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Background/purpose To compare the clinical outcomes of Taiwanese patients with ovarian clear cell carcinomas (CCCs) and serous carcinomas (SCs). Methods We retrieved the clinical records of women with epithelial ovarian cancer (Stage I–IV) who received primary surgeries between 2000 and 2013. Cancer-specific survival (CSS), progression-free survival, and survival after recurrence (SAR) of CCC and SC patients were retrospectively compared. Multivariate analysis was used to identify the independent predictors of survival. Results Of 891 women diagnosed with epithelial ovarian cancer, 169 CCCs and 351 high-grade SCs were analyzed. The 5-year CSS rates of CCC patients were significantly lower than those of SC for both Stage III (22.3% vs. 47.3%, p = 0.001) and Stage IV (0% vs. 24.4%, p = 0.001) disease. In the absence of gross residual malignancies, the 5-year CSS rate was better for CCC (82.3%) than SC (75.2%, p = 0.010). The 5-year SAR rate was significantly lower for CCC than SC (14.3% vs. 24.4%, p = 0.002). Old age and residual malignancies were independent prognostic factors for CSS in the entire cohort of CCC patients. In the subgroup of Stage I CCC, positive cytology was identified as the only adverse prognostic factor for CSS. Conclusion The clinical outcomes of CCC are generally poorer than SC. Complete cytoreduction to no gross residual disease should be ideally achieved in CCC patients. A greater understanding of the molecular pathogenesis of CCC may lead to tailored therapies, ultimately optimizing outcomes.

Objectives: This multi-center international study (Asian Gynecologic Oncology Group [AGOG]13-001/Taiwanese Gynecologic Oncology Group [TGOG]1006) was to validate human papillomavirus (HPV)16 as an independent prognostic factor of cervical adenocarcinoma and adenosquamous carcinoma (AD/ASC). Methods: Retrospective and prospective collection of patients receiving primary treatment at AGOG and TGOG member hospitals for cervical AD/ASC were enrolled. The cases treated between 1993 and 2014 were retrospectively collected, and the prospective enrollment was started since 2014. Those endometrial origin (by immunohistochemistry and imaging studies) cannot rule out were excluded for analysis. Results: A total of 354 patients were enrolled, 287 (81.1%) of which had HPV-positive tumors. The top-3 types among HPV-positive cases was HPV 18 (50.8%), HPV16 (22.9%) and HPV45 (4.0%). A total of 322 patients were eligible for prognostic analyses. Patient with HPV16-positivity had significantly longer progression-free survival (PFS) and overall survivals (OS) than those without HPV16 (p=0.001 and 0.026, respectively). By multivariate analysis, advanced FIGO stage (HR5.7, 2.4-13.5), lymph node metastasis (HR4.6, 2.7-7.9), tumor size (>4 cm HR3.3), and HPV16-positivity (HR0.3, 0.1-0.7) were independent prognostic factors for PFS. Only the former 2 variables remained significant, while HPV16-positivity was marginally significant (p=0.064) for OS. HPV-negativity rates varied across hospitals, yet it seemed to be increasing over time (4.4% versus 12.5%, p Conclusions: This study confirmed that HPV16-positivity was a good prognostic factor for PFS, yet the increasing HPV-negative AD/ASCs seemed to be a trend that needs attention.

e17563 Background: The histological criteria of predicting risk of progression of endometrial hyperplasia (EH) to endometrial cancer (EC) is based on the degree of architectural crowding and nuclear atypia. We aim to investigate the cumulative rate of progression to EC in simple or complex hyperplasia without atypia (SH/CH-nonA) and the molecular biomarkers for risk of developing EC in women with SH/CH-nonA. Methods: EH tissues of EC patients with preceding SH/CH-nonA (case) were compared to SH/CH-nonA patients without progression to EC (control) using miRNA array, followed by reverse transcription and quantitative real-time polymerase chain reaction (RT-qPCR), and verified in an independent cohort. Results: The 10-year and 15-year cumulative rates were 8% and 10%, respectively by the hospital medical records. The median time from EH to EC was 8.71 years (range, 0.55-19.84). Twenty miRNAs (p < 0.05, fold change > 4) were significantly different in SH/CH-nonA cases (n = 6) compared to SH/CH-nonA controls (n = 12) by miRNA array. Multiplex RT-qPCR validation (51 SH/CH-nonA controls and 19 SH/CH-nonA cases) selected miR30a-3p, miR141, miR200a, and miR200b. Area under the curve values for tissue miR30a-3p (p = 0.043), miR141(p = 0.003), miR-200a (p < 0.001), and miR200b (p = 0.004) in discriminating cases from controls were 0.658, 0.734, 0.811, and 0.710, and the sensitivity and specificity rates were 56.9% and 76.5%, 73.7% and 74.5%, and 68.4% and 100%, 47.4% and 100%, respectively. Conclusions: MiR30a-3p, miR141, miR-200a, and miR200b are useful tissue biomarkers for predicting future risk of developing EC for patients with SH/CH-nonA.

With aging and stress, the myocardium undergoes structural remodeling, often leading to fibrosis. The purpose of this study is to examine whether lumican, one of the class II small leucine-rich proteoglycans, has a protective role in cardiac remodeling and fibrosis. In attempts to elucidate the hypothesis that lumican may have a protective role in cardiac remodeling and fibrosis, we compared the cardiac phenotypes of young (3-month-old) and elder (6-month- and 12-month-old) lumican-null (Lum-/-) mice. Extra-cellular matrix remodeling and apoptosis are examined to determine the roles of lumican on age-dependent cardiac fibrosis induced by isoproterenol. Compared to wild type littermates, Lum-/- mice exhibited higher mortality due to significantly impaired systolic function, which was associated with an increase of atrial natriuretic peptide (ANP) secreted by the ventricles in response to excessive stretching of myocytes. Masson's Trichrome and silver stains showed significantly more severe ventricle fibrosis in Lum-/- mice. Interestingly, rate of cell death mediated via apoptosis illustrated by the expression of caspase 3 and TUNEL assay was lower in Lum-/- mice after isoproterenol infusion. In addition, Lum-/- mice exhibited higher levels of TGF-β, collagen I/III, and membrane-type matrix metalloproteinase-1 (MT1-MMP/MMP-14) during cardiac remodeling. This study shows that alternations of lumican might be implicated in the pathogenesis of cardiac fibrosis and suggests lumican as novel targets for cardiac fibrosis therapy. Further studies are required to define the mechanism by which lumican modulates cardiac remodeling.

Background: Local chemotherapy with carmustine (BCNU) wafer implantation has survival benefits for malignant glioma patients. However, available data regarding its association with O6-methylguanine-DNA-methyltransferase (MGMT) are scant. Purpose: To evaluate whether MGMT hypermethylation has prognostic effects in malignant glioma patients with interstitial BCNU wafer implants. Methods: From September 2004 to August 2007, 32 patients with malignant gliomas underwent surgical resection plus interstitial BCNU wafer implantation at our hospital. Results and Conclusion: BCNU wafer implantation was performed in 18 patients with newly diagnosed gliomas and in 14 with recurrent gliomas. All patients had a Karnofsky performance status of ≥70. The median age was 51 years. At a median follow-up of 31 months, the 1- and 2-year overall survival (OS) rate was 43% and 22%, respectively. OS rates did not significantly differ between the newly diagnosed and recurrent patients. Gross total tumor resection was achieved in 19 (59%) patients, and MGMT hypermethylation was noted in 13 (41%) tumor specimens. Multivariate analysis demonstrated that patients with MGMT hypermethylation in their tumors and gross total tumor removal have more favorable survival rates (P = 0.03).

Background Neurenteric cysts are rare central nervous system lesions derived from an endodermal origin. There is no consensus concerning pathogenesis because of the paucity of occurrences. We report an immunohistochemical study of 10 cases with neurenteric cysts and postulate its pathogenesis. Methods Ten patients underwent surgical treatment for neurenteric cysts from 1995 to 2015. We retrospectively reviewed clinical, radiologic, operative, and pathologic findings for these patients. Immunohistochemical stains were completed in all cases to distinguish cell type and origin. Results Three cell types were identified: pseudostratified-ciliated, goblet-columnar, and simple cuboidal cells. All cases were positive for cytokeratin 7, and negative for cytokeratin 20, caudal-type homeobox 2, mucin 2, thyroid transcription factor 1, human chorionic gonadotropin, placental alkaline phosphatase, and cluster of differentiation 31. Four of them had positive staining for mucin 5AC, with expression only in goblet-columnar cells. According to the immunohistochemical results, the cells resembled the respiratory tract (pseudostratified-ciliated), stomach (goblet-columnar), and respiratory bronchioles (simple cuboidal). Seventy-five percent of cases with recurrence had a goblet-columnar component, emphasizing the importance of total resection of the cyst and complete pathologic examination. Conclusions We postulate that the cystic tumor was derived from multipotent endodermal cells that migrated and traveled along the neuroectoderm, with incomplete differentiation into various cell types as a result of an unsuitable microenvironment. Because the neurenteric canal was only the channel of migration rather than a component of the cysts, the term neuroendodermal cysts is more precise in presenting the embryopathogenesis.

Objectives Synchronous endometrial and ovarian carcinomas (SEOCs) present gynecologic oncologists with a challenging diagnostic puzzle: discriminating between double primary cancers and single primary cancer with metastasis. We aimed to determine the clonal relationship between simultaneously diagnosed endometrial and ovarian carcinomas. Methods Fourteen pairs of SEOCs of endometrioid type and two pairs of SEOCs with disparate histologic types (control for dual primary tumors) were subjected to massively parallel sequencing (MPS) and molecular inversion probe microarrays. Results Thirteen of the 14 pairs of SEOCs harbored somatic mutations shared by both uterine and ovarian lesions, indicative of clonality. High degree of chromosomal instability in the tumors from 10 patients who received adjuvant chemotherapy, of whom 9 had synchronous carcinomas with significantly overlapping copy number alterations (CNAs), suggestive of single primary tumors with metastasis. The clonal relationship determined by genomic analyses did not agree with clinicopathological criteria in 11 of 14 cases. Minimal CNAs were identified in both ovarian and endometrial carcinomas in 4 patients, who did not receive adjuvant chemotherapy and experienced no recurrent diseases. In contrast, two of the 10 patients with chromosomally unstable cancers developed recurrent tumors. Conclusion Our findings support a recent paradigm-shifting concept that most SEOCs originate from a single tumor. It also casts doubt on the clinicopathological criteria used to distinguish between dual primary tumors and single primary tumor with metastasis. Testing of CNAs on SEOCs may help determining the need of adjuvant therapy.

OBJECTIVES An Asian Gynecologic Oncology Group phase III randomized trial was conducted to determine whether maintenance chemotherapy could improve progression-free survival (PFS) in stages III/IV ovarian cancer. METHODS Between 2007 and 2014, 45 newly-diagnosed ovarian cancer patients were enrolled after complete remission and randomized (1:1) to arm A (4-weekly carboplatin area under the curve 4 and pegylated liposomal doxorubicin [PLD] 30 mg/m², n=24) for 6 cycles or arm B (observation, n=21). The primary end-point was PFS. A post hoc translational study was conducted to deep sequence BRCA/homologous recombination deficiency (HRD) genes, because BRCA/HRD mutations (BRCA/HRDm) are known to be associated with better prognosis. RESULTS Enrollment was slow, accrual was closed when 7+ years had passed. With a median follow-up of 88.9 months, the median PFS was significantly better in arm A (55.5 months) than arm B (9.2 months) (hazard ratio [HR]=0.40; 95% confidence interval [CI]=0.19-0.87; p=0.020), yet the median overall survival was not significantly different in arm A (not reached) than arm B (95.1 months) (p=0.148). Overall grade 3/4 adverse events were more frequent in arm A than arm B (60.9% vs 0.0%) (p

Pituicytoma is a rare low-grade glioma arising from the pituicytes of the posterior pituitary. To date, the clinical and pathological correlates of pituicytoma have not been investigated. This study was thus designed to examine the correlation between pituicytoma and the normal pituitary gland.The records of patients who underwent pituitary surgery at Chang Gung Memorial Hospital in Linkou, Taiwan between 2000 and 2016 were reviewed. Patients who received a pathological diagnosis of pituicytoma were included; however, those with inadequate specimens for pathological study were excluded. Clinical information, including patients' presenting symptoms, serum hormone levels, neuroimages, and specimens, were collected. Hematoxylin and eosin stains and immunohistochemical (IHC) stains were performed for differential diagnosis.Among the 1532 patients who underwent pituitary surgery, nine (0.59%) received a pathological diagnosis of pituicytoma. Two patients were excluded due to inadequate specimens. Among the seven remaining patients, six presented with hormone changes. The IHC stains revealed that pituicytoma has no secretory function; however, the resected pituitary glands showed positive results for hormone change. Coexisting pituicytoma and adrenocorticotropic hormone adenoma were identified in one patient with a diagnosis of Cushing disease.Pituicytoma revealed a negative endocrine secretory function through IHC staining. Additionally, pituicytoma is associated with hypersecretion of the pituitary gland both clinically and pathologically. Diagnosing pituicytoma before pathological confirmation is difficult because the tumour may present with hormone dysfunction. Therefore, IHC staining of specimens is useful to exclude the possibility of coexisting pituicytoma and pituitary adenoma.

The objective of this study was to investigate two patients with porphyric neuropathy in a family with acute intermittent porphyria. Molecular analysis of the porphobilinogen deaminase (PBGD) gene was performed. We analyzed the clinical course of peripheral neuropathy and serial changes in nerve conduction studies (NCS) of the two patients. We also examined the pathological findings of sural nerve biopsy in one patient. Molecular analysis of the PBGD gene revealed a missense mutation (Arg26His) in exon 2 for two patients and their family members. Distal polyneuropathy was noted in the patients with chronic porphyric neuropathy. In the follow-up NCS, recovery was relatively poor in the lower limb in one patient with severe polyneuropathy, and NCS evidence of deterioration was found following frequent hormone-related porphyric attacks in another patient. The sural nerve biopsy showed marked loss of myelinated and unmyelinated fibers in one patient with chronic porphyric neuropathy. In contrast to radial and fibular motor nerves in acute porphyric neuropathy, the sural nerve is vulnerable to involvement in chronic porphyric neuropathy following repeated porphyric attack as seen in the NCS.

Solitary fibrous tumor (SFT) is characterized by the inv12(q13q13)-derived NAB2-STAT6 fusion, which exhibits variable breakpoints and drives STAT6 nuclear expression. The implications of NAB2-STAT6 fusion variants in pathological features and clinical behavior remain to be characterized in a large cohort of SFTs. We investigated the clinicopathological correlates of this genetic hallmark and analyzed STAT6 immunoexpression in 28 intrathoracic, 37 extrathoracic, and 23 meningeal SFTs. These 88 tumors were designated as histologically nonmalignant in 75 cases and malignant in 13, including 1 dedifferentiated SFT. Eighty cases had formalin-fixed and/or fresh samples to extract assessable RNAs for RT-PCR assay, which revealed NAB2-STAT6 fusion variants comprising 12 types of junction breakpoints in 73 fusion-positive cases, with 65 (89%) falling into 3 major types. The predominant NAB2ex4-STAT6ex2 (n=33) showed constant breakpoints at the ends of involved exons, whereas the NAB2ex6-STAT6ex16 (n=16) and NAB2ex6-STAT6ex17 (n=16) might exhibit variable breakpoints and incorporate NAB2 or STAT6 intronic sequence. Including 73 fusion-positive and 7 CD34-negative SFTs, STAT6 distinctively labeled 87 (99%) SFTs in nuclei, exhibited diffuse reactivity in 73, but did not decorate 98 mimics tested. In seven fusion-negative cases, 6 were STAT6-positive, suggesting rare fusion variants not covered by RT-PCR assay. Regardless of histological subtypes, intrathoracic SFTs affected older patients (P=0.035) and tended to be larger in size (P=0.073). Compared with other variants, NAB2ex4-STAT6ex2/4 fusions were significantly predominant in the SFTs characterised by intrathoracic location (P

Stress-induced phosphoprotein 1 (STIP1)—a co-chaperone of heat shock proteins—promotes cell proliferation and may act as an oncogenic factor. Similarly, glycogen synthase kinase-3 beta (GSK3β)-mediated phosphorylation of lysine-specific demethylase 1 (LSD1)—an epigenetic regulator—can contribute to the development of an aggressive cell phenotype. Owing to their ability to tether different molecules into functional complexes, scaffold proteins have a key role in the regulation of different signaling pathways in tumorigenesis. Here, we show that STIP1 acts as a scaffold promoting the interaction between LSD1 and GSK3β. Specifically, the TPR1 and TPR2B domains of STIP1 are capable of binding with the AOL domain of LSD1, whereas the TPR2A and TPR2B domains of STIP1 interact with the kinase domain of GSK3β. We also demonstrate that STIP1 is required for GSK3β-mediated LSD1 phosphorylation, which promoted LSD1 stability and enhanced cell proliferation. After transfection of cancer cells with double-mutant (S707A/S711A) LSD1, subcellular localization analysis revealed that LSD1 was translocated from the nucleus to the cytoplasm. In vitro experiments also showed that the LSD1 inhibitor SP2509 and the GSK3β inhibitor LY2090314 acted synergistically to induce cancer cell death. Finally, the immunohistochemical expression of STIP1 and LSD1 showed a positively correlation in human cancer specimens. In summary, our data provide mechanistic insights into the role of STIP1 in human tumorigenesis by showing that it serves as a scaffold for GSK3β-mediated LSD1 phosphorylation. The combination of LSD1 and GSK3β inhibitors may exert synergistic antitumor effects and deserves further scrutiny in preclinical studies.

We investigated whether genomic scar signatures associated with homologous recombination deficiency (HRD), which include telomeric allelic imbalance (TAI), large-scale transition (LST), and loss of heterozygosity (LOH), can predict clinical outcomes in patients with ovarian clear cell carcinoma (OCCC). We enrolled patients with OCCC (n = 80) and high-grade serous carcinoma (HGSC; n = 92) subjected to primary cytoreductive surgery, most of whom received platinum-based adjuvant chemotherapy. Genomic scar signatures based on genome-wide copy number data were determined in all participants and investigated in relation to prognosis. OCCC had significantly lower genomic scar signature scores than HGSC (p 0.001). Near-triploid OCCC specimens showed higher TAI and LST scores compared with diploid tumors (p 0.001). While high scores of these genomic scar signatures were significantly associated with better clinical outcomes in patients with HGSC, the opposite was evident for OCCC. Multivariate survival analysis in patients with OCCC identified high LOH scores as the main independent adverse predictor for both cancer-specific (hazard ratio [HR] = 3.22, p = 0.005) and progression-free survival (HR = 2.54, p = 0.01). In conclusion, genomic scar signatures associated with HRD predict adverse clinical outcomes in patients with OCCC. The LOH score was identified as the strongest prognostic indicator in this patient group.Genomic scar signatures associated with HRD are less frequent in OCCC than in HGSC. Genomic scar signatures associated with HRD have an adverse prognostic impact in patients with OCCC. LOH score is the strongest adverse prognostic factor in patients with OCCC.

Introduction: A case series of acute intermittent porphyria (AIP) is described that focuses on the clinical course of the disease with regard to neurological manifestations of the peripheral nervous system. Methods: Eight patients were diagnosed with AIP on the basis of characteristic clinical findings, erythrocyte porphobilinogendeaminase activity, neuropathic patterns, serial changes in nerve conduction studies (NCS), and temporal relationship of central nervous system involvement. Results: Six patients diagnosed with AIP 2 months after symptom onset had distal sensorimotor polyneuropathy. Conclusions: The findings from this case series suggest that the peripheral nerves may be differentially and selectively involved in different diagnostic stages of porphyric neuropathy. Muscle Nerve 51: 363–369, 2015

Primitive neuro-ectodermal tumors (PNET) are rare malignant brain tumors, mostly undifferentiated, that tend to spread through the cerebrospinal fluid (CSF). Extra-pineal supratentorial PNET in adults are very rare. Published guidelines for adult PNET were not available until 2011, and at our institute surgeons and oncologists did not have consensus on imaging evaluation or treatment protocols between 1994 to 2008. Twenty-two consecutive adult patients with extra-pineal supratentorial PNET from this period were reviewed in this retrospective study. Their clinical profiles and radiologic images were evaluated. A pathological review based on the 2007 World Health Organization criteria was also conducted. Prognostic factors were analyzed. The 1 and 3 year overall survival rates were 64% and 32% for adult extra-pineal supratentorial PNET, respectively. Limited by the small number of tumors in this series, we suggest that negative prognostic factors are multiplicity at onset, initial CSF seeding, and tumor differentiation. Although age of onset, extent of resection, radiation and chemotherapy were assumed to be good prognostic factors, the analysis did not reveal strong significance for overall survival with univariate and multivariate analysis. We believe more detailed investigations on the genetic/molecular basis of supratentorial PNET and their clinical outcomes are warranted.

// Angel Chao 1, 2, * , Ting-Chang Chang 1, 2, * , Nina Lapke 3, * , Shih-Ming Jung 4 , Peter Chi 5 , Chien-Hung Chen 3 , Lan-Yan Yang 6 , Cheng-Tao Lin 1, 2 , Huei-Jean Huang 1, 2 , Hung-Hsueh Chou 1, 2 , Jui-Der Liou 1, 2 , Shu-Jen Chen 3 , Tzu-Hao Wang 1, 2, 7 , Chyong-Huey Lai 1, 2 1 Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan 2 Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan 3 ACTGenomics, Co. Ltd., Taiwan 4 Department of Pathology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan 5 Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taiwan 6 Clinical Trial Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan 7 School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan * These authors have contributed equally to this work Correspondence to: Shu-Jen Chen, email: sjchen@actgenomics.com Tzu-Hao Wang, email: knoxtn@cgmh.org.tw Chyong-Huey Lai, email: laich46@cgmh.org.tw Keywords: BRCA1/2, germline mutations, somatic mutations, ovarian cancer Received: August 20, 2016 Accepted: October 28, 2016 Published: November 19, 2016 ABSTRACT Germline and somatic BRCA1/2 mutations define a subset of patients with ovarian cancer who may benefit from treatment with poly (ADP-ribose) polymerase inhibitors. Unfortunately, data on the frequency of BRCA1/2 germline mutations in Taiwanese patients with ovarian cancer are scarce, with the prevalence of somatic mutations being unknown. We aim to investigate the occurrence of BRCA1/2 mutations in 99 Taiwanese patients with ovarian cancer which included serous (n = 46), endometrioid (n = 24), and clear cell (n = 29) carcinomas. BRCA1/2 mutations were identified using next-generation sequencing of formalin-fixed paraffin-embedded tumor samples. Pathogenic variants ( BRCA1 : n = 7; BRCA2 : n = 6) were detected in 12.1% (12/99) of the study patients. Somatic and germline BRCA1/2 mutation rates in serous ovarian cancer are 4/46 (8.7%) and 8/46 (17%), respectively. All of the pathogenic BRCA1/2 mutations were identified in serous carcinoma samples (12/46; 26.1%). One-third (4/12) of the deleterious BRCA1/2 mutations occurred in tumor tissues only (somatic mutations). All of them coexisted with loss of heterozygosity, resulting in biallelic BRCA inactivation. Five novel pathogenic mutations were identified, including four somatic variants ( BRCA1 p.S242fs, BRCA1 p.F989fs, BRCA1 p.G1738fs, and BRCA2 p.D1451fs) and a germline variant ( BRCA2 p.E260fs). We also detected additional six novel mutations (three in BRCA1 and three in BRCA2) with pathogenic potentials. We conclude that BRCA1/2 mutations are common in Taiwanese patients with serous ovarian carcinoma and similar to mutation rates in other ethnic groups. The analysis of BRCA1/2 somatic mutations is crucial for guiding therapeutic decisions in ovarian cancer.

Oligodendrogliomas occurring rarely in children are incompletely characterized. The purpose of this study was to identify prognostic factors affecting the local control and survival in the management of children with oligodendrogliomas. We retrospectively analyzed clinical data on 20 pediatric patients with oligodendrogliomas treated at Chang Gung Children's Hospital between 1994 and 2014. There were 12 males and 8 females with a median age of 9.2 years at diagnosis (range, 3 mo to 18 y). Eighteen (90%) tumors were located in the cerebral hemispheres, 10 cases were located on the right, 8 on the left. One was located in the third ventricle and 1 in the thoracic spine. Presenting symptoms included seizures (n=7), headache (n=5), visual field defects (n=3), limb weakness (n=2), vomiting (n =1), back pain (n=1), and increased head circumference (n=1). All patients underwent craniotomy: 8 gross total resections, 8 subtotal resections, and 4 biopsies. Nine of the patients had pure oligodendroglioma and 11 had anaplastic oligodendroglioma (WHO grade III or IV). Ten children had adjuvant therapy including radiation (n=7), chemotherapy (n=1) or both (n=2). With the median follow-up of 5.3 years (range, 1.2 to 14.7 y), the 5-year overall survival and disease-free survival rates were 78.9% with 65.0%, respectively. Total tumor resection offers better overall survival regardless of the histologic grading. Our data demonstrate that patients with less than gross total resections are at increased risk for progression and may benefit from more aggressive therapy.

Benign epithelial inclusions are rarely found in peripancreatic lymph nodes and have not been studied by up-to-date immunohistochemistry. Here, we describe 2 cases of benign epithelial inclusions in the peripancreatic lymph nodes with discussion of differential diagnosis. The first case was a 2.2 cm lymph node from a 61-year-old woman with pancreatic ductal adenocarcinoma. The second case was a 4.3 cm lymph node from a 28-year-old man with distal common bile duct cholangiocarcioma. The epithelial inclusions in the first case consisted of several small squamous cell nests with central duct-like lumina. The lymph node from the second case showed convoluted cystic inclusions lined by a single layer of bland cuboidal epithelium with scattered mucin-producing cells. We also conducted literature review on similar lesions and found that some lesions were associated with pancreatic hetertopia. It is imperative in clinical practice to distinguish these epithelial inclusions in the lymph nodes from tumor metastasis. A hypothetic connection of these benign epithelial inclusions in the peripancreatic lymph nodes to the enigmatic pancreatic lymphoepithelial cysts is suggested.

Human papilloma virus infection is critical but not sufficient to cause cervical cancer. Molecular markers of cervical carcinogenesis are essential. The aim of this study was to identify aberrantly expressed proteins in cervical cancer and determine their clinical significance. A two-dimensional polyacrylamide gel electrophoresis (2-DE) proteomic strategy was used for screening candidate proteins. Immunoblotting and immunohistochemical (IHC) analyses were performed to confirm the results of 2-DE, and the clinical significance was estimated. Glucose-regulated protein 58 (Grp58) was overexpressed in 73% of cancers. The IHC staining showed that the Grp58 histoscore was significantly higher in patients with adenocarcinoma (AD) compared with squamous cell carcinoma (P < 0.05). Grp58 staining was intense in AD with a penetration depth greater than half of the cervical stroma (P = 0.033). High Grp58 expression was associated with low overall survival and recurrence-free survival (RFS) rates (P = 0.007 and P = 0.013, respectively). In multivariate analysis, high Grp58 expression (P = 0.042) and lymph node metastasis (P = 0.026) were determined as independent prognostic factors for RFS. Patients exhibiting both high Grp58 expression and lymph node metastasis displayed poorer outcomes than the other patient groups. In functional studies, knockdown of Grp58 in HeLa cells led to decreased cell invasiveness and inhibition of lung metastasis in a xenograft mouse model. In conclusion, Grp58 serves as a potent prognostic factor of cervical AD. Estimation of the Grp58 index in conjunction with the lymph node metastasis status might aid in predicting the prognosis of cervical AD.

Background/Purpose Anatomical pathology was not popular in Taiwan a few decades ago, with a severe shortage of pathologists. However, there has been a steady increase in recent years, and now there is a threat of oversupply We evaluated supply and demand over the past three decades and compared the findings with other countries. Methods We collected the enrollment data of pathologists and physicians from the Taiwan Society of Pathology, the Department of Health, Executive Yuan, and Taiwan Medical Association, and analyzed equivalent data from other countries. We sent questionnaires to pathology chiefs to inquire about future job vacancies. Results The number of pathologists has increased at an annual rate of 4.93% between 2004 and 2008, in contrast to 3.7% for all physicians. There has been a net annual increase of 12 pathologists in the past 13 years. The estimated average number of consultant posts per year was nine, which was only one-third of the average number of first-year residents (R1s). The number of pathologists/million population in Taiwan was 14.83, which was comparable to that in Japan and South Korea but much smaller than that in Canada and the United States. The ratio of pathologists to physicians in Taiwan was 0.97%, which was higher than that in Japan (0.68%) and South Korea (0.64%), but lower than in Canada (1.32%) and the United States (1.46%). On average, 1.79% of medical graduates chose pathology for their R1 training in Taiwan, which was higher than that in the United States (1.50%) and Canada (1.10-1.20%). Conclusion Anatomical pathology is no longer a specialty that is facing a physician shortage in Taiwan, and there is now a relatively high pathologist/physician ratio among Asian countries. We suggest that a decrease in the number of R1s in pathology is needed to maintain a balance between supply and demand.

Cardiac myxoma is the most common primary tumor of the heart. The existence of apoptosis in cardiac myxoma has been demonstrated. The purpose of this investigation was to elucidate the pathway of apoptosis and the cell cycle in cardiac myxomas. This study had 2 parts: investigation of a cultured cardiac myxoma cell line and the analysis of data from 20 patients with cardiac myxoma that was surgically excised. Apoptosis signal transduction was determined by assessing DNA fragmentation, Fas ligand (FasL), Fas, tumor necrosis factor-α (TNF-α), caspase-3, and terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) assay through immunohistochemical stain, quantitative reverse transcriptase— polymerase chain reaction (RT-PCR), and Western blot analysis. The patient population consisted of 12 (60%) women and 8 (40%) men with a mean age of 46 years (range = 32-64 years). All cases of myxoma were sporadic myxomas rather than familial. Clinical presentations included asymptomatic (26%), dyspnea (44%), stroke (9%), chest pain (9%), and fever (11%). All myxomas were located in the left atrium. Pathological scores for inflammation, cellularity, calcification, and thrombosis were not related to myxoma location or clinical events. In cardiac myxoma, apoptosis documented by TUNEL (70.9% ± 17.6%) and the caspase-3 (66.5% ± 32.5%) final common pathway is characterized by the extrinsic Fas/ FasL dependent pathway (positive stained 70.9% ± 19.2%; 26.0% ± 17.2%, respectively), but not the intrinsic pathway. The RT-PCR and Western Blot analysis (Fas/FasL, TNF-α, caspase-3, and apoptosis) of the cardiac myxoma and cultured cardiac myxoma cells confirmed the immunochemical results. The extrinsic Fas/FasL-dependent apoptosis pathways in cardiac myxomas were proved by both RNA and protein levels.

Summary Background Previous studies have demonstrated that the lack of lumican delayed corneal wound healing in lumican-null (Lum−/−) mice. This defect is rescued by the addition of glycosylated lumican core protein to the injured corneas. Objectives We examined the hypothesis that lumican is also required for the healing of cutaneous wounds using Lum−/− mice. Methods We demonstrated the basic thinner skin phenotypes in Lum−/− mice at different time points and the changes in arrangement of collagen fibres by transmission electron microscopy (TEM). A full skin thickness wound was generated by punch biopsy (6 mm diameter) in experimental Lum−/− and wild-type mice. The closure of injured skin was measured after various periods of time (3, 6, 12, 18 days). Specimens of injured and uninjured skin (serving as control) were then subjected to morphological examination with haematoxylin and eosin and Masson trichrome stains, and by TEM. Immunohistochemical staining with anti-CD68 antibody was used to assess the presence of macrophages in injured skin healing for various periods of time. Semiquantitative reverse transcription–polymerase chain reaction (RT-PCR) was used to elucidate the transforming growth factor (TGF)-β1-induced myofibroblast phenotypic genes. Results Skin of adult Lum−/− mice (3 months and older) was much thinner (40% less) than that of age-matched wild-type mice. This phenomenon was aggravated in older mice. TEM revealed disoriented and irregular collagen fibrils in the dermis of Lum−/− mice. Delayed wound healing with an increase in inflammatory macrophages was compatible with the delayed response of the expression of TGF-β1, type I collagen α1 and fibronectin at the mRNA level by semiquantitative RT-PCR in the Lum−/− mice. Conclusions Our data demonstrate that lumican plays pivotal roles in skin collagen fibrillogenesis and wound healing.

A rare case of a congenital brain tumor was diagnosed by sonography in a fetus at 37 weeks’ gestation. The ultrasound examination showed a large area of both increased echogenicity and echolucency in one hemisphere suggestive of brain tumor or hemorrhage. Extensive surgical removal of the tumor was performed and revealed an extremely rare histological type of hemangioma. We reported an interesting case of neonatal cavernous hemangioma, mimicking a large prenatal brain tumor and treated successively in neonatal period.

Purpose Cholangiocarcinoma (CCA) is a lethal malignancy that afflicts thousands of patients worldwide. Stratifin has been shown to participate in mediating G2 arrest in several cancers, and cells that express stratifin could contribute to the chemo- and radioresistance of cancers and poor prognosis. However, the clinical impact of stratifin on clinicopathological features of mass forming (MF)-CCA is still unclear. Methods Seventy-eight patients with MF-CCA who had undergone hepatectomy were selected for an immunohistochemical study of stratifin. Sixteen clinicopathological variables were used for the survival analyses. Results Seventy-eight MF-CCA patients (36 men and 42 women) were studied. Cytoplasmic immunostaining with membrane prominence was found in 52.6% (41/78) of patients with MF-CCA after hepatectomy; this was significantly associated with elevated carcinoembryonic antigen (CEA) levels. During the median follow-up duration of 13.6 months, the 5-year overall survival (OS) rate was 14.9%. Univariate analysis showed that an absence of clinical symptoms, better nutritional status, lower alkaline phosphatase, smaller tumor, negative lymph node metastasis, negative stratifin staining, and curative hepatic resection were associated with favorable OS rate for MF-CCA patients after hepatectomy. Multivariate Cox proportional hazard analysis showed that the absence of clinical symptoms, negative lymph node metastasis, and curative hepatectomy independently predicted MF-CCA patients with favorable OS rate after hepatectomy. Conclusions Overexpression of stratifin was significantly associated with elevated CEA levels in patients with MF-CCA. The favorable OS for MF-CCA patients depends on the absence of clinical symptoms, negative lymph node metastasis, and curative hepatectomy. J. Surg. Oncol. 2010;102:608–614. © 2010 Wiley-Liss, Inc.

Background. This study was undertaken to show how an excisional biopsy procedure can be used to remove the entire specimen for oral lesions with difficult diagnoses. Methods. We retrospectively reviewed 52 cases with 56 oral lesions either suspected to be malignant or with a prelimi- nary controversial diagnosis. These were treated by excisional biopsy with frozen section intraoperatively between January 2003 and June 2008. Results. Twenty-eight of 56 lesions were diagnosed with malignancy. We found a high underdiagnosis rate (7 of 12) in patients who had a preliminary controversial diagnosis. Twenty-one patients without preoperative biopsy were diag- nosed to have malignancies. Of the 28 malignant cases, all surgical margins were negative. Neck ultrasound scans with fine-needle aspiration cytology was carried out and no patient demonstrated simultaneous neck metastasis. One patient died of locoregional recurrence. Two patients died of a second pri- mary cancer. Conclusion. Excisional biopsy with margin control is useful both in diagnosis and treatment of oral cancers. V

Background This report analyzed a research project supported nationwide expert consultation of anatomic pathology in Taiwan. Methods The data were collected from the requisitions and consultation reports of 2,686 cases in this project from 2003 to 2006. The number of cases, tissue origin, additional special stains, turnaround time (TAT), concordance, discordance, referring pathologists, and consultants were analyzed. Results Skin, hematopoietic system, and bone and soft tissue were the most common (48.3%) specimens sent for consultation. The tentative diagnosis and consultation diagnosis were discordant in 1,074 (64.3%) cases. Major discrepancy was seen in 205 (12.3%) cases, of which 66.8% were changed from malignant to benign, 21.0% were changed from benign to malignant, whereas 12.2% were changed from one category of malignancy to another. Additional special stains were performed on 38.7% of cases and hematology specimen was the most frequent. The mean TAT was 3.4 days. Pathologists working in institutes having fewer pathologists sent more cases for consultation. The opinion of the estimated annual consultation rate from the pathologists in Taiwan was 0.7%. Conclusions This program was beneficial simply by helping the referring pathologists in the workup and diagnosis. This result made the entire program a reasonable quality improvement program. J. Surg. Oncol. 2010; 101:430–435. © 2010 Wiley-Liss, Inc.

We investigated whether the intensity of thymidylate synthase (TS) staining in tissue samples obtained from gastric cancer (GC) patients undergoing gastrectomy could predict response to 5-FU-based adjuvant chemotherapy after gastrectomy.Clinicopathological features of 124 patients with histologically proven GC who underwent radical gastrectomy were retrospectively reviewed. Tissue samples obtained from these patients were immunohistochemically stained for assessing TS expression. We arbitrarily classified the TS staining results as low (20% cytoplasmic immunostaining) and high (or =20% cytoplasmic immunostaining) TS expression.The clinicopathological features of the low TS expression group patients were typically similar to those of the high TS expression group patients. However, multivariate forward stepwise logistic regression analysis revealed that low TS expression was independently associated with females and responders to 5-FU-based adjuvant chemotherapy. The median follow-up duration for the 124 GC patients who had undergone curative resection was 41.3 months. The GC patients who showed poor tumor differentiation and high TS expression had short disease-free survival (DFS) and overall survival (OS).Low TS expression is significantly associated with female GC patients and responders to 5-FU-based adjuvant chemotherapy. It predicts longer DFS and OS in selected GC patients treated with 5-FU-based adjuvant chemotherapy after curative resection. The results suggest that prospective assessment of TS staining intensity in tissue samples obtained from GC patients undergoing gastrectomy would be useful to predict the patients who would be benefited from 5-FU-based adjuvant chemotherapy after gastrectomy.

Little is known about acquisition of human papillomavirus (HPV) and its outcome among older women with negative HPV testing and normal cytology. A longitudinal 3-yr follow-up of nested-cohort subjects (n = 8825) from a population-based cervical cancer screening study whose Pap and HPV tests were negative at baseline were conducted. Every active HPV-negative (n = 413) participant had 12-mo follow-ups of Pap smear and HPV testing. Colposcopy was performed if either HPV-positive or cytology was abnormal. The cytology and histology information of the remaining subjects (passive HPV-negative, n = 8412) was obtained from national registry database. Median age of participants was 45 yr (range, 30-73 yr). The incidence of new acquisition was 4.2/100 woman-years. The 3-yr cumulative total HPV acquisition rate was 11.1% (95% confidence interval [CI]: 8.1-14.1). Increased number of sexual partners (> or =2 vs. 1) of the participant was associated with risk of acquisition (odds ratio [OR]: 5.0, 95% CI: 2.0-12.6) by multivariate analysis. Three cases of > or = cervical intraepithelial neoplasia (CIN) 2 were identified in 3-yr follow-up in active HPV-negative subjects. HPV genotypes in the dysplastic tissue were actually present at baseline samples after reanalysis. From the passive HPV-negative group, only 1 case progressed to CIN2 probably after HPV acquisition. Negative Pap and HPV tests assured a very low risk of developing > or = CIN2 within 3 yr despite incident HPV infection.

This study investigates the bioavailability of carboxymethyl dextran-coated magnetic nanoparticles (CMD-MNP) to the brain. The cytotoxicity of CMD-MNP was assessed by co-culture with C6, a rat glioma cell line. To investigate the effects of an external magnetic field on the biodistribution of nanoparticles in a rat model, a magnet of 0.3 Tesla was applied externally over the cranium and the particles injected via the external jugular vein. Nanoparticles were also injected into rats implanted with C6 tumor cells. Staining of histological samples with Prussian blue to detect iron particles revealed that the external magnetic field enhanced the aggregation of nanoparticles in the rat brain; this enhancement was even more pronounced in the tumor region.

Primary osteosarcoma of the calvarium is rare. A 22-year-old female patient was admitted for a progressively enlarging, indurated mass under her scalp for 6 months. A computed tomographic scan revealed a 4 x 3 x 2-cm3 osteolytic lesion over the right parietal cortex with a sunburst appearance. The patient underwent en bloc tumor resection using bicortical parietal craniectomy with a 2-cm margin of normal bone, including the tightly adherent periosteum over the tumor. Immediate cranioplasty was performed with split-thickness autogenous calvarial bone grafts. Histopathologic examination showed the tumor to be a primary high-grade osteosarcoma of the skull. She received postoperative chemotherapy. She has recovered well and remains without any evidence of disease at her most recent, 8-year follow-up. The key to disease-free survival in treating primary osteosarcoma of the calvarium is complete surgical resection with immediate reconstruction followed by adjuvant chemotherapy.

Failure of arteriovenous access is mostly due to graft thrombosis and multifactorial, with medical and surgical etiologies. Apoptosis of blood cells, such as macrophages, lymphocytes and eosinophils, may play an important role in thrombus formation. We also investigated caspase-3-dependent apoptosis in thrombi. We recorded clinical parameters in 43 consecutive patients with vascular access failure (13 men, 30 women; mean age+/-SD, 64.6+/-14.2 years) who underwent surgical thrombectomy. Major presentations included absent (92%) and/or near near-absent (16%) flow through the access during hemodialysis. Cardiovascular risk factors were hypertension (70%), hyperlipidemia (47%), diabetes mellitus (47%), chronic obstructive pulmonary disease (12%), heart failure (12%), coronary artery disease (21%), and stroke (16%). Laboratory data included hemoglobin level of 100+/-17 g/L, total white blood cell count of 7.65+/-2.14 x 10(9)/L, and platelet count of 205.6+/-57.9 1000/iL. Abnormal biochemistry data included elevated blood urea nitrogen level of 63.5+/-24.4 mg/dL and creatinine level of 8.6+/-4.0 mg/dL (normal

Adenomatoid tumors are benign mesothelial neoplasms most commonly found in the male and female genital tracts. Extragenital adenomatoid tumors are rare, most of them being solitary tumors. To our knowledge, only one case of multiple extragenital adenomatoid tumors, involving the liver and peritoneum, has been reported to date. Here we report another case of multiple extragenital adenomatoid tumors involving the mesocolon and omentum. A 47-year-old woman presented with a delayed menstrual period. Ultrasonography revealed a left adnexal mass, and surgical resection was attempted at a local hospital. The patient was transferred to our hospital without resection due to the intraoperative finding of multiple peritoneal tumors. At our hospital, an 8.0x7.5x6.0 cm tumor at the mesocolon of the sigmoid colon and three omental nodules measuring up to 2.5x2.0x1.7 cm were resected. Grossly, they were well circumscribed, gray-tan and elastic with small cystic spaces. Microscopically, they were composed of tubules and anastomosing channels lined by flattened or cuboidal cells with bland nuclei. Immunohistochemically, the tumor cells were positive for pan-cytokeratin AE1/AE3, vimentin, cytokeratin 5/6 and calretinin. The postoperative course was uneventful, and the patient was well 10 months after the operation. Despite their rarity, adenomatoid tumors should be included in the differential diagnosis of multiple intra-abdominal tumors.

Among patients with medulloblastoma, an unrare aggressive central nervous system (CNS) tumor found mostly in the posterior fossa, drop metastasis from primary location to anatomically lower sites including whole spinal cord is known as a potential way for tumor to spread. There were already lots of extensive discussions regarding diagnosis and treatment for such common neurologic complication in systemic cancer; however, fewer were found about medulloblastoma. This study aimed to reexamine the possible known prognostic factors, especially drop metastasis, and defined the influence of them. We retrospectively review a series of 36 patients who suffered from posterior fossa medulloblastoma and found leptomeningeal metastasis in 12 of them. Incidence, diagnosis, prognostic factors, and treatments for this common complication are discussed. The magnetic resonance images (MRI) of these patients were reviewed. The time sequence between primary surgical procedure and development of MRI evidences of drop metastasis was used for subgrouping. Log-rank test was used for survival analysis. By survival analysis, patients with late drop metastasis, defined as new radiologic evidence of leptomeningeal involvement after primary CNS procedures, were found to have significant survival difference to those with early metastasis defined as drop metastasis found at the time of diagnosis (log-rank test, p = 0.0047). Further stratification of patients within this group may help in evaluation of prognosis and development of different treatment strategies.

Background Reviewing the literature on central neurocytoma revealed that functional outcomes traditionally have been assessed by KPS. However, KPS is not sufficiently sensitive to assess functional outcomes compared with the Barthel Index and the Functional Independence Measure (the FIM™ instrument). Discussion of other functional assessments and various aspects of central neurocytomas has never been documented clearly. Methods Nine case series of primary central neurocytomas received total or STR at our hospital. The clinical features, neuroradiologic findings, histopathologic features, and functional outcomes were listed and analyzed. Moreover, the functional outcomes were assessed using KPS, Barthel Index, and FIM™ instrument. The follow-up period ranged from 8 to 33 months after surgery. Results Patients with increased GFAP positivity or MIB-1 index greater than 3% did not have the worst scores in functional assessments. The functional outcomes of the cases presented here, including KPS, Barthel Index, and FIM™ instrument, were listed in Table 4. Most patients achieved good functional outcomes. The average KPS, Barthel Index, and FIM™ instrument were 86.25 ± 14.08 (range, 60-100), 86.88 ± 17.31 (range, 50-100), and 111 ± 17.02 (range, 78-126), respectively. Conclusion Most of the patients in this investigation achieved good ability to independently perform daily activity. Whether the high score of functional outcome was correlated with benign tumor course or 5-year survival rate remains uncertain. We recommend regular follow-up for detecting tumor growth or recurrence, although central neurocytomas are always benign.

Determining the primary site of a brain metastasis can be difficult, particularly if there is no organ-specific tumor histology. Thyroid transcription factor-1 (TTF-1) is a marker commonly expressed in lung and thyroid carcinomas. We studied the value of TTF-1 staining to identify brain metastases from a lung primary. Forty-three consecutive patients metastatic carcinomas of the brain were reviewed from a 4 year period. Twenty-one (75%) of the 28 metastatic pulmonary carcinomas were TTF-1 positive (+), whereas only one metastatic papillary thyroid carcinoma (7%) out of 15 metastatic non-pulmonary carcinomas was TTF-1 (+). We also studied the cytokeratin profile of these tumors. However, cytokeratin profile, either alone or combined with TTF-1 staining, was not better than TTF-1 staining alone in identifying brain metastases of pulmonary origin. Overall, TTF-1 positivity is a useful indicator of pulmonary origin in brain metastases, with a very high positive predictive value (95%) and a moderate negative predictive value (67%).

// Chia-Lung Tsai 1, * , Angel Chao 1, 2, * , Shih-Ming Jung 3 , Chi-Neu Tsai 4 , Chiao-Yun Lin 2 , Shun-Hua Chen 2, 5 , Shih-Che Sue 6 , Tzu-Hao Wang 1, 2, 7 , Hsin-Shih Wang 2 , Chyong-Huey Lai 2 1 Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan 2 Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan 3 Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan 4 Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan 5 Graduate Institute of Biomedical Science, School of Medicine, Chang Gung University, Taoyuan, Taiwan 6 Department of Life Sciences, Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Taiwan 7 School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan * These authors have contributed equally to this work Correspondence to: Tzu-Hao Wang, email: knoxtn@cgmh.org.tw Keywords: JAK2, STIP1, cancer Received: March 08, 2016 Accepted: June 17, 2016 Published: July 8, 2016 ABSTRACT Overexpression of stress-induced phosphoprotein 1 (STIP1) − a co-chaperone of heat shock protein (HSP) 70/HSP90 – and activation of the JAK2-STAT3 pathway occur in several tumors. Combined treatment with a HSP90 inhibitor and a JAK2 inhibitor exert synergistic anti-cancer effects. Here, we show that STIP1 stabilizes JAK2 protein in ovarian and endometrial cancer cells. Knock-down of endogenous STIP1 decreased JAK2 and phospho-STAT3 protein levels. The N-terminal fragment of STIP1 interacts with the N-terminus of JAK2, whereas the C-terminal DP2 domain of STIP1 mediates the interaction with HSP90 and STAT3. A peptide fragment in the DP2 domain of STIP1 (peptide 520) disrupted the interaction between STIP1 and HSP90 and induced cell death through JAK2 suppression. In an animal model, treatment with peptide 520 inhibited tumor growth. In summary, STIP1 modulates the function of the HSP90-JAK2-STAT3 complex. Peptide 520 may have therapeutic potential in the treatment of JAK2-overexpressing tumors.

Background Primary central nervous system lymphomas (PCNSLs) are relatively rare brain tumors. Accurate diagnosis is usually made by surgical biopsy. In addition to surgical biopsy and decompression, treatment options include high-dose methotrexate and chemotherapy, radiation therapy, and stem cell therapy. Because of the rarity of this disease, guidelines for PCNSL diagnosis and treatment usually are formed from a large series of experiences. Methods We retrospectively reviewed 79 patients in our tertiary referral center during a 13-year period. All patients with PCNSL underwent surgical or bone marrow biopsy procedures, and diagnoses were confirmed by hematologists or neuropathologists. At the time of diagnosis, 44 patients presented with a single lesion. Human immunodeficiency virus was confirmed positive in 1 patient. The standard therapy protocol included high-dose methotrexate (intravenous and intrathecal) and chemotherapy with cytosine arabinoside, followed by external irradiation of the brain. Results Significant prognostic factors in these patients were low serum lactate dehydrogenase levels and radiation therapy. Multiplicity of lesions at time of diagnosis did not imply a worse outcome, and surgical resection and debulking did not show a significant survival benefit. Conclusions PCNSL has a poor prognosis. Further clinical trials and diagnostic tools are needed to reveal the complexity of this disease.

Purpose: To investigate the effects of single and fractionated doses of radiation on tumors and tumor-associated macrophages (TAMs), and to elucidate the potential of TAMs to influence tumor growth. Methods and Materials: A murine prostate cell line, TRAMP-C1, was grown in C57Bl/6J mice to 4-mm tumor diameter and irradiated with either 25 Gy in a single dose, or 60 Gy in 15 fractions. The tumors were removed at the indicated times and assessed for a variety of markers related to TAM content, activation status, and function. Results: In tumors receiving a single radiation dose, arginase (Arg-I), and cycloxygenase-2 (COX-2) mRNA expression increased as a small transient wave within 24 h and a larger persistent wave starting after 3 days. Inducible nitric oxide synthase (iNOS) mRNA was elevated only after 3 days and continued to increase up to 3 weeks. After fractionated irradiation, Arg-1 and COX-2 mRNA levels increased within 5 days, whereas iNOS was increased only after 10 fractions of irradiation had been given. Increased levels of Arg-I, COX-2, and, to a lesser extent, iNOS protein were found to associate with TAMs 1–2 weeks after tumor irradiation. Function of TAMs were compared by mixing them with TRAMP-C1 cells and injecting them into mice; TRAMP-C1 cells mixed with TAMs from irradiated tumors appeared earlier and grew significantly faster than those mixed with TAMs from unirradiated tumors or TRAMP-C1 alone. Conclusions: Tumor-associated macrophages in the postirradiated tumor microenvironment express higher levels of Arg-1, COX-2, and iNOS, and promote early tumor growth in vivo .

This study investigates the effect of external magnetic fields on the biodistribution of nanoparticles (NP). A NdFeB magnet of 2.4 kG was externally applied over the left femoral artery or right kidney. The 250 nm dextran-coated Fe 3 O 4 NP was injected via tail vein in healthy rats, and organs were taken 1 or 24 h later. Prussian blue stain revealed that NP were more rapidly retained in the liver and spleen than in the lungs. NP aggregation observed in the kidney and femoral artery after application of external magnets was time dependent. Hollow organs such as the intestine, colon, and urinary bladder retained little NP.

Case report.Tertiary referral center hospital in Taiwan.To report a case of spinal Rosai-Dorfman disease (RDD) presenting with paraparesis and also preceding by relapsing uveitis for 6 months. A thoracic laminectomy was performed to remove the solid mass. The pathological diagnosis reveals infiltrating histiocytes, emperipolesis and positivity for S-100. There is no recurrence 1 year later with MR imaging.The relapsing idiopathic uveitis may be a prodrome for this unusual disease, because RDD is associated closely to defective immunogical response. Early and accurate diagnosis of CNS RDD may reverse the neurologic deficits by early decompression.

Small-cell cervical cancer (SCCC) is rare and prone to metastasize. We conducted a prospective study to evaluate the role of (18)F-FDG PET in the management of this aggressive malignancy.Patients with untreated primary, histologically confirmed SCCC were enrolled. (18)F-FDG PET (or PET/CT) was performed immediately after MRI or CT, for primary staging, monitoring response to treatment or restaging when there was suspicion of recurrence. The clinical impact of PET was determined on a scan basis.A total of 25 patients were recruited and 43 PET scans were performed. The PET images were obtained for primary staging (25 patients), monitoring response (10 patients) and restaging when there was suspicion of recurrence (8 patients). The median follow-up time in event-free patients was 109.3 months (range 97.5 - 157.7 months). A positive impact of PET was found in 8 (18.6 %) of the 43 scans, which included detection of additional regions of distal lymph node (LN) metastasis (one primary staging scan, two restaging scans), bone metastasis (two primary staging scans, one monitoring response scan), and exclusion of false-positive lesions on MRI (one primary staging scan, one restaging scan). On the other hand, one negative impact was recorded as one false-positive lesion on a restaging PET scan. One positive impact was noted for monitoring response (bone metastasis). The impact of three scans was indeterminate. The positive impact of down-staging in avoiding overtreatment but finding additional distal LN (except one on restaging) or bone metastases had no beneficial effect on long-term survival.The results of this preliminary study suggest that PET is useful in the management of SCCC. PET could have more value in detecting occult metastases if future novel therapies are able to offer better control of extensive SCCC.

✓ The authors report on the first case of corpus callosum glioblastoma multiforme (GBM) with diffusion-weighted (DW) magnetic resonance (MR) imaging findings that mimicked those for lymphoma but with MR spectroscopy results absent of lymphoma characteristics. This 68-year-old man presented with rapid, progressive impairment in short-term memory as well as slow responses and a change in his personality within 3 weeks of admission. Results of cranial computed tomography revealed a slightly hyperdense corpus callosum tumor with bihemispheric involvement. Magnetic resonance images showed a homogeneous mass with strong enhancement. The mass showed water restriction on DW MR images and apparent diffusion coefficient (ADC) maps but no markedly elevated lipid resonance on MR spectroscopy. The patient underwent tumor resection. Results of pathological studies with immunohistochemical analysis confirmed that the lesion was GBM. Diffusion-weighted MR imaging together with ADC mapping and MR spectroscopy was reported to be useful in differentiating GBM and primary brain lymphoma. The lymphomas were hyperintense to gray matter on DW MR images and isointense to hypointense on ADC maps because of water restriction. In contrast, the GBMs were hyperintense to gray matter on both DW MR images and ADC maps because of the T2 shine-through effect. On MR spectroscopy, lipid resonance was markedly elevated in lymphoma but only slightly elevated in GBM.

Purpose The role of positron emission tomography (PET) with [18F]-fluoro-2-deoxy-d-glucose (FDG) in early-stage cervical cancer is unclear. We aimed to investigate the clinical benefit of FDG-PET in primary staging before radical hysterectomy and pelvic lymphadenectomy (RH-PLND). Patients and Methods Patients with untreated stage IA2 to IIA adenocarcinoma (AD) or adenosquamous carcinoma (ASC) or nonbulky (≤ 4 cm) squamous cell carcinoma cervical cancer with magnetic resonance imaging (MRI) –defined negative nodal metastasis were enrolled onto a prospective study with a two-stage design. All patients had a preoperative dual-phase FDG-PET, technetium-99m–sulfur colloid lymphoscintigraphy, and intraoperative sentinel lymph node (LN) detection at RH-PLND. The gold standard of LN metastasis is histologic. A sample size of 120 patients was calculated to fit study aims (diagnostic efficacy of PET and sentinel LN sampling). An interim analysis was performed when 60 patients were accrued, which led to the current report. Results There were 36 SCCs, 20 ADs, and four ASCs. Of the 60 patients, 10 (16.7%) had pelvic LN metastases, and one (1.7%) had para-aortic LN (PALN) metastasis histologically. FDG-PET detected the single PALN metastasis (one of one patient) but detected only one (10%) of the 10 pelvic LN metastases. The PET false-negative pelvic LN micrometastases measured a median of 4.0 × 3.0 mm (range, 0.5 × 0.5 to 7 × 6 mm). The second stage of this trial will be continued without PET. Conclusion This study shows that dual-phase FDG-PET has little value in primary, nonbulky, stage IA2 to IIA and MRI-defined, LN-negative cervical cancer.

We conducted a pilot trial to evaluate the value of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in gestational trophoblastic tumours (GTTs).Patients with placental site trophoblastic tumour (PSTT), high-risk GTT (World Health Organisation scoreor =8, disease onset at postpartum or greater than 6 months after antecedent pregnancy), metastatic GTT, recurrent/resistant GTT after chemotherapy, or post-molar GTT with unexplained abnormal beta-hCG regression and patients undergoing re-evaluation after salvage treatment were enrolled. PET was undertaken within 1 week after computed tomography (CT). Clinical impacts of additional PET were determined on a scan basis.A total of 14 patients were recruited. Sixteen PET scans were performed, with one patient having three serial studies. Benefits of additional PET were seen in 7 of 16 (43.8%) scans; these benefits included disclosure of chemotherapy-resistant lesions (n = 2), exclusion of false-positive CT lesions (n = 1), detection of an additional lesion not found by conventional imaging (n = 1) in high-risk GTT at the start of primary chemotherapy, and confirmation of complete response to treatment for PSTT or to salvage therapy for recurrent/resistant GTT (n = 3). On the other hand, in two instances there were false-negative PET findings, six scans yielded no benefit, and one showed an indeterminate lesion.Our preliminary results suggest that 18F-FDG PET is potentially useful in selected patients with GTT by providing precise mapping of metastases and tumour extent upfront, by monitoring treatment response and by localising viable tumours after chemotherapy. A larger study is necessary to further define the role of 18F-FDG PET in GTT.