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Plasminogen activators, such as recombinant tissue-type plasminogen activators (rtPAs), while effective in treating thromboembolic diseases, often induce hemorrhagic complications due to non-specific enzyme activities in the systemic circulation. This study evaluated the targeting efficiency, efficacy, biodistribution, and potential toxicity of a rtPA covalently attached to chitosan-coated magnetic nanoparticles (chitosan-MNP-rtPA). The thrombolytic activity of a chitosan-MNP-rtPA was preserved by protection from an endogenous plasminogen activator inhibitor-1 (PAI-1) in whole blood and after circulation in vivo, as examined by thromboelastometry. Single-photon emission computed tomography (SPECT) demonstrated real-time retention of a 99mTc-MNP-rtPA induced by magnet application in a rat embolic model; an 80% reduction in rtPA dosage for a chitosan-MNP-rtPA with magnetic guidance was shown to restore blood flow. After treatment, iron deposition was observed in the reticuloendothelial systems, with portal edema and neutrophil infiltration in the liver at a ten-fold higher dose but not the regular dose. Nevertheless, no liver or renal toxicity was observed at this higher dose. In conclusion, the liver may still be the major deposit site of rtPA nanocomposites after targeted delivery; chitosan-coated MNPs are potentially amenable to target therapeutics with parenteral administration.

Background: We investigated whether mutations in plasma circulating tumor DNA (ctDNA) can provide prognostic insight in patients with different histological types of ovarian carcinoma. We also examined the concordance of mutations detected in ctDNA samples with those identified in the corresponding formalin-fixed paraffin-embedded (FFPE) tumor specimens. Methods: Between July 2016 and December 2017, 29 patients with ovarian carcinoma were prospectively enrolled. FFPE tumor specimens were obtained from all participants. A total of 187 blood samples for ctDNA analysis were collected before surgery (C0), immediate after surgery before adjuvant chemotherapy (C1), and at six-month intervals. Progression-free survival (PFS) and overall survival (OS) served as the main outcome measures. Results: The study cohort consisted of 13 (44.8%) patients with high-grade serous carcinomas (HGSC), 9 (31.0%) with clear cell carcinoma, 2 (6.9%) with mucinous carcinomas, 4 (13.8%) with low-grade serous carcinomas, and 1 (3.4%) with endometrioid carcinoma. Twenty-four (82.8%) patients had at least one detectable ctDNA variant. The concordance rate between mutations identified in pretreatment ctDNA and corresponding FFPE tumor specimens was 92.3% for patients with HGSC and 58.6% for the entire cohort. The median follow-up time was 33.15 months (range: 0.79–46.13 months). Patients with an advanced stage disease more likely had detectable ctDNA mutations before surgery (C0) and after surgery at C1, while those with HGSC more likely had ctDNA mutations detected before surgery. The presence of ctDNA mutations at C1 was an independent predictor of worse OS with a hazard ratio of 6.56 (95% confidence interval, (1.07–40.17) for detectable versus undetectable C1 ctDNA variants, p = 0.042). Conclusions: ctDNA mutations are common in patients with ovarian carcinoma. The presence of ctDNA mutations after surgery was an independent predictor of less favorable PFS and OS.

Angiostrongylus cantonensis, the causative agent of human eosinophilic meningitis and eosinophilic meningoencepalitis, has been reported to cause cognitive impairments in the host. To determine whether drug treatment improves the cognitive functions, BALB/c mice infected with 50 third-stage larvae were treated with albendazole, dexamethasone, or co-therapy since day 7 or 14 post-infection for one or two weeks. Abilities of spatial memory and learning of these animals were assessed with the Morris water maze.Our results showed that body weight was significant higher then infected group in the albendazole and combined therapy groups. Significantly lower worm recovery rates were found in mice treated with the same groups. The mice treated with dexamethasone since day 7 for 14 day had significant longer time in the remaining groups were found in forced swimming test. The animals treated with albendazole and combined therapy since day 7 for 14 days was demonstrated to have significantly shorter latencies to the platform in learning memory on day 3 and 4. Mice in these two groups were demonstrated to have significantly higher sores in spatial memory tests. These results indicate that treatment with albendazole or combined therapy may be more efficient in preventing brain damages and depression as well as preserving their capabilities in learning and memory. Therefore, administration of albendazole alone or combined with dexamethasone should have higher efficacies than dexamethasone alone in treatment of BALB/c mice infected with a heavy dose of 50 third-stage larvae of A. cantonensis.

Objective: This study (Asian Gynecologic Oncology Group [AGOG]13-001/Taiwanese Gynecologic Oncology Group [TGOG]1006) was to validate human papillomavirus (HPV)16 as an independent good prognostic factor and investigate the impact of treatment modalities to cervical adenocarcinoma and adenosquamous carcinoma (AD/ASC). Materials and methods: Patients receiving primary treatment at AGOG and TGOG member hospitals for cervical AD/ASC were retrospectively (1993–2014) and prospectively (since 2014) enrolled. DNA extraction from paraffin-embedded tissue (FFPE) specimens was used for HPV genotyping. Those with suspected endometrial origin were excluded for analysis. Results: A total of 354 patients with valid HPV results were enrolled, 287 (81.1%) of which had HPV-positive tumors. The top-3 types were HPV 18 (50.8%), HPV16 (22.9%) and HPV45 (4.0%). The HPV16-negativity rates varied widely across hospitals. 322 patients were eligible for prognostic analyses. By multivariate analysis, advanced stage (HR5.8, 95% confidence interval [CI] 2.1–15.8; HR5.8, 95% CI 1.6–20.5), lymph node metastasis (HR4.6, 95% CI 2.7–7.9; HR7.3, 95% CI 3.8–14.0), and HPV16-positivity (HR0.3, 95% CI 0.1–0.6; HR0.3, 95% CI 0.1–0.9) were independent prognostic factors for progression-free survival (PFS) and overall survival (OS). Stage I patients with primary surgery had better 5-year PFS (82.8% vs 50.0% p = 0.020) and OS (89.3% vs 57.1%, p = 0.017) than those with non-primary surgery, while the propensity scores distribution were similar among the treatment groups. Conclusion: This study confirmed that HPV16-positivity was a good prognostic factor for PFS and OS in AD/ASC, and patients seemed to have better outcome with primary surgery than non-primary surgery.

Abstract Background Angiostrongylus cantonensis is also known as rat lungworm. Infection with this parasite is a zoonosis that can cause eosinophilic meningitis and/or eosinophilic meningoencephalitis in humans and may lead to fatal outcomes in severe cases. In this study, we explored the mechanisms of the impairments in the cognitive functions of mice infected with A. cantonensis. Methods In infected mice with different infective intensities at different timepoint postinfection, loss and recovery of cognitive functions such as learning and memory abilities were determined. Neuronal death and damage to synaptic structures were analyzed by Western blotting and IHC in infected mice with different infection intensities at different timepoint postinfection. Results The results of behavioral tests, pathological examinations, and Golgi staining showed that nerve damage caused by infection in mice occurred earlier than pathological changes of the brain. BDNF was expressed on 14 day post-infection. Cleaved caspase-3 increased significantly in the late stage of infection. However, IHC on NeuN indicated that no significant changes in the number of neurons were found between the infected and uninfected groups. Conclusions The synaptic loss caused by the infection of A. cantonensis provides a possible explanation for the impairment of cognitive functions in mice. The loss of cognitive functions may occur before severe immunological and pathological changes in the infected host.

Cadmium (Cd) is hazardous to human health because of its toxicity and long half-life of clearance. Many studies have explored the relationship between chronic Cd exposure and different human diseases. However, most of the studies limited the study targets of Cd toxicity to two or three organ systems. The goal of this study was to establish a mouse model of Cd accumulation in most organ systems and to particularly investigate the potential toxic effects of Cd to the cardiovascular system. Mice were divided into three groups: the control group, Cd-100 group, and Cd-200 group. In the control group, Cd was detected in the kidney, lung, liver, heart and urine but was undetectable in the aorta, intestine, thigh bone, spinal bone and serum. Upon chronic exposure in the Cd-100 and Cd-200 groups, Cd accumulated in all tissues, with a dramatic increase in concentration. We confirmed that Cd could accumulate significantly in the heart and aorta upon chronic exposure. This finding might help to explain the potential toxic effects of Cd on these organs. In addition, the calcium concentration in the bones and kidney declined when the exposure to Cd increased. This finding aligned with the negative effects of Cd on bony mineralization and the potential direct toxic effects of Cd on bones. The impacts of Cd on the cardiovascular system were explored. Histologically, chronic Cd exposure led to myocytes hypertrophy and myocardial architecture disarray in the Cd-100 group compared to those in the control group. Our research confirms that Cd can accumulate in all of the organs studied upon chronic exposure, and suggests that the toxicity of Cd accumulation may play important roles in mediating the pathophysiologic effects in these target organs, especially the bone and heart.

Abstract Background Spinal dural arteriovenous fistula (SDAVF) usually occurs during the 4th to 6th decades of life, and adolescent SDAVF is rarely reported. SDAVF arising around a tumor is also rare, and reported tumors are mostly schwannoma and lipoma. Case presentation We reported a 16-year-old male presented with progressive weakness and numbness of lower limbs for 3 months. A SDAVF was found, which was fed by right radicular arteries from segmental artery at L2 level and drained retrogradely into perimedullary veins. A concomitant spinal extradural nodular fasciitis at right L1/L2 intervertebral foramen was also noted. The SDAVF was completely obliterated by endovascular treatment and the tumor was debulked. The patient recovered well after the procedures. Conclusions Our case report suggests SDAVF can occur in adolescent. The concomitant presence with a nodular fasciitis indicates that although it usually arises in subcutaneous tissue but can rarely form on the dura of spine.

Abstract Asunercept (company code APG101 [Apogenix AG]; company code CAN008 [CANbridge Pharmaceuticals]) is a novel glycosylated fusion protein that has shown promising effectiveness in glioblastoma. This Phase I study was initiated to evaluate the tolerability and safety of asunercept in combination with standard radiotherapy and temozolomide (RT/TMZ) in Asian patients with newly diagnosed glioblastoma. This was the Phase I portion of a Phase I/II open label, multicenter trial of asunercept plus standard RT/TMZ. Adults with newly-diagnosed glioblastoma received surgical resection followed by standard RT/TMZ plus asunercept 200 mg/week (Cohort 1) or 400 mg/week (Cohort 2) by 30-min IV infusion. The primary endpoint was the safety and tolerability of asunercept during concurrent asunercept and RT/TMZ; dose-limiting toxicities were observed for each dose. Secondary endpoints included pharmacokinetics (PK) and 6-month progression-free survival (PFS6). All patients (Cohort 1, n = 3; Cohort 2, n = 7) completed ≥ 7 weeks of asunercept treatment. No DLTs were experienced. Only one possibly treatment-related treatment emergent adverse event (TEAE), Grade 1 gingival swelling, was observed. No Grade > 3 TEAEs were reported and no TEAE led to treatment discontinuation. Systemic asunercept exposure increased proportionally with dose and showed low inter-patient variability. The PFS6 rate was 33.3% and 57.1% for patients in Cohort 1 and 2, respectively. Patients in Cohort 2 maintained a PFS rate of 57.1% at Month 12. Adding asunercept to standard RT/TMZ was safe and well tolerated in patients with newly-diagnosed glioblastoma and 400 mg/week resulted in encouraging efficacy. Trial registration NCT02853565, August 3, 2016.

Background/Purpose: Ovarian clear cell carcinoma (OCCC) accounts for approximately 18% of all epithelial ovarian malignancies in Taiwan and portends a poor prognosis. Here, we sought to investigate whether immunohistochemistry with an anti-pan-cytokeratin antibody cocktail (AE1/AE3) can be used as an adjunct to hematoxylin and eosin (H&E) staining for improving the detection of isolated tumor cells (ITCs) and micrometastasis to pelvic lymph nodes (LNs). We also assessed whether these lesions may predict disease recurrence. Methods: Pelvic lymphadenectomy specimens were obtained from 197 patients with stage 1 OCCC who had undergone surgery between 2000 and 2018 from Linkou and Kaohsiung Chang Gung Memorial Hospital. Immunohistochemical staining with AE1/AE3 was applied to a total of 1186 slides. Clusters of metastatic tumor cells, detected immunohistochemically, were classified as ITCs (clusters with diameters of ≤0.2 mm) or micrometastases (tumor cell clusters of >0.2 but ≤2.0 mm). We also assessed the diameter of metastases in patients with positive lymph nodes (stage IIIA1, n = 3, 7 positive nodes). Results: Clusters with a positive AE1/AE3 staining were identified in five (2.53%) of the 197 patients (ITCs, n = 3; micrometastasis, n = 2). Four patients had no evidence of disease recurrence but a patient recurred at follow-up. Metastatic foci of patients with stage IIIA1 disease were all >2.0 mm in size. Conclusion: Immunohistochemical staining with AE1/AE3 can identify micrometastasis or ITCs in LNs missed on routine H&E staining. The role of micrometastasis in predicting recurrent OCCC and implementing on treatment strategies requires further investigation.

Abstract Background Due to the difficulties in early diagnosing and treating hepatocellular carcinoma (HCC), prognoses for patients remained poor in the past decade. In this study, we established a screening model to discover novel prognostic biomarkers in HCC patients. Methods Candidate biomarkers were screened by liquid chromatography with tandem mass spectrometry (LC-MS/MS) analyses of five HCC normal (N)/tumor (T) paired tissues and preliminarily verified them through several in silico database analyses. Expression levels and functional roles of candidate biomarkers were respectively evaluated by immunohistochemical staining in N/T paired tissue (n = 120) and MTS, colony formation, and transwell migration/invasion assays in HCC cell lines. Associations of clinicopathological features and prognoses with candidate biomarkers in HCC patients were analyzed from GEO and TCGA datasets and our recruited cohort. Results We found that the transmembrane P24 trafficking protein 9 (TMED9) protein was elevated in HCC tissues according to a global proteomic analysis. Higher messenger (m)RNA and protein levels of TMED9 were observed in HCC tissues compared to normal liver tissues or pre-neoplastic lesions. The TMED9 mRNA expression level was significantly associated with an advanced stage and a poor prognosis of overall survival (OS, p = 0.00084) in HCC patients. Moreover, the TMED9 protein expression level was positively correlated with vascular invasion (p = 0.026), OS (p = 0.044), and disease-free survival (p = 0.015) in our recruited Taiwanese cohort. In vitro, manipulation of TMED9 expression in HCC cells significantly affected cell migratory, invasive, proliferative, and colony-forming abilities. Conclusions Ours is the first work to identify an oncogenic role of TMED9 in HCC cells and may provide insights into the application of TMED9 as a novel predictor of clinical outcomes and a potential therapeutic target in patients with HCC.

Background: Craniopharyngiomas are benign tumors of embryologic origin located in the sellar region. Patients have both neurological and endocrinological symptoms. Symptoms may be subtle in the early clinical course, which leads to delayed diagnosis. This study evaluated the clinical and endocrinological manifestations of childhood-onset craniopharyngioma. Methods: We retrospectively reviewed medical records of 45 children diagnosed as having craniopharyngioma between 1995 and 2019. We collected data on clinical symptoms and signs, height, weight, biochemical and hormone data, images, operation records, and pathology reports. A three-graded classification system was applied to define the degree of hypothalamic damage (HD). We analyzed clinical and endocrinological manifestations among patients with and without obesity, with short and normal stature, and with differing degrees of HD. Results: Clinical endocrinologic manifestations included adrenocortical insufficiency (42%), central hypothyroidism (37%), short stature (31%), obesity (20%), weight

Background: Intracranial pure germinoma is a rare extragonadal neoplasm. Affected patients may have motor impairment, visual disturbance, neurological signs, and endocrine disorder, depending on the size and location of the tumor. This study investigated and analyzed patients’ demographic data and neuroimaging, clinical, laboratory, and endocrinological findings. Methods: We performed a retrospective chart review of 49 children diagnosed with pure germinoma in Taiwan from 1990 to 2018. The initial clinical presentation, tumor markers (beta-hCG, alpha fetoprotein, and carcinoembryonic antigen), pituitary function, and brain images were reviewed and analyzed. Results: This study included 49 patients (37 boys and 12 girls). Their ages ranged from 7.5 to 17.9 years, and the mean age at diagnosis was 13.6 years. Initial symptoms included visual disturbance (n = 23, 47.9%), motor impairment (n = 20, 40.8%), polyuria (n = 20, 40.8%), headache (n = 17, 34.7%), dizziness or vertigo (n = 14, 28.6%), nausea/vomiting (n = 13, 26.5%), and short stature (n = 8, 18.2%). Laboratory data indicated growth hormone deficiency or low IGF-1 levels (n = 18, 85.7%), adrenal insufficiency (n = 21, 77.8%), central diabetes insipidus (n = 27, 55.1%), central hypothyroidism (n = 15, 48.4%), and hypogonadotropic hypogonadism (n = 4, 44.4%). Conclusion: Intracranial pure germinomas may initially manifest as neurological symptoms or endocrinological findings at diagnosis. As endocrinologic presentation is related to delayed diagnosis, clinicians should be aware of patients with such complaints. Laboratory data should be surveyed carefully, and neuroimaging must be considered if the result is abnormal.

Background: Angiostrongylus cantonensis is an important etiologic agent of eosinophilic meningitis and/or eosinophilic meningoencephalitis in humans. Th2 responses have been considered to be predominant in non-permissive hosts. However, changes of cytokines in the central nervous system of the host remain unclear. The present study was conducted to determine the temporal-spatial expressions of IL-4, IL-10, and IL-13 in the brains of infected C57BL/6 and BALB/c mice by immunohistochemistry. Methods: After infecting each mouse with 25 third-stage larvae (L3), brain specimens were collected on day 7 and day 28 post-infection. Each specimen was cut into five sections and stained with corresponding antibodies of the three cytokines. Results: In infected C57BL/6 mice, high IL-4 expressions were found in the isocortex, IL-10 in the isocortex, olfactory area, hippocampus, cerebral nuclei, hypothalamus, cerebellum nuclei, and medulla, and IL-13 in the isocortex and cerebellum. In infected BALB/c mice, IL-4 and IL-10 were highly expressed in the isocortex, olfactory areas, cerebral nuclei, hypothalamus, and cerebellum nuclei and IL-13 in the thalamus and hypothalamus. High levels of the cytokines were usually detected in on day 7 in BALB/c mice and day 28 in C57BL/6 mice. Conclusion: The special temporal-spatial expression changes of these three cytokines in the infected mouse brain may explain the differences in the survival and the time of occurrence of immune responses in the hosts after A. cantonensis infection.

Background/purpose: Ovarian clear cell carcinoma (OCCC) with recurrence/progression after treatment has dismal prognosis. We aimed to investigate the management and outcomes of such patients. Methods: OCCC patients who were treated between 2000 and 2013 with cancer recurrence or progression after primary treatment were analyzed. Univariate and multivariate analyses were used to identify the independent predictors of survival after recurrence (SAR) and cancer-specific survival (CSS). Results: A total of 64 patients experienced treatment failure (49 recurred after remission and 15 progressed without remission). The 5-year CSS rates of recurrent/progressive OCCC patients were 22.9% (progression group: median CSS 5.9 months [range, 0.8–25.2] vs recurrence group: 43.6 months [range, 7.1–217.8]; p 12 months (HR: 0.22–0.40, p = 0.001 and p = 0.023), CA125

Background: Pasteurella aerogenes is a gram-negative coccobacilli commensal in animals, rarely describe in human infection. We describe the first case of infective endocarditis caused by Pasteurella aerogenes, a rare pathogen in human infections that usually results from domestic animal bites. Case presentation: This is a case of a 21-year old Taiwanese man who initially presented headache and intermittent fever without any specific neurologic sign. Investigations revealed a diagnosis of infective endocarditis with mitral valve involvement and blood culture growing P. aerogenes. He recovered well after surgical intervention with the completion of antibiotic therapy. Conclusion: P. aerogenes cause human infection, mostly soft tissue infection by exposure to domestic animals and pets. Our case highlights that endocarditis should be considered in bacteremia with this pathogen.

Inflammatory pseudotumor (IPT) is a non-neoplastic condition of unknown etiology. IPT with lower cranial nerve (CN IX, X, XI, XII) neuropathies is extremely rare. In this study, we systematically reviewed all previously reported cases regarding the management of IPT with lower cranial nerve neuropathies. We searched the PubMed/MEDLINE database for reports related to IPT with lower cranial nerve neuropathies. A total of six papers with 10 cases met the inclusion criteria (mean age 51.6 years, 70% male). The mean follow-up period was 15.4 months (range: 1–60 months). The most frequent treatment was corticosteroids alone (60%), followed by surgery alone (20%), and multimodal treatment (20%). Corticosteroid therapy was associated with an excellent (100%) response rate at 6 months of follow-up, and half of the patients were in complete remission after 9 months. Both cases who received surgery had persistent neurological deficits. Immediate complete remission of neurological symptoms and resolution on imaging after decompression surgery via an endoscopic endonasal approach (EEA) with corticosteroids was demonstrated in our representative case. This review suggests that EEA is a preferred method for diagnosis and treatment, a promising approach associated with favorable outcomes, and a viable first-line treatment for selected cases, followed by multimodal therapy.

PURPOSE: The aim is to describe histopathologic observations in eyes enucleated after selective ophthalmic arterial injection (SOAI) of melphalan for retinoblastoma (RB). STUDY DESIGN: This is retrospective clinical study. PATIENTS AND METHODS: Histopathologic analysis of 14 eyes (13 patients) from May 2008 through January 2015 at Chang Gung Memorial Hospital. RESULTS: The eyes after SOAI were enucleated due to tumor viability (n = 7, 2 with vitreous hemorrhage), neovascular glaucoma (n = 4), lens drop to vitreous with total hyphema and elevated intraocular pressure (n = 1), retinal detachment (RD) progressed (n = 1), and persistent RD with phthisis change (n = 1). Almost all of the eyes showed vitreous seeding (n = 11 eyes) before treatment. After the treatment of SOAI, the histopathological examination revealed complete regression in four eyes with one was clinically diagnosed as viable tumor and progression, one with RD progression, and two as neovascular glaucoma. Six eyes showed invasion into the optic nerves, reaching the lamina cribrosa in five eyes, and six eyes with invasion into the choroid were observed. All of the cases with lamina cribrosa involvement showed tumor progression before enucleation, four cases with lamina cribrosa involvement expired later. CONCLUSION: Although some cases of RB can be controlled effectively with SOAI, but for refractory cases after SOAI, earlier decision of enucleation may be needed.

Background: Pituicytes are glial cells supporting hypothalamic axons in the posterior pituitary gland. Pituicytoma arises from pituicytes, and is currently classified as a World Health Organization grade I central nervous system tumor. Clinically, some patients with pituicytoma are misdiagnosed with functioning pituitary adenoma before surgical interventions and pathological examinations. This study was designed to investigate the correlation between pituicytoma and abnormal hormone function. Methods: The records of patients who underwent pituitary surgery at Linkou Chang Gung Memorial Hospital between 2000 and 2016 were reviewed. Patients with a pathological diagnosis of pituicytoma were included. Among these patients, those with inadequate data and/or specimens were excluded. Clinical information including presenting symptoms, serum hormone level, neuroimages, and results of pathological examinations including hematoxylin and eosin stains and immunohistochemical stains were collected for analysis. Results: Between 2000 and 2016, eight patients were pathologically diagnosed with pituicytoma. Two patients were excluded due to missing data and/or specimens. Among the six remaining patients, five presented with hormone changes. The immunohistochemical stains of pituicytoma confirmed no secretory function; however, the surrounding pituitary glandular tissue showed positive results responsible for clinical hormone changes. Conclusions: Pituicytoma had a negative endocrine secretory function in this study. However, pituicytoma was associated with hyperactivity of the surrounding pituitary glandular tissue, which resulted in clinically abnormal hormone secretion. The diagnosis of pituicytoma before a thorough pathological examination is difficult when the patients present with hormone dysfunction. Therefore, maximum resection of the pituitary tumor is necessary to make the diagnosis of pituicytoma and to exclude pituitary adenoma. Keywords: Pituicytoma, Pituitary gland, Abnormal hormone secretion, Pituitary adenoma, Immunohistochemical stain

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.

Abstract Background To present a case of conjunctival lymphoma in a young woman complicated by pregnancy. Case presentation A 38-year-old previously healthy woman presented with a 2-year history of progressive right blepharoptosis. Giant papillomatous sessile masses were identified in the upper and lower fornix bilaterally and involved the tarsus of the right upper lid. The remaining ophthalmic examination was unremarkable. Histopathology and immunohistochemistry showed mucosa-associated lymphoid tissue (MALT) lymphoma with immunoglobulin kappa monotype. Further workup showed no evidence of systemic lymphoma or orbital involvement. Conclusions Partial regrowth of conjunctival lymphoma occurred 6 months after excision and the MALT lymphoma remained indolent during the course of her pregnancy without radiotherapy.

Administration of albendazole alone was not very suitable for the treatment of cerebral angiostrongyliasis. This study was designed to evaluate the effects of the co-therapy of this drug and dexamethasone in Th-1 and Th-2 dominant mice infected with Angiostrongylus cantonensis. Each of BALB/c and C57BL/6 mice infected with 50 A. cantonensis third-stage larvae were administered albendazole (10 mg/kg/day) alone, dexamethasone (0.5 mg/kg/day) alone, or co-therapy of the two drugs from day 7 or 14 post-infection for 7 or 14 days. After sacrifice, coronal slices were prepared from five brain regions and stained with hematoxylin and eosin. Eight pathological changes were employed to determine the therapeutic effectiveness using a scoring system. RNA-seq analysis was performed to confirm the histopathological findings. The infected BALB/c and C57BL/6 mice had similar patterns in the pathological changes. Meningitis, hemorrhage, size of worms, and encephalitis in the cerebral parenchyma were slighter in the mice treated with co-therapy than the remaining groups. Mice treated from day 14 had more severe changes than those from day 7. The histopathological findings were found to be consistent to immune responses determined by RNA-seq analysis. Co-therapy was determined to reduce pathological changes after administration to mice infected with A. cantonensis.

Human papillomavirus (HPV) is associated with neuroendocrine carcinoma of the cervix and lung. However, these two uncommon cancers rarely occur in a single patient, especially with the same HPV type. We herein present a 65-year-old non-smoker female who developed mixed adenoneuroendocrine carcinoma of the lung with lymph node, brain and adrenal gland metastases 6 years after the diagnosis of stage IA1 cervical mixed adenoneuroendocrine carcinoma. The patient's brain, lung and previous cervix specimens were identically HPV type 18 positive. To our knowledge, this is the first report of a patient with the same HPV type associated mixed adenoneuroendocrine carcinoma in different sites.

Background/Objective: Microwave-based devices target sweat glands through energy delivery at the dermal–subcutaneous interface. These devices have been approved by the Food and Drug Administration as a noninvasive treatment for axillary hyperhidrosis. Treatment for osmidrosis has only been reported in one preliminary study. This study aimed to investigate the efficacy, safety, and histological changes of the microwave-based devices in treating axillary osmidrosis. Methods: We conducted a prospective study in a tertiary referral center in Taiwan. Patients with axillary osmidrosis were recruited and received two consecutive treatment sessions with a 3-month interval. Skin biopsy was obtained to evaluate histological changes. The efficacy was determined by odor reduction using a patient reported 10-point odor scale. Responders were defined as participants with a reduction of at least 3 points of the Odor-10 score at their 90-day follow-up visit. Results: Seven patients were enrolled. Mean reduction of odor was 61.8%. Six patients met the primary endpoint of odor reduction. Skin biopsy specimens reveled 93% reduction of apocrine glands. Histopathological changes include dermal fibrosis, necrosis of sweat glands, and subcutaneous fat necrosis. Transient swelling, bruise, numbness, lumps, and hypotrichosis were possible side effects. No patient reported disabling side effects. Conclusion: Microwave-based devices are noninvasive and a potential alternative therapeutic modality for axillary osmidrosis treatment.

Malignant triton tumor (MTT) is a highly aggressive malignant neoplasm, classified as a variant of malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation. MTT is rarely reported in children, and its true prevalence may be underestimated. We herein report such a case in an 8-year-old boy who presented with a mass over the trapezius muscle. He was previously diagnosed with neurofibromatosis in the same area. Four years later, a follow-up magnetic resonance imaging revealed an intradural tumor recurrence at the level of C1–C7. An immunohistochemical test result was positive for S-100 protein and desmin, which confirmed the diagnosis. The patient outcome was fatal despite multimodal therapy. The possibility of this rare but devastating tumor must always be considered when patients present with new compressive spinal symptoms.

Objective: To evaluate the efficacy and toxicity of topical imiquimod for the treatment of persistent human papillomavirus (HPV) infection in patients with or without cervical/vaginal intraepithelial neoplasia (CIN/VAIN). Methods: Patients with persistent HPV infection (≥1 year) after a history of treatment for cervical or vaginal neoplasm but normal histology and cytology, abnormal Papanicolaou (Pap) smears without abnormal histology, and untreated histology-documented CIN/VAIN Grade 1/2/3 with HPV-positive testing were recruited. Patients were instructed to apply 250 mg of 5% imiquimod cream intravaginally on consecutive days or at least twice weekly on an outpatient basis for a minimum of 12 doses. A group of age- and previous diagnosis-matched, imiquimod-untreated historical controls (n = 20) were selected. The main outcome measures included HPV DNA detection, cytology, and colposcopy/histology at 6 months after treatment. Results: A total of 72 patients were eligible for analysis. At a median follow-up of 33.6 months, 37 patients (51.4%) had cytological/histological regression and tested HPV-negative. Six patients (8.3%) had progressive cytology/histology with persistent HPV infections. Of the 72 treated patients, 26 patients who had a normal Pap test but were persistently HPV-positive for at least 1 year had a complete regression rate of 65.4%, which was significantly different from the rate (30%) observed in the untreated historical control (p = 0.036). Six patients with histologically proven CIN2/3 or VAIN2/3 had a complete regression rate of 66.6% (4/6). Conclusions: The tolerability of intravaginal self-administered imiquimod is confirmed. Its efficacy in the treatment of women with persistent HPV infection and normal cytology warrants further randomized, controlled trials to determine appropriate dosages and scheduling.

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.

We report the case of a 68-year-old man with a 6-year history of renal cell carcinoma (RCC), who presented with severe low backache and paraparesis for a month before admission. In addition, he experienced urinary retention for 2 weeks. A spinal magnetic resonance imaging scan revealed the presence of an intradural extramedullary solitary mass at the conus medullaris. We performed a laminectomy and completely excised the tumor. The histopathological findings were suggestive of spinal metastasis of RCC. After the operation, the patient did not complain of backache and urinary retention, and paraparesis improved significantly. Spinal metastases of RCC are usually extradurally located. Intradural metastases of RCC are rare. Thus far, only six cases of RCC metastasizing to the cauda equina have been reported; however, RCC metastasis to the conus medullaris has not yet been reported. Conus medullaris lesions may cause symmetrical motor and sensory deficits accompanied by early autonomic system impairment. Surgery is the treatment of choice in cases of resectable RCC metastases, especially in cases of solitary metastasis.

Brain-specific angiogenesis inhibitor 1 (BAI1)-associated protein 2-like 1 (BAIAP2L1), also known as insulin receptor tyrosine kinase substrate (IRTKS), is involved in plasma membrane protrusion and actin formation during cell morphogenesis and migration. BAIAP2L1 is recently reported to promote cell proliferation through activation of the EGFR-ERK pathway in hepatocellular carcinoma. In this study, we report the first comprehensive study of BAIAP2L1 upregulation in human ovarian cancer. Upregulation of BAIAP2L1 in ovarian tumors was first found during RNA screening and confirmed by immunohistochemical studies on ovarian cancers and other cancer types. Significant upregulation of BAIAP2L1 in ovarian cancer was validated by analyzing multiple independent cohorts in publicly available data sets. Furthermore, BAIAP2L1 protein expression in metastatic lesions was higher than the corresponding primary tumors. Functional assays in ovarian cancer cells revealed that BAIAP2L1 is involved in promoting cell proliferation and avoiding apoptosis. In conclusion, results of this study not only indicate that BAIAP2L1 can be used as a biomarker for human ovarian cancer but also reveal its role in cancer biology. Further elucidation of the role of BAIAP2L1 in context of the insulin receptor signaling pathways of cancer cells is warranted for developing cancer therapeutics by targeting cancer-specific metabolism.

Objectives. Pantothenate kinase-associated neurodegeneration (PKAN) is a rare disease caused by pantothenate kinase 2 (PANK2, OMIM 606157) mutations. This study is aimed to investigate clinical presentations, pathologies, and genetics in patients with PKAN. Methods. Two patients with PKAN were reported. We reviewed the literature to include additional 19 patients with PKAN in Eastern Asia. These patients were divided into classic and atypical groups by the age of onset. We compared the data on PKAN patients of Asian and Caucasian populations. Results. We found iron deposits in the globus pallidus in our Patient 1 and a heterozygous truncating mutation (c.1408insT) in Patient 2. Literature review shows that generalized dystonia and bulbar signs are more common in classic PKAN patients, whereas segmental dystonia and tremors are more specific to atypical ones. Asian patients have less complex presentations—lower prevalence of pyramidal signs, mental impairment, and parkinsonism—than Caucasians. D378G in exon 3 is the most frequent mutation (28%) in Asians. Conclusions. Our study demonstrates that the distribution of dystonia is the major distinction between subgroups of PKAN. Caucasian patients have more complex presentations than Asians. Exon 3 and 4 are hot spots for screening PANK2 mutations in Asian patients.

In 1998, an outbreak of enterovirus 71-associated hand, foot, and mouth disease occurred in Taiwan. Pathologic studies of two fatal cases with similar clinical features revealed two different causative agents, emphasizing the need for postmortem examinations and modern pathologic techniques in an outbreak investigation.