type of pancreatic cancer in children. Here, we describe a case in which Beckwith-Wiedemann syndrome (BWS) was first suspected because of placental mesenchymal dysplasia. Although the baby did not show the stigmata characteristic of BWS or abnormal peripheral blood methylation, she developed a massive pancreatoblastoma 2 months later. She survived after partial excision of the tumor and chemotherapy. The methylation pattern of the pancreatoblastoma tissue was typical of BWS. Single nucleotide polymorphism (SNP) array analyzes revealed that the pancreatoblastoma tissue had genome-wide loss of maternal alleles. Peripheral blood and nontumor pancreatic tissue showed normal biparental genomic contribution. Interphase fluorescence in situ hybridization analysis with centromeric probes for chromosomes 2 and 11 revealed haploid pancreatoblastoma cells, whereas the placental mesenchymal dysplasia tissue and nontumor pancreas tissue showed diploidy. SNP genotype analysis suggested the presence of mosaicism with the pancreatoblastoma tissue having a different paternal haplotype than that of the peripheral blood and nontumor pancreatic tissue. We report for the first time mosaic paternal haploidy associated with pancreatoblastoma. Babies with placental mesenchymal dysplasia, even those without a definitive diagnosis of BWS, need to be closely followed for the occurrence of embryonic tumors.

Purpose To report an outbreak of microsporidial keratoconjunctivitis resulting from a swimming pool in Taiwan. Design Retrospective case series. Methods The records of 13 teenagers (15 eyes) contracting microsporidial keratoconjunctivitis after swimming in a local swimming pool were reviewed. Corneal scrapings were collected in all eyes at a tertiary referred hospital in June 2017. Gram stain, modified Kinyoun acid-fast stain, polymerase chain reaction (PCR), and gene analysis of the microsporidian 16S ribosomal RNA (rRNA) were examined in all 15 cases. Results Symptoms occurred 1–12 days after the water contact. At presentation, all eyes showed nonpurulent conjunctivitis and small, plaque-like epithelial lesions peripherally (n = 6), centrally (n = 3), both peripherally and centrally (n = 5), or centrally with superficial punctate keratopathy (n = 1). During the follow-up period, 10 eyes developed central superficial punctate keratopathy (n = 6) or subepithelial haze or infiltrates, which were distributed centrally (n = 2) or peripherally (n = 3), following development of plaque-like epithelial lesions. The results of Gram stain and modified Kinyoun's acid-fast stain were confirmatory in 10 cases (67%). All 15 cases yielded positive PCR results and were all identified to be Vittaforma corneae. All followed-up eyes healed without sequelae using topical levofloxacin and betamethasone eye drops. Conclusions Microsporidial keratoconjunctivitis can develop from contact with swimming pool water. The clinical course initially manifested as rapidly resolving conjunctivitis and peripheral plaque-like epithelial lesions, followed by paracentral or central plaque-like epithelial lesions, which evolved into subepithelial haze or infiltrates.

Aims MED12 exon 2 mutations have been identified in most uterine leiomyomas and mammary fibroepithelial tumours. MED12 has not been genotyped in most other gynaecological mesenchymal tumours. The purpose of this study was to determine the prevalence of MED12 mutations in uncommon gynaecological mesenchymal tumours. Methods and results Sixty-eight uncommon gynaecological mesenchymal tumours were genotyped for MED12 exon 2, including 27 Mullerian adenosarcomas (including three tentatively diagnosed as ‘variant adenosarcomas’), six cellular angiofibromas, six aggressive angiomyxomas, five angiomyofibroblastomas, five superficial myofibroblastomas, five atypical polypoid adenomyomas, and 14 endometrial stromal sarcomas. Immunohistochemistry for CD10, myogenic markers, hormone receptors, MDM2, and CDK4, and fluorescence in-situ hybridization (FISH) for JAZF1, PHF1 and YWHAE rearrangement, were performed on selected cases. The three ‘variant adenosarcomas’ harboured MED12 exon 2 mutations (including p.L36R hotspot mutation, recurrent p.L39_A50del, and a novel splice site mutation). Three endometrial stromal sarcomas with JAZF1–SUZ12 or JAZF1–PHF1 fusion harboured unprecedented mutations (p.D54G in two, and p.Q48* in one). All remaining tumours were wild-type. The three MED12-mutated ‘variant adenosarcomas’ showed distinctive morphological features, including ‘fibromyomatous’ cytomorphology, a close association with adenomyosis, clustered thick-walled vessels, focal conspicuous hyalinization, and intralymphovascular tumour growth. Features of conventional adenosarcomas, including nuclear atypia, mitotic activity, periglandular condensation, and phyllodes-like architecture, were inconspicuous. All three cases showed immunoreactivity for desmin and hormone receptors, while being negative for MDM2 and CDK4; they showed no JAZF1, PHF1 or YWHAE rearrangement. Despite deep myoinvasion, these tumours followed an indolent clinical course. Conclusions These MED12-mutated adenosarcoma-like tumours might represent a distinct entity that requires more studies for its identification. MED12 exon 2 mutations seemed to have no significant role in other uncommon gynaecological mesenchymal tumours.

Familial amyloid polyneuropathy (FAP) is a rare, hereditary peripheral neuropathy commonly caused by mutations in human transthyretin (TTR) gene. Clinically, FAP caused by TTR mutations (TTR-FAP) involves both large and small nerve fibers. Details of early electrophysiological features in TTR-FAP remain unclear. To address this issue, we evaluated nerve excitability (NET) results in motor axons of control mice and two transgenic mouse models carrying V30M (TTRV30M) or A97S (TTRA97S) mutations that simulate clinical features of TTR-FAP. Transgenic TTRV30M and TTRA97S mice demonstrated significant increases in latency in hindlimb withdraw tests, as well as, poor rotarod test performance, compared to TTRORF mice. NET evaluation showed reduced S2 accommodation, and increased TEdundershoot during threshold electrotonus (TE) in motor axons of both TTRV30M and TTRA97S mice, indicating that axonal membranes were in a depolarized state. Decreased rheobase combined with increased refractoriness in the transgenic mice suggested that there were reduced sodium currents. Further immunohistochemical study of the sciatic nerves revealed the significantly decrease of voltage-gated sodium channel expression in the transgenic mice. Moreover, superexcitability during the recovery cycle is significantly increased in transgenic mice compared with control mice, which is attributed to increased internodal capacitance. Finally, the electron microscopy demonstrated the reduced g-ratio in TTRA97S mice may correlate with an atrophic change of axons and/or increase of myelin thickness. In summary, we evaluated NET results in transgenic mice which modeled the clinical features presented in TTR-FAP patients. Reduced sodium channel expression and increased internodal capacitance are factors contributing to the electrophysiological changes in TTR-FAP.

Purpose: To determine the prevalence, clinical manifestations, and treatment outcomes of IgG4-related ophthalmic disease (IgG4-ROD) in previously diagnosed idiopathic orbital inflammation (IOI).Mat...

Epithelial ovarian cancer patients usually relapse after primary management. We utilized the support vector machine algorithm to develop a model for the chemo-response using the Cancer Cell Line Encyclopedia (CCLE) and validated the model in The Cancer Genome Atlas (TCGA) and the GSE9891 dataset. Finally, we evaluated the feasibility of the model using ovarian cancer patients from our institute. The 10-gene predictive model demonstrated that the high response group had a longer recurrence-free survival (RFS) (log-rank test, p = 0.015 for TCGA, p = 0.013 for GSE9891 and p = 0.039 for NTUH) and overall survival (OS) (log-rank test, p = 0.002 for TCGA and p = 0.016 for NTUH). In a multivariate Cox hazard regression model, the predictive model (HR: 0.644, 95% CI: 0.436&ndash, 0.952, p = 0.027) and residual tumor size &lt, 1 cm (HR: 0.312, 95% CI: 0.170&ndash, 0.573, p &lt, 0.001) were significant factors for recurrence. The predictive model (HR: 0.511, 95% CI: 0.334&ndash, 0.783, p = 0.002) and residual tumor size &lt, 1 cm (HR: 0.252, 95% CI: 0.128&ndash, 0.496, p &lt, 0.001) were still significant factors for death. In conclusion, the patients of high response group stratified by the model had good response and favourable prognosis, whereas for the patients of medium to low response groups, introduction of other drugs or clinical trials might be beneficial.

The objective of this article was to report the clinicopathological characteristics, treatment modalities, and outcomes of patients with clear cell carcinoma (CCC) of the abdominal wall. Medical records of six patients diagnosed with CCC of the abdominal wall between May 2003 and May 2018 at the National Taiwan University Hospital were reviewed. All patients had prior obstetric or gynecologic surgeries. The primary clinical presentation was enlarging abdominal masses at previous surgical scars. Four patients underwent initial/primary surgeries with/without adjuvant chemotherapy. One patient received neoadjuvant chemotherapy followed by surgical intervention and adjuvant chemotherapy, the other received chemotherapy and sequential radiotherapy without any surgical intervention. Two of four patients undergoing initial/primary surgeries had disease recurrence and the remaining two cases without initial surgery experienced disease progression during primary treatment. Inguinal lymph nodes were the most frequent sites of recurrence. In conclusion, previous obstetric or gynecologic surgery can be a risk factor for CCC of the abdominal wall. Complete resection of abdominal wall tumor and suspected intra-abdominal lesions with hysterectomy and bilateral inguinal lymph nodes dissection may be the primary treatment. Adjuvant chemotherapy would be considered for potential benefits. For patients without bilateral inguinal lymph nodes dissection, careful inguinal lymph node palpation during postoperative surveillance is necessary. More cases are still needed to elucidate the clinical management of this disease.

Aims Our study aimed to investigate the influence of different glycemic statuses and their fasting plasma glucose/2-hour post-load glucose on uric acid level. Methods A total of 14,787 subjects were recruited after excluding subjects with medication for hyperuricemia or diabetes. Fasting plasma glucose (FPG), 2-hour post-load glucose (2hPG), and uric acid (UA) were measured. Then, subjects were divided into normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetes. Results After adjustment for clinical variables, in NGT group, there was no significant relationship found between UA level and FPG. However, there was a positive association between UA level and 2hPG (β = 0.003, 95% CI: 0.002~0.004). A similar trend was also observed between UA level and 2hPG in IFG group (β = 0.004, 95% CI: 0.000~0.009) and IGT group (β = 0.005, 95% CI: 0.002~0.008), but relationship between UA level and FPG remained insignificant. In diabetes group, UA level was negatively associated with both FPG (β = −0.008, 95% CI: −0.010 ~ −0.007) and 2hPG (β = −0.005, 95% CI: −0.006 ~−0.003). Conclusions In non-diabetic individuals, UA level increased with 2hPG, but not with FPG, and UA level was inversely associated with both FPG and 2hPG in diabetic population.

Müllerian adenosarcomas are malignant gynecologic neoplasms. Advanced staging and sarcomatous overgrowth predict poor prognosis. Because the genomic landscape remains poorly understood, we conducted this study to characterize the genomewide copy number variations in adenosarcomas. Sixteen tumors, including eight with and eight without sarcomatous overgrowth, were subjected to a molecular inversion probe array analysis. Copy number variations, particularly losses, were significantly higher in cases with sarcomatous overgrowth. Frequent gains of chromosomal 12q were noted, often involving cancer-associated genes CDK4 (six cases), MDM2, CPM, YEATS4, DDIT3, GLI1 (five each), HMGA2 and STAT6 (four), without association with sarcomatous overgrowth status. The most frequent losses involved chromosomes 13q (five cases), 9p, 16q and 17q (four cases each) and were almost limited to cases with sarcomatous overgrowth. MDM2 and CDK4 amplification, as well as losses of RB1 (observed in two cases) and CDKN2A/B (one case), was verified by FISH. By immunohistochemistry, all MDM2/CDK4-coamplified cases were confirmed to overexpress both encoded proteins, whereas all four cases with (plus an additional four without) gain of HMGA2 overexpressed the HMGA2 protein. Both cases with RB1 loss were negative for the immunostaining of the encoded protein. Chromothripsis-like copy number profiles involving chromosome 12 or 14 were observed in three fatal cases, all of which harbored sarcomatous overgrowth. With whole chromosome painting and deconvolution fluorescent microscopy, dividing tumor cells in all three cases were shown to have scattered extrachromosomal materials derived from chromosomes involved by chromothripsis, suggesting that this phenomenon may serve as visual evidence for chromothripsis in paraffin tissue. In conclusion, we identified frequent chromosome 12q amplifications, including loci containing potential pharmacological targets. Global chromosomal instability and chromothripsis were more frequent in cases with sarcomatous overgrowth. To our knowledge, this is the first time that evidence of chromothripsis has been demonstrated in paraffin-embedded clinical tissues and in adenosarcomas.

Background: Intravascular leiomyomatosis (IVL) is relatively rare. The optimal surgical method and long-term outcomes are not completely understood. Methods: Medical records between 2007 and 2017 in our hospital were analyzed to identify IVL cases with surgical intervention. Their medical records, operative details, and follow-up were collected by chart review and telephone communication. Results: Eight patients with IVL were included in the study, accounting for 0.26% of all uterine leiomyoma cases. Primary IVL was confined to pelvic cavity in three patients, extended to the inferior vena cava (IVC) below renal vein in one, reached IVC and right atrium in three, and reached main pulmonary artery in one. One-stage operation was performed for seven patients. Cardiopulmonary bypass was done in four patients, and aortic cross-clamp and temporary circulatory arrest was performed in two patients. None of the four patients with intrapulmonary tumors received concomitant pulmonary tumor resection. There was no operative mortality and four morbidities, including ureter injury (2), bladder injury (1), and femoral vein thrombosis (1). During follow-up, two patients exhibited local recurrence of the tumor in the pelvis, and one patient had rapidly growing intrapulmonary tumor three months post-operatively. Intrapulmonary tumors in the other three patients remained stationary at 6, 84, and 120 months post-operatively. Conclusion: One-stage operation to completely remove IVL is feasible and with good long-term outcomes, which is recommended if the patient can tolerate the operation. Concomitant intrapulmonary tumors can be followed up watchfully except when associated with pleural effusion or the pathology indicating trend of increasing malignancy. Keywords: Intravascular leiomyomatosis, Intracardiac leiomyomatosis, Cardiac tumor, Surgery, Cardiopulmonary bypass, Follow-up

Merkel cell carcinoma (MCC), an uncommon and highly aggressive cutaneous malignancy, usually occurs on the sun-damaged skin of the elderly and is characterized by coexpression of neuroendocrine markers and CK20, a discriminant from other types of visceral neuroendocrine neoplasias. Since the discovery of Merkel cell polyomavirus (MCV), many researchers have confirmed its presence in about 80% of cutaneous MCCs.1 Although some cutaneous MCCs were reported to be associated with squamous cell carcinomas (SCCs), such combined cases accounted for only a minor portion and the viral status appeared to be different from pure MCC.1, 2, 3, 4 Rarely, primary MCCs occur on the female vulva,5 with or without combined SCCs,6, 7 the latter is often human papillomavirus (HPV) related.

Proteus mirabilis is a common human pathogen causing recurrent or persistent urinary tract infections (UTIs). The underlying mechanisms for P. mirabilis to establish UTIs are not fully elucidated. In this study, we showed that loss of the sigma factor E (RpoE), mediating extracytoplasmic stress responses, decreased fimbria expression, survival in macrophages, cell invasion, and colonization in mice but increased the interleukin-8 (IL-8) expression of urothelial cells and swarming motility. This is the first study to demonstrate that RpoE modulated expression of MR/P fimbriae by regulating mrpI , a gene encoding a recombinase controlling the orientation of MR/P fimbria promoter. By real-time reverse transcription-PCR, we found that the IL-8 mRNA amount of urothelial cells was induced significantly by lipopolysaccharides extracted from rpoE mutant but not from the wild type. These RpoE-associated virulence factors should be coordinately expressed to enhance the fitness of P. mirabilis in the host, including the avoidance of immune attacks. Accordingly, rpoE mutant-infected mice displayed more immune cell infiltration in bladders and kidneys during early stages of infection, and the rpoE mutant had a dramatically impaired ability of colonization. Moreover, it is noteworthy that urea (the major component in urine) and polymyxin B (a cationic antimicrobial peptide) can induce expression of rpoE by the reporter assay, suggesting that RpoE might be activated in the urinary tract. Altogether, our results indicate that RpoE is important in sensing environmental cues of the urinary tract and subsequently triggering the expression of virulence factors, which are associated with the fitness of P. mirabilis , to build up a UTI.

Recently, mutations of telomerase reverse transcriptase (TERT) promoter were found in several types of cancer. A few reports demonstrate TERT promoter mutations in ovarian clear cell carcinomas but endometrial clear cell carcinoma has not been studied. The aims of this study were to compare differences of molecular alterations and clinical factors, and identify their prognostic impact in endometrial and ovarian clear cell carcinomas. We evaluated mutations of the TERT promoter and PIK3CA, expression of ARID1A, and other clinicopathological factors in 56 ovarian and 14 endometrial clear cell carcinomas. We found that TERT promoter mutations were present in 21% (3/14) of endometrial clear cell carcinomas and 16% (9/56) of ovarian clear cell carcinomas. Compared with ovarian clear cell carcinomas, endometrial clear cell carcinomas showed older mean patient age (P0.001), preserved ARID1A immunoreactivity (P=0.017) and infrequent PIK3CA mutation (P=0.025). In ovarian clear cell carcinomas, TERT promoter mutations were correlated with patient age45 (P=0.045) and preserved ARID1A expression (P=0.003). In cases of endometrial clear cell carcinoma, TERT promoter mutations were not statistically associated with any other clinicopathological factors. In ovarian clear cell carcinoma patients with early FIGO stage (stages I and II), TERT promoter mutation was an independent prognostic factor and correlated with a shorter disease-free survival and overall survival (P=0.015 and 0.009, respectively). In recurrent ovarian clear cell carcinoma patients with early FIGO stage, TERT promoter mutations were associated with early relapse within 6 months (P=0.018). We concluded that TERT promoter mutations were present in endometrial and ovarian clear cell carcinomas. Distinct molecular alteration patterns in endometrial and ovarian clear cell carcinomas implied different processes of tumorigenesis in these morphologically similar tumors. In ovarian clear cell carcinoma of early FIGO stage, patients with TERT promoter mutation require close follow-up during the initial 6 months following chemotherapy.

The ultra-slim flexible glass is demonstrated as the substrate with metal meshed antenna for developing thinner, lighter and fulltransparent smart devices. The linewidth and spacing of the meshed grids are 3 µm and 200–300 µm. The return loss of the mesh antenna has good performance (

Epithelioid trophoblastic tumor (ETT) is a rare chemoresistant gestational trophoblastic neoplasm that typically presents as an intrauterine lesion. To our knowledge, no isolated abdominal wall ETT around a Cesarean scar has been reported. Here we describe a 54-yr-old woman with a complex obstetric history who presented with a solitary abdominal wall tumor adjacent to the abdominal Cesarean section scar. The tumor demonstrated typical morphologic and immunophenotypic features of ETT. The gestational origin of the tumor was confirmed by microsatellite genotyping. The tumor enlarged despite the patient undergoing multiagent chemotherapy. Whole-exome sequencing was performed to explore the mechanisms underlying chemoresistance. The ATP-binding cassette subfamily B member 1 (ABCB1) 3435CC genotype, and a putative deleterious x-ray cross-complementing group 4 (XRCC4) Ala73Pro mutations were found. In conclusion, ETT may present as a solitary abdominal wall lesion and microsatellite genotyping could facilitate the determination of its gestational origin. More studies are required to provide mechanistic insights into the chemoresistance of ETT.

Hematopoietic stem cell transplant (HSCT) recipients have a higher risk of cervical cancer. Papanicolaou (Pap) smear is the standard tool for screening cervical cancer, but there is limited research about the cervical cytology in HSCT recipients. Here, we retrospectively included adult female patients who underwent allogeneic or autologous HSCT at National Taiwan University Hospital during 2009 to 2015 and reviewed their Pap smears before and after HSCT. There were 248 allogeneic and 131 autologous HSCT recipients in our study. In allogeneic HSCT recipients, 38.7% (96 of 248) had pre-HSCT Pap smears and 17.1% (44 of 248) had post-HSCT Pap smears. In the autologous HSCT recipients, 35.1% (46 of 131) had pre-HSCT Pap smears and 13.7% (18 of 131) had post-HSCT Pap smears. Compared with allogeneic HSCT recipients without post-HSCT Pap smears, more recipients with post-HSCT Pap smears received bone marrow-derived stem cells (18.2% versus 4.9% respectively; P = .0077) and had longer overall survival (median overall survival, not reached versus 22.1 months; P .0001). The abnormal rates of post-HSCT Pap smear were 13% (6 of 44) and 11% (2 of 18) in allogeneic and autologous recipients respectively, higher than in the general Taiwanese population (1.22%). Infections were rare in post-HSCT Pap smears. Of note, 11% (5 of 44) of post-HSCT Pap smears from allogeneic recipients showed therapy-related atypia, manifesting as enlarged hyperchromatic nuclei, vacuolated cytoplasm, and occasional tadpole-like cells. These atypical cytological features mimic precancerous lesions, but cervical biopsies and human papilloma virus tests were negative. The atypical cytological features resolved spontaneously in the subsequent follow-up Pap smears. On average, Pap smears with therapy-related atypia were sampled at day +77, significantly earlier than those without therapy-related atypia (P = .016). Therapy-related atypia was more frequent in post-HSCT Pap smears sampled within 100 days after HSCT (before day +100, 4 of 5, 80%, versus after day +100, 1 of 39, 2.56%; P = .0002). The strong temporal relationship suggests these atypical cytological changes resulted from conditioning regimen, most likely busulfan-containing chemotherapy. No therapy-related atypia were observed after total body irradiation or nonbusulfan-containing chemotherapy. In conclusion, therapy-related atypia was common in post-HSCT Pap smears sampled within 100 days after HSCT. Clinical information is critical for correct cytological diagnosis.