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PurposeThe current study aimed to identify the overall characteristics of cancer-related emergency department (ED) visits by adult in Korea, including analyses of factors associated with ED stay time and outcomes nationwide. Materials and MethodsWe collected data on cancer-related ED visits from the National Emergency Department Information System (NEDIS) database between 2017 and 2019. ResultsED visits by cancer patients comprised 5.5% (667,935 visits) of total ED visits from 2017 to 2019, which was slightly higher than in other counties. Patients with cancer who visited the ED were over 50 years old, the majority being males, and patients with cancer visited EDs in certified tertiary hospitals more frequently than patients without cancer. In multivariate analyses, the adjusted odds ratio for a length of stay more than 8 hours in the ED of certified tertiary hospitals was 126.34 (95% confidence interval, 1.422 to 1.460) when compared to hospitals. Nevertheless, the longer the patients stayed in the ED, the more likely they were to be admitted. ConclusionThe longer ED stay and higher proportion of cancer patient hospitalizations suggest that cancer patients visit ED to be admitted as well as to receive acute care. The frequency of ED visits and admission may be adjusted to some extent depending on outpatient education, such as self-management of symptoms and situations. Improving cancer care in local communities should be met though provisions such as linking treatment between hospitals or supplying appropriate medical personnel, even for the efficient use of ED resources in hospitals.

Background and aims Oxidative stress contributes to development of diabetic nephropathy. We implicated SH3YL1 in oxidative stress-induced inflammation and examined whether SH3YL1 could be used as a new biomarker of diabetic nephropathy. Methods and results In this study, we investigated the relationship between plasma level of SH3YL1 and diabetic nephropathy in patients with type 2 diabetes. In addition, we examined the physiological role of SH3YL1 in db/db mice and cultured podocytes. Plasma SH3YL1 concentration was significantly higher in patients with diabetes than in controls, even in normoalbuminuric patients, and was markedly increased in the macroalbuminuria group. Plasma SH3YL1 level was positively correlated with systolic blood pressure, HOMA-IR, postprandial blood glucose, plasma level of retinol binding protein 4 (RBP 4), and urinary albumin excretion (UAE) and was inversely correlated with BMI. Regression analysis showed that plasma level of RBP 4, UAE, and BMI were the only independent determinants of plasma SH3YL1 concentration. In db/db mice, plasma and renal SH3YL1 levels were significantly increased in mice with diabetes compared with control mice. In cultured podocytes, high glucose and angiotensin II stimuli markedly increased SH3YL1 synthesis. Conclusion These findings suggest that plasma level of SH3YL1 offers a promising new biomarker for diabetic nephropathy.

Purpose It is important to understand the differences between men and women when it comes to attitudes and risk perception toward disease. This study aimed to explore the fear of cancer from the standpoint of themselves and the opposite sex by cancer type. Materials and methods A cross-sectional survey with a representative sample was conducted. Results The least and the most feared cancers in men were thyroid cancer and lung cancer, respectively. When men assumed the perspective of women, the least and the most feared cancer were thyroid cancer and stomach cancer, respectively. The least and the most feared cancers in women were thyroid cancer and stomach cancer, respectively. When women assumed the perspective of men, the least and the most feared cancer were prostate cancer and lung cancer, respectively. When both men and women assume the perspective of the opposite sex, the fear of sex-specific cancer was relatively low compared to the actual responses of both men and women. The top six of the most feared side effects of cancer treatment were pain, psychological problems, general weakness, digestive dysfunction, fatigue, and appearance change. These were the same between men and women. Conclusion Health care providers and caregivers in the family should provide care with more attention to the differences in thoughts about cancer between men and women. Health care providers should provide care with more attention to the differences in these problems between men and women.

Endoplasmic reticulum (ER) stress is associated with tumor development and progression via pro-tumorigenic and anti-tumorigenic effects. However, the clinicopathological implications of the ER stress pathway in non-small cell lung cancer remain unclear. Therefore, we sought to address these issues in this study.Expression of two ER stress-related proteins, GRP78 and XBP1 spliced-form (XBP1s), was evaluated in pulmonary adenocarcinoma (pADC; n = 369) and squamous cell carcinoma (pSqCC; n = 246) using immunohistochemistry.Expression levels of GRP78 and XBP1s were significantly higher in pADCs and pSqCCs, respectively (both, P0.0001). In the pADC group, XBP1s expression was higher in patients with ALK translocation than in those with wild-type ALK, wild-type EGFR, or EGFR mutation (P0.005). No significant difference in GRP78 expression according to ALK or EGFR status was noted. pADC harboring high GRP78 expression exhibited an increased XBP1s expression (P = 0.0067). Higher XBP1s expression was associated with shorter disease-free survival (DFS) in patients with pADC (P = 0.026) and in those with ALK translocation (P = 0.001). Higher GRP78 expression was associated with shorter DFS in patients with pADC (P = 0.029) and those with EGFR mutation (P = 0.005). Multivariate survival analysis revealed that high XBP1s expression was an independent predictor of poor DFS in pADC (P = 0.004, hazard ratio [HR] = 3.115), and that high GRP78 expression was an independent predictor of poor DFS in EGFR-mutated pADC (P = 0.007, HR = 2.168). Taken together, high expression of XBP1s or GRP78 was an independent poor prognostic factor in pADC (P = 0.002, HR = 2.403).GRP78 and XBP1s are expressed variably in pADC, but their overexpression is associated with poor patient prognosis. The ER stress pathway may be a prognostic biomarker and potential therapeutic target for pADC.

ObjectiveChanges in the clinicopathological characteristics and genetic alterations of follicular thyroid cancer (FTC) over time have not been reported. Moreover, the prognostic effects ofRASandTERTpromoter mutations in FTC have not been clearly elucidated. We investigated changes in the clinicopathological characteristics of patients with FTC over four decades, as well as the clinical significance of genetic mutations of FTC.Design and methodsThis retrospective study included 690 patients with FTC who underwent thyroidectomy between 1973 and 2015 at the Seoul National University Hospital. In 134 samples, genetic tests forN/H/KRASandTERTpromoter mutations andPAX8/PPARγrearrangement were performed.ResultsThe age at diagnosis has increased (P P = 0.033). Other clinicopathological characteristics and prognosis of FTC have not significantly changed. The prevalence ofRASmutations decreased (P = 0.042) over time, whereas that ofTERTpromoter mutations remained stable.RASmutations were associated with distant metastasis and persistent disease, andTERTpromoter mutations were associated with distant metastasis, advanced TNM stage, recurrence and disease-specific mortality. FTC patients with coexistentRASandTERTpromoter mutations showed a higher recurrence risk than those with only one mutation.ConclusionsThe age at diagnosis of FTC and the frequency of extrathyroidal extension have changed over four decades. Moreover, the prevalence ofRASmutations decreased.RASandTERTpromoter mutations may be associated with poor clinical outcomes in FTC, especially when the two mutations coexist.

PURPOSE As the recent term of "financial toxicity" implies, cancer causes a treatment-related financial harm. Financial Aid Program for Cancer Patient (FAPCP) is a government's financial support for low-income patients in the Republic of Korea. This study aimed to describe FAPCP applicants' condition and to investigate factors influencing financial burden, which would provide the basis for implementing a strategy for FAPCP administration. Materials and Methods The telephone survey results from 2,700 FAPCP participants were analyzed, including demographic, socioeconomic, and disease characteristics and experiences associated with financial burden and the actions or measures to cope with them. RESULTS Overall, 87.6% experienced financial burden more than moderate degree, 39.2% got financial help/a loan, 17.8% disposed of their property, and 10.2% changed or stopped treatment owing to medical costs. Monthly household income was connected to financial burden, and the highest income group was associated with the lowest financial burden (odds ratio [OR], 0.21; 95% confidence interval [CI], 0.11 to 0.38) and the lowest rate of changing/stopping care (OR, 0.23; 95% CI, 0.05 to 1.00). Parents of childhood cancer patients got financial help/a loan (OR, 2.24; 95% CI, 1.03 to 4.88) and disposed of their property (OR, 3.18; 95% CI, 1.40 to 7.22) more frequently, and Medical Aids applicants showed the highest rate of changing/stopping care (OR, 3.01; 95% CI, 1.89 to 4.78). CONCLUSION FAPCP targets low income groups; however, financial burden and the consequent actions taken still exist disproportionately, depending on the income of the applicants. FAPCP should focus on more vulnerable groups including Medical Aid applicants and parents of childhood cancer patients, by increasing funds and expanding their support coverage.

To evaluate the prognostic significance of phosphorylated Akt (p-Akt), phosphorylated mammalian target of rapamycin (p-mTOR), and total phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expressions in patients undergoing adjuvant chemoradiotherapy (CRT) for proximal extrahepatic bile duct (EHBD) cancer.Sixty-three patients with proximal EHBD cancer who underwent curative resection followed by adjuvant CRT were enrolled into this study. Postoperative radiotherapy was delivered to tumor bed and regional lymph nodes up to a median of 40 Gy (range, 40 to 54 Gy). Fifty-nine patients also received fluoropyrimidine chemotherapy as a radiosensitizer. p-Akt, p-mTOR, and PTEN expression were assessed with immunohistochemical staining on the tissue microarray.p-Akt, p-mTOR, and PTEN were expressed in 23 (36.5%), 17 (27.0%), and 24 patients (38.1%), respectively. p-Akt expression was associated with distant metastasis and overall survival (OS), but not with locoregional recurrence. The 5-year distant metastasis-free and OS rates were 25.8% versus 58.2% (P=0.007), and 27.5% versus 50.2% (P=0.0167) in patients with negative and positive expression, respectively. On multivariate analysis, nodal involvement was the only significant prognosticator predicting inferior distant metastasis-free survival (P=0.0105), whereas p-Akt expression had a borderline significance (P=0.0541). As for OS, p-Akt expression was a marginally significant prognosticator (P=0.0635), whereas other risk factors lost the statistical significance.p-Akt expression tended to be associated with a favorable prognosis in patients undergoing curative resection followed by adjuvant CRT for proximal EHBD cancer.

Background Fibroblasts are ubiquitous cells in the human body and are absolutely necessary for wound healing such as for injured skin. This role of fibroblasts was the reason why we aimed to differentiate human adipose-derived stem cells (hADSCs) into fibroblasts and to test their wound healing potency. Recent reports on hADSC-derived conditioned medium have indicated stimulation of collagen synthesis as well as migration of dermal fibroblasts in wound sites with these cells. Similarly, human fibroblast-derived conditioned medium (F-CM) was reported to contain a variety of factors known to be important for growth of skin. However, it remains unknown whether and how F-CM can stimulate hADSCs to secrete type I collagen. Methods In this study, we obtained F-CM from the culture of human skin fibroblast HS27 cells in DMEM media. For an in-vivo wound healing assay using cell transplantation, balb/c nude mice with full-thickness skin wound were used. Results Our data showed that levels of type I pro-collagen secreted by hADSCs cultured in F-CM increased significantly compared with hADSCs kept in normal medium for 72 h. In addition, from a Sircol collagen assay, the amount of collagen in F-CM-treated hADSC conditioned media (72 h) was markedly higher than both the normal medium-treated hADSC conditioned media (72 h) and the F-CM (24 h). We aimed to confirm that hADSCs in F-CM would differentiate into fibroblast cells in order to stimulate wound healing in a skin defect model. To investigate whether F-CM induced hADSCs into fibroblast-like cells, we performed FACS analysis and verified that both F-CM-treated hADSCs and HS27 cells contained similar expression patterns for CD13, CD54, and CD105, whereas normal medium-treated hADSCs were significantly different. mRNA level analysis for Nanog, Oct4A, and Sox2 as undifferentiation markers and vimentin, HSP47, and desmin as matured fibroblast markers supported the characterization that hADSCs in F-CM were highly differentiated into fibroblast-like cells. To discover the mechanism of type I pro-collagen expression in hADSCs in F-CM, we observed that phospho-smad 2/3 levels were increased in the TGF-β/Smad signaling pathway. For in-vivo analysis, we injected various cell types into balb/c nude mouse skin carrying a 10-mm punch wound, and observed a significantly positive wound healing effect in this full-thickness excision model with F-CM-treated hADSCs rather than with untreated hADSCs or the PBS injected group. Conclusions We differentiated F-CM-treated hADSCs into fibroblast-like cells and demonstrated their efficiency in wound healing in a skin wound model.

Background/aims Recent studies have suggested an important role of adipokines in the development of insulin resistance and diabetes mellitus. The clinical relevance of adipokines on long-term outcomes in patients with diabetes and chronic kidney disease is uncertain. The purpose of this study was to identify a predictable factor in patients with long-term diabetic complications. Methods A total of 161 diabetic individuals were followed-up from 2002 to 2013. Circulating plasma levels of adiponectin, glypican-4, irisin, visfatin, and visit-to-visit glucose variability were measured in diabetic patients. Associations among adipokines and variable metabolic parameters and microvascular, and macrovascular complications were evaluated. Results Plasma adiponectin and glypican-4 levels were significantly increased in patients with renal insufficiency. These adipokines were negatively associated with estimated glomerular filtration rate and positively associated with urinary albumin excretion. The relative risk of renal progression to dialysis increased independently with increasing level of adiponectin. Glypican-4 and visfatin were not predictive of any microvascular or macrovascular complications. Glucose variability increased the risk of diabetic nephropathy and cerebrovascular complications. Conclusions Adiponectin and glypican-4 were associated with renal function and might be able to predict renal progression. Glucose variability was a predictable factor for diabetic nephropathy and cerebrovascular complications.

The concentration of adenosine in the normal kidney increases markedly during renal hypoxia, ischemia, and inflammation. A recent study reported that an A3 adenosine receptor (A3AR) antagonist attenuated the progression of renal fibrosis. The adriamycin (ADX)-induced nephropathy model induces podocyte injury, which results in severe proteinuria and progressive glomerulosclerosis. In this study, we investigated the preventive effect of a highly selective A3AR antagonist (LJ1888) in ADX-induced nephropathy. Three groups of six-week-old Balb/c mice were treated with ADX (11 mg/kg) for four weeks and LJ1888 (10 mg/kg) for two weeks as following: 1) control; 2) ADX; and 3) ADX + LJ1888. ADX treatment decreased body weight without a change in water and food intake, but this was ameliorated by LJ1888 treatment. Interestingly, LJ1888 lowered plasma creatinine level, proteinuria, and albuminuria, which had increased during ADX treatment. Furthermore, LJ1888 inhibited urinary nephrin excretion as a podocyte injury marker, and urine 8-isoprostane and kidney lipid peroxide concentration, which are markers of oxidative stress, increased after injection of ADX. ADX also induced the activation of proinflammatory and profibrotic molecules such as TGF-β1, MCP-1, PAI-1, type IV collagen, NF-κB, NOX4, TLR4, TNFα, IL-1β, and IFN-γ, but they were remarkably suppressed after LJ1888 treatment. In conclusion, our results suggest that LJ1888 has a renoprotective effect in ADX-induced nephropathy, which might be associated with podocyte injury through oxidative stress. Therefore, LJ1888, a selective A3AR antagonist, could be considered as a potential therapeutic agent in renal glomerular diseases which include podocyte injury and proteinuria., Graphical Abstract

Objectives: Previous studies have obtained conflicting findings regarding possible associations between indices measuring carbohydrate intake and dyslipidemia, which is an established risk factor of coronary heart disease. In the present study, we examined cross-sectional associations between carbohydrate indices, including the dietary glycemic index (GI), glycemic load (GL), total amount of carbohydrates, and the percentage of energy from carbohydrates, and a range of blood lipid parameters. Methods: This study included 1530 participants (554 men and 976 women) from 246 families within the Healthy Twin Study. We analyzed the associations using a generalized linear mixed model to control for familial relationships. Results: Levels of the Apo B were inversely associated with dietary GI, GL, and the amount of carbohydrate intake for men, but these relationships were not significant when fat-adjusted values of the carbohydrate indices were used. Triglyceride levels were positively associated with dietary GI and GL in women, and this pattern was more notable in overweight participants (body mass index [BMI] ≥25 kg/m2). However, total, low-density lipoprotein and high-density lipoprotein cholesterol levels were not significantly related with carbohydrate intake overall. Conclusions: Of the blood lipid parameters we investigated, only triglyceride levels were positively related with dietary carbohydrate indices among women participants in the Healthy Twin Study, with an interactive role observed for BMI. However, these associations were not observed in men, suggesting that the association between blood lipid levels and carbohydrate intake depends on the type of lipid, specific carbohydrate indices, gender, and BMI.

Background Mesenteric lymphatic malformations (MLs) are a heterogeneous group of benign diseases of the lymphatic system that present with cystic dilated lymphatics of the mesentery. MLs are rare and represent less than 5% of all lymphatic malformations. The aims of this study were to analyze the characteristics of MLs in children and to suggest a modified classification. Patients and methods We investigated 25 patients who underwent ML surgery. The clinical data and pathological findings were reviewed retrospectively. We divided the patients into 4 groups according to the operative findings. Group 1 included patients with MLs involving the intestinal walls. Group 2 included patients with pedicle-type MLs with no relationship to the mesenteric vessels. Group 3 patients presented with MLs located in the mesenteric boundaries near the mesenteric vessels. Group 4 patients had multicentric and diffusely infiltrated MLs. Result The male-to-female ratio was 11:14, and the median age at diagnosis was 5years of age. The most common symptom was abdominal pain. The jejunal mesentery was the most frequently involved site in this study. Five patients showed the macrocystic type and 20 patients showed the mixed cystic type. With the exception of one patient with a large mixed cystic-type ML who underwent incomplete mass excision, 24 patients underwent complete mass excision. The group 1 patients (n=14) underwent mass excision performed with segmental resection of the bowel. The group 2 patients (n=3) only underwent mass excision surgery. The patients in group 3 (n=7) underwent mass excision with segmental resection of the intestine because ML excision altered the blood supply of the adjacent intestines. The group 4 patients (n=1) presented with MLs involving the entire mesentery and underwent incomplete excision. Conclusion The relationships between MLs and the neighboring organs determine the surgical strategy, and the size and location of MLs affect the operative methods. The modified classification based on these findings can facilitate effective treatment planning.

We prepared a bone plate enabled with the local, sustained release of alendronate, which is a drug known to inhibit osteoclast-mediated bone resorption and also expedite the bone-remodeling activity of osteoblasts. For this, we coated a bone plate already in clinical use (PLT-1031, Inion, Finland) with a blend of alendronate and a biocompatible polymer, azidobenzoic acid-modified chitosan (i.e., Az-CH) photo-crosslinked by UV irradiation. As we performed the in vitro drug release study, the drug was released from the coating at an average rate of 4.03μg/day for 63days in a sustained manner. To examine the effect on bone regeneration, the plate was fixed on an 8mm cranial critical size defect in living rats and the newly formed bone volume was quantitatively evaluated by micro-computed tomography (micro-CT) at scheduled times over 8weeks. At week 8, the group implanted with the plate enabled with sustained delivery of alendronate showed a significantly higher volume of newly formed bone (52.78±6.84%) than the groups implanted with the plates without drug (23.6±3.81%) (p

Acute invasive fungal rhinosinusitis (AIFRS) is a life-threatening disease that is difficult to diagnose. Its overall imaging features have not been evaluated and the prognostic impact is unclear. The purpose of our study was to present MR imaging features and their impact on prognosis of AIFRS. MR images and clinical records of 23 patients with AIFRS were retrospectively evaluated to identify the imaging features and to determine the factors affecting patients’ survival. A multivariable Cox proportional hazard model was used to estimate the hazard ratio of the prognostic factors, and Kaplan-Meier survival curves were compared by using a log-rank test. All cases showed extra-sinonasal involvement and the orbit was the most common (65.2%, 15/23) location. The lesion enhancement pattern was classified into lack of contrast enhancement (LoCE) (47.8%, 11/23) and homogeneous (34.8%, 8/23) and heterogeneous (17.4%, 4/23) enhancement. Although LoCE showed variable signal intensity (SI), homogeneously or heterogeneously enhancing lesions showed exclusively low SI (100%, 12/12) on T2WI. Among various clinical and imaging factors, LoCE was correlated with coagulation necrosis, probably provoked by numerous fungal hyphae, and was found to be a sole independent prognostic factor for disease-specific mortality (hazard ratio = 16.819; 95% CI, 1.646–171.841, p = 0.017). In addition, patients with LoCE showed worse survival than patients without LoCE (p = 0.008). AIFRS showed frequent extra-sinonasal involvement and variable MR enhancement patterns. An enhancement pattern of LoCE was seen in about half of the cases and was a unique prognostic factor among the various clinico-radiologic factors.

Background To better understand cancer-related health behaviors, it is critical to know how general populations with different socioeconomic and demographic backgrounds perceive cancer. The current paper explored differences in general attitudes and beliefs towards cancer among Koreans. Methods A cross-sectional national survey was conducted for 1,000 Korean participants who were not cancer patients and did not have immediate family members with cancer via proportional quota random sampling. General attitudes and beliefs about cancer were measured by face-to-face interview using the awareness and beliefs about cancer (ABC) measure. Results Most respondents (84.8%–88.5%) had optimistic attitudes towards cancer. However, 35.6% to 87.7% agreed with negative cancer beliefs across all age groups simultaneously. Socioeconomic disparity of positive cancer beliefs was not evident. Unexpectedly, the highest income group agreed more strongly with the negatively framed statements that cancer treatment is worse than the cancer itself (odds ratio [OR], 2.68; 95% confidence interval [CI], 1.31–5.53), that they would not want to know if they have cancer (OR, 1.61; 95% CI, 0.94–2.75), and that a cancer diagnosis is a death sentence (OR, 2.32; 95% CI, 1.34–4.01), than the lowest income group. Conclusion The present results imply a complicated context of cancer beliefs in Korea, unlike those shown in the studies of western populations. While the contradictory attitudes toward cancer can be attributable to the dual nature of information processing, social environment might have played a role. The association between socioeconomic status and negative attitudes toward cancer may vary depending on the diversity of the contexts., Graphical Abstract

Immunotherapies targeting the programmed cell death-1/programmed cell death-ligand 1 pathway have emerged as promising therapeutic strategies for lung cancer. However, the expression pattern and prognostic implications of programmed cell death-ligand 1 and 2 and programmed cell death-1 in comparison with the histology and genetic alterations in pulmonary adenocarcinomas remains unclear and thus were addressed here. Programmed cell death-ligand 1 and 2 expression in tumor cells and the quantities of programmed cell death-1(+) and CD8(+) tumor-infiltrating lymphocytes were immunohistochemically evaluated in 497 resected pulmonary adenocarcinomas and analyzed according to clinicopathological and genetic statuses. Programmed cell death-ligand 1 and 2 expression were observed in 59% and 64% of pulmonary adenocarcinomas, respectively, and showed a strong positive correlation with each other (P < 0.001). Programmed cell death-ligand 1 expression was higher in nodal metastasis cases (P = 0.006), smokers (P = 0.056), poorly differentiated tumors and histologic subtypes of solid and micropapillary patterns (P < 0.001). There was no significant difference in programmed cell death-ligand 1 and 2 expression according to EGFR mutation status. However, programmed cell death-ligand 1 expression was correlated with ALK translocation (P =0.054) and expression of EGFR and MET (P < 0.001). Meanwhile, programmed cell death-ligand 2 expression was correlated with ALK translocation (P = 0.052), and expression of MET (P < 0.001) and ERBB2 (P = 0.013). The numbers of CD8(+) and programmed cell death-1(+) lymphocytes were higher in smokers (P = 0.012 and 0.016) and MET-expressing adenocarcinomas (P < 0.001). Patients expressing programmed cell death-ligand 1 and/or high ratios of programmed cell death-1(+)/CD8(+) lymphocytes showed shorter disease-free survival (P = 0.001). Our study demonstrated that programmed cell death-ligand 1 and 2 expression varied with histology, EGFR, ALK, MET, and ERBB2 statuses, and activation of the programmed cell death-1/programmed cell death-ligand 1 pathway may be a poor prognostic factor in pulmonary adenocarcinomas.

This study was performed to determine the benefits of core needle biopsy (CNB), as compared with fine-needle aspiration (FNA), for the diagnosis of thyroid nodules with macrocalcifications.The institutional review board approved this retrospective study, and informed consent was waived. From February 2010 to March 2012, the study included 147 thyroid nodules with macrocalcification of 145 consecutive patients who underwent simultaneous FNA and CNB for each nodule. Diagnostic accuracy and inconclusive diagnoses, including nondiagnostic reading and atypia of undetermined significance or follicular lesion of undetermined significance reading were compared among FNA, CNB, and a combination of FNA and CNB (FNA/CNB) using McNemar's test; the benefits of CNB were calculated.Compared to FNA, CNB and FNA/CNB showed fewer inconclusive diagnoses (FNA vs. CNB: 62/147 [42.2%] vs. 14/147 [9.5%], p0.001; FNA vs.62/147 [42.2%] vs. 14/147 [9.5%], p0.001), resulting in the avoidance of repeat FNA or diagnostic surgery in 48 of 62 patients (77.4%, respectively in CNB and FNA/CNB) who would have undergone these procedures if only FNA was performed. Compared to FNA, FNA/CNB showed higher sensitivity and accuracy (sensitivity: 23/32 [71.9%] vs. 31/32 [96.9%], p=0.008; accuracy: 77/86 [89.5%] vs. 85/86 [98.8%], p=0.008), resulting in avoidance of delayed surgery in eight of nine patients (88.9%) with thyroid cancer in whom the surgery would have been missed if FNA only had been performed.In the workup of thyroid nodules with macrocalcification, compared with FNA alone, FNA/CNB decreases inconclusive diagnoses and increases sensitivity, thereby reducing repeated FNA procedures, diagnostic surgeries, and delayed therapeutic surgeries.

The number of patients requiring flat bone transplantation continues to increase worldwide. Cell transplantation has been successfully applied clinically; however, it causes another defect site and the time requirements to harvest cells and expand them are considerable. In this study, KLD12/KLD12-SP (KLD12+KLD12-substance P [SP]) was designed to mimic endogenous tissue-healing processes. The structures of KLD12, KLD12-SP, and KLD12/KLD12-SP were observed by transmission electron microscopy and circular dichroism spectra. KLD12/KLD12-SP nanofibers (5–10 nm) were created under physiological conditions by formation of a β-sheet structure. The ability of mesenchymal stem cells (MSCs) to recruit KLD12/KLD12-SP was observed by using an in vivo fluorescence imaging system. Labeled human bone marrow stromal cells supplied via an intravenous injection were recruited to the scaffold containing KLD12/KLD12-SP. Polylactic acid/beta-tricalcium phosphate (PLA/β-TCP) scaffolds filled with KLD12/KLD12-SP were applied to repair calvarial defects. The composite constructs (groups: defect, PLA/β-TCP, PLA/β-TCP/KLD12, and PLA/β-TCP/KLD12/KLD12-SP) were implanted into rat defect sites. Bone tissue regeneration was evaluated by observing gross morphology by hematoxylin and eosin and Masson's trichrome staining at 12 and 24 weeks after surgery. Gross morphology showed that the defect site was filled with new tissue that was integrated with host tissue in the KLD12/KLD12-SP group. In addition, from the staining data, cells were recruited to the defect site and lacunae structures formed in the KLD12/KLD12-SP group. From these results, the PLA/β-TCP+KLD12/KLD12-SP composite construct was considered for enhancement of bone tissue regeneration without cell transplantation.

The anaplastic lymphoma kinase (ALK) gene is frequently rearranged in various types of cancer and is highly responsive to targeted therapeutics. We developed a system to detect rearrangement of ALK in a large group of Korean thyroid cancer patients. We screened 474 malignant or benign thyroid tumor cases to identify ALK fusions. Expression and translocation of the ALK gene were analyzed by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and digital multiplexed gene expression (DMGE) analysis in formalin-fixed paraffin-embedded tissues. Four cases of rearrangement of ALK were detected by IHC, and these cases were validated with FISH on 189 samples. On the other hand, DMGE analysis using Nanostring detected three out of four IHC-positive cases. Two rearrangements of ALK were striatin (STRN)–ALK fusions, which were identified by 5′ RACE analysis. Rearrangements of ALK were found exclusively in v-raf murine sarcoma viral oncogene homolog B (BRAF) WT papillary carcinomas. Given the wide availability and accuracy of IHC for detecting ectopic expression of ALK in the thyroid, we suggest that IHC-based screening can be a practical method for identifying patients with ALK rearrangements in differentiated thyroid cancer.

Objectives The prevalence and risk of malignancy in thyroid incidentalomas has been investigated in previous studies; however, these studies have not looked at the characteristics of incidental thyroid cancer (ITC) detected by fluorine-18 fluorodeoxyglucose PET. Therefore, we aimed to assess the clinicopathologic features of ITC. Methods From March 2008 to December 2011, a total of 2892 patients underwent total thyroidectomy for papillary thyroid cancer. Among them, patients belonging to the ITC group were defined as those in whom focal thyroid uptake was reported as an incidental finding on PET imaging and further evaluation revealed the presence of malignancy. In addition, two control groups with non-PET incidental thyroid cancer (NITC) were selected: NITC-A patients (n=48) who underwent a total thyroidectomy in March 2008 and NITC-B patients (n=48) who underwent a total thyroidectomy for papillary thyroid cancer and were matched for the confounding effects of age and sex. Results There were no significant differences in clinicopathologic features, except for age and tumour node metastasis (TNM) staging, between ITC and NITC-A patients. More ITC than NITC-A patients were aged 45 years or older. Although T, N, or M staging was not different between ITC and NITC-A, there were more ITC patients with stage III/IV tumours. After matching for age and sex, none of the clinicopathologic features showed significant differences between ITC and NITC-B patients. Conclusion No significant differences were observed between ITC and NITC patients except for age and TNM staging. More ITC patients had advanced TNM stage most likely due to patient age.

Summary Aim: Serum antithyroglobulin antibody (TgAb) has been reported as a surrogate marker for differentiated thyroid cancer (DTC) in some conditions. We investigated changes in serum TgAb levels after stimulation with thyroid- stimulating hormone (TSH) and the clinical implications for monitoring DTC. Patients, methods: We retrospectively enrolled 53 DTC patients who had undergone total thyroidectomy and were negative for serum Tg and positive for TgAb. Patients underwent highdose radioactive iodine treatment, and serum TgAb was measured before (TgAbBAS) and after TSH stimulation (TgAbSTIM). TgAb was followed up 6 to 12 months later (TgAbF/U). The change in TgAb after TSH stimulation ΔTgAb- STIM) was calculated as a percentage of the baseline level. Patient disease status was classified into no residual disease (ND) and residual or recurred disease (RD) by follow-up imaging studies and pathologic data. The characteristics and diagnostic value of serum TgAb levels and ΔTgAbST|M were investigated with respect to disease status. Results: 38 patients were in the ND group and 15 were in the RD group. TgAbBAS, TgAbSTIM and TgAbF/U were significantly higher in the RD compared to the ND group (p = 0.0008, 0.0002, and < 0.0001, respectively). ΔTgAbSTIM was also significantly higher in the RD group (p = 0.0009). In the patients who presented with obviously high (> 50%) or low (< -50%) ΔTgAbSTIM, the proportions in the RD group were markedly different at 100% and 7%, respectively. ΔTgAbSTIM had significant diagnostic value for RD (p < 0.001). Conclusion: The change in serum TgAb level after TSH stimulation is different between the RD and ND groups, and thus, it may be used as a surrogate diagnostic marker for DTC when the serum Tg is negative and TgAb is positive.

Objective To retrospectively evaluate the risk of thyroid cancer in patients with hyperfunctioning thyroid nodules through ultrasonographic-pathologic analysis. Materials and methods Institutional review board approval was obtained and informed consent was waived. From 2003 to 2007, 107 patients consecutively presented with hot spots on thyroid scans and low serum thyroid-stimulating hormone levels. Among them, 32 patients who had undergone thyroid ultrasonography were analyzed in this study. Thyroid nodules depicted on ultrasonography were classified based on size and categorized as benign, indeterminate, or suspicious malignant nodules according to ultrasonographic findings. The thyroid nodules were determined as either hyperfunctioning or coexisting nodules and were then correlated with pathologic results. Results In 32 patients, 42 hyperfunctioning nodules (mean number per patient, 1.31; range, 1-6) were observed on thyroid scans and 68 coexisting nodules (mean, 2.13; range, 0-7) were observed on ultrasonography. Twenty-five patients (78.1%) had at least one hyperfunctioning (n = 17, 53.1%) or coexisting (n = 16, 50.0%) nodule that showed a suspicious malignant feature larger than 5 mm (n = 8, 25.0%), or an indeterminate feature 1 cm or greater (n = 20, 62.5%) in diameter, which could have been indicated by using fine needle aspiration (FNA). Seven patients were proven to have 11 thyroid cancers in 3 hyperfunctioning and 8 coexisting nodules. All of these had at least one thyroid cancer, which could have been indicated by using FNA. The estimated minimal risk of thyroid cancer was 6.5% (7/107). Conclusion Patients with hyperfunctioning nodules may not be safe from thyroid cancer because hyperfunctioning nodules can coexist with thyroid cancer nodules. To screen out these cancers, ultrasonography should be performed.

On occasion, a microscopic anaplastic focus (MAF) is discovered in papillary thyroid carcinoma (PTC). The relevance of MAF has not been well studied with regard to its clinical implications. MAF is defined as the microscopic presence of focally dedifferentiated follicular cells within the PTC.A total of 3,606 patients who underwent primary thyroid surgery between 1995 and 2007 were selected from the database of Seoul National University Hospital. Patients were divided into 3 groups based on histology: PTC without MAF (3,574 patients), PTC with MAF (13 patients), and anaplastic thyroid carcinoma (19 patients).Mean ± standard deviation age was 48 ± 12 years (range, 17-83) in the PTC without MAF group, 57 ± 14 years (range, 29-76) in the PTC with MAF group, and 64 ± 14 years (range, 24-86) in the ATC group (P.001). Mean tumor sizes were 1.2 ± 0.9 cm (range, 0.5-13), 2.1 ± 1.2 cm (range, 0.7-5), and 3.7 ± 1.4 cm (range, 0.4-6), respectively (P.001). The median follow-up was 32 months. The cause-specific survival at 5 years was 98% in the PTC without MAF group, 64% in the PTC with MAF group, and 11% in the ATC group (P.001). Multivariate analysis showed that MAF was a prognostic factor for the outcome of PTC patients (hazard ratio, 12.9; 95% confidence interval, 3.1-54.1; P.001).MAF negatively influenced the prognosis of patients with PTC. Further research and the design of more aggressive treatment strategies for MAF might be helpful for patients with PTC.

Several pathologic characteristics are associated with an adverse clinical outcome in papillary thyroid carcinoma (PTC), including the histological variant. This study aimed to investigate immunohistochemical expression and BRAF mutation status based on the histological variant and evaluated potential markers of aggressive behavior of PTC in Korean patients. In all, 407 PTC cases were classified to each histological variant, and the 94 representative cases were subjected to immunohistochemistry and BRAF mutation analysis. The classic type, follicular variant (FV) and tall cell variant (TCV) represented 76.9%, 14.2% and 6%, respectively. TCV showed a larger tumor size (P = 0.009), frequent extrathyroidal extension (P = 0.022) and cervical lymph node (LN) metastasis (P = 0.018). TCV and FV showed the reduced expression of galectin-3 (P = 0.003) and HBME1 (P = 0.114). Regardless of histology, PTEN loss and diffuse S100A4 expression were associated with LN metastasis (P = 0.007, P = 0.013). All TCVs harbored BRAF V600E mutation, and FV harbored less BRAF V600E mutation (P = 0.043). Immunohistochemical evaluation showed characteristic patterns in histological variants. PTEN and S100A4 expression are suggested as indicators of regional lymph node metastasis.

Recent studies have suggested that renal Nox is important in the progression of diabetic nephropathy. Therefore, we investigated the effect of a novel pan-NOX-inhibitor, APX-115, on diabetic nephropathy in type 2 diabetic mice. Eight- week-old db/m and db/db mice were treated with APX-115 for 12 weeks. APX-115 was administered by oral gavage at a dose of 60 mg/kg per day. To compare the effects of APX-115 with a dual Nox1/Nox4 inhibitor, db/db mice were treated with GKT137831 according to the same protocol. APX-115 significantly improved insulin resistance in diabetic mice, similar to GKT137831. Oxidative stress as measured by plasma 8-isoprostane level was decreased in the APX-115 group compared with diabetic controls. All lipid profiles, both in plasma and tissues improved with Nox inhibition. APX-115 treatment decreased Nox1, Nox2, and Nox4 protein expression in the kidney. APX-115 decreased urinary albumin excretion and preserved creatinine level. In diabetic kidneys, APX-115 significantly improved mesangial expansion, but GKT137831 did not. In addition, F4/80 infiltration in the adipose tissue and kidney decreased with APX-115 treatment. We also found that TGF-β stimulated ROS generation in primary mouse mesangial cells (pMMCs) from wild-type, Nox1 KO, and Duox1 KO mice, but did not induce Nox activity in pMMCs from Nox2 knockout (KO), Nox4 KO, or Duox2 KO mice. These results indicate that activating Nox2, Nox4, or Duox2 in pMMCs is essential for TGF-β-mediated ROS generation. Our findings suggest that APX-115 may be as effective or may provide better protection than the dual Nox1/Nox4 inhibitor, and pan-Nox inhibition with APX-115 might be a promising therapy for diabetic nephropathy.

Context: γ-Aminobutyric acid-B receptor 1 (GABABR1) forms a heterodimeric complex with calcium-sensing receptor (CaSR) in human brain tissue. However, the expression and implication of GABABR1 in human parathyroid adenoma has not yet been examined. Objective: The objective of the study was to examine a possible link between GABABR1 and PTH secretion in human parathyroid adenoma Design and Methods: Sixty-five patients who underwent parathyroidectomy for primary hyperparathyroidism (PHPT) and 29 control patients with normal parathyroid glands were retrospectively included. All patients diagnosed with PHPT had parathyroid adenomas. We evaluated the protein expression of GABABR1, glutamic acid decarboxylase 65/67 (GAD65/67), and various factors proposed as regulators of PTH secretion including CaSR, vitamin D receptor (VDR), CYP24A1, CYP27B1, fibroblast growth factor, and α-klotho in parathyroid tissues from patients with parathyroid adenomas using immunohistochemistry. Results: Expressions of CaSR, GABABR1, and VDR were significantly lower in PHPT patients than in control subjects (P < .001 for CaSR and GABABR1; P = .006 for VDR). Protein expression of GAD65/67, which indicates local production and regulation of GABAergic pathway, was significantly increased in PHPT (P < .001). There were no significant differences in CYP24A1, CYP27B1, fibroblast growth factor, and α-klotho expression between the two groups. Expression of GAD65/67 was significantly correlated with VDR, CYP24A1, CYP27B1, and α-klotho in PHPT (all P < .01) but not in the control groups. CaSR expression was positively associated with serum phosphorus level (r = 0.274, P = .029) and GAD65/67 was negatively correlated with serum PTH level (r = −0.342, P = .005). Conclusions: Local production and action of GABA may be regulated in human parathyroid adenomas. This suggests a possible link between PTH secretion and local regulation of GABA in parathyroid adenomas.

We evaluate the gray-scale ultrasonographic characteristics that differentiate between nodular hyperplasia (NH) and neoplastic follicular-patterned lesions (NFPLs) of the thyroid gland. Ultrasonographic features of 750 patients with 832 thyroid nodules (NH, n = 361; or NFPLs, follicular adenoma, n = 123; follicular carcinoma, n = 159; and follicular variant papillary carcinoma, n = 189) were analyzed. Except for echogenicity, over two-thirds of the cases of NH and NFPLs share the ultrasonographic characteristics of solid internal content, a well-defined smooth margin and round-to-ovoid shape. Independent predictors for NH were non-solid internal content (sensitivity 27.1%, specificity 90.2%), isoechogenicity (sensitivity 69.5%, specificity 63.5%) and an ill-defined margin (sensitivity 18.8%, specificity 94.5%). Independent predictors for NFPLs were hypoechogenicity (sensitivity 60.5%, specificity 70.4%), marked hypoechogenicity (sensitivity 2.8%, specificity 99.4%) and taller-than-wide shape (sensitivity 6.6%, specificity 98.1%). Although NH and NFPLs commonly share ultrasonographic characteristics, non-solid internal content and ill-defined margin are specific to NH and marked hypoechogenicity and taller-than-wide shape are specific to NFPLs.

Purpose To evaluate the efficacy of stereotactic radiotherapy in patients with brain metastases by comparing two different treatment regimens, single-dose radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT). Methods and Materials Between November 2003 and December 2008, 98 patients with brain metastases were included. Fifty-eight patients were treated with SRS, and forty were treated with FSRT. Fractionated stereotactic radiotherapy was used for large lesions or lesions located near critical structures. The median doses were 20 Gy for the SRS group and 36 Gy in 6 fractions for the FSRT group. Results With a median follow-up period of 7 months, the median survival was 7 months for all patients, with a median of 6 months for the SRS group and 8 months for the FSRT group ( p = 0.89). Local progression–free survival (LPFS) rates at 6 months and 1 year were 81% and 71%, respectively, for the SRS group and 97% and 69%, respectively, for the FSRT group ( p = 0.31). Despite the fact that FSRT was used for large lesions and lesions in adverse locations, LPFS was not inferior to SRS. Toxicity was more frequently observed in the SRS group than in the FSRT group (17% vs. 5%, p = 0.05). Conclusions Because patients treated with FSRT exhibited similar survival times and LPFS rates with a lower risk of toxicity in comparison to those treated with SRS, despite the fact that FSRT was used for large lesions and lesions in adverse locations, we find that FSRT can particularly be beneficial for patients with large lesions or lesions located near critical structures. Further investigation is warranted to determine the optimal dose/fractionation.

The utility of combined metabolic and volumetric (18)F-FDG PET/CT indices for predicting tumour necrosis fractions following neoadjuvant chemotherapy has not been extensively studied in osteosarcoma. Furthermore, little is known of the early PET/CT responses after only one chemotherapy course.Enrolled in the study were 20 children and young adults with resectable osteosarcoma who had undergone (18)F-FDG PET/CT scans before and after neoadjuvant chemotherapy. Maximum standardized uptake value (mSUV), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were measured. From among the 20 patients, 14 were prospectively recruited and underwent an additional PET/CT scan after one chemotherapy course. Histopathological necrosis fractions were compared with the above-mentioned PET/CT indices and their ratios.MTV at the SUV threshold of 2 g/ml was closely correlated with the magnetic resonance image volumes before therapy (r = 0.91). In the prospective cohort, five patients were classified as good responders and nine as poor responders. All the metabolic indices (mSUV and its ratio) and combined metabolic/volumetric indices (MTV, TLG, and their ratios) except the mSUV ratio determined after therapy showed significant differences between good and poor responders (P0.05). Differences were also noted for all of these indices determined after one chemotherapy course. Furthermore, most of these indices determined after therapy as well as after one chemotherapy course had good sensitivity, specificity, positive predictive value and negative predictive value with respect to predicting histological response to chemotherapy.In our osteosarcoma patient population, (18)F-FDG PET/CT indices (either combined metabolic/volumetric or metabolic indices) determined after neoadjuvant chemotherapy were useful in predicting tumour responses. This held true after only one chemotherapy course.

The majority of patients having a diagnosis of Hürthle cell neoplasm (HCN) on fine-needle aspiration (FNA) of a thyroid nodule have a diagnostic thyroid lobectomy to make the final diagnosis. If the nodule is malignant, they require a completion thyroidectomy. The objective of this study was to devise a simple clinical scheme capable of predicting malignancy in patients with cytologic diagnosis of HCN and, therefore, guide the extent of initial thyroid surgery.A total of 57 patients who underwent thyroid surgery after an FNA diagnosis of HCN were retrospectively studied. The patients were examined for clinical features, preoperative imaging studies, and pathology reports. The risk of malignancy was calculated using a multiple logistic regression model.The overall rate of malignancy in patients with HCN was 46% (26/57). The predictors of malignancy based on multiple logistic regression analysis were tumor size1.5 cm (odds ratio [95% confidence interval] = 8.0 [1.9-33.4]) and patient age45 years (odds ratio [95% confidence interval] = 2.3 [0.6-8.6]). In patients with nodules larger than 1.5 cm, the predicted probability of malignancy was greater in patients over 45 years than in younger patients (65% for45 years vs. 44% for ≤45 years). In patients with a nodule 1.5 cm or less, the probability of malignancy was relatively low and not significantly different between the two age categories (18% for45 years vs. 10% for ≤45 years).This study suggests that tumor size and age can be integrated into decision making for patients with an FNA diagnosis of HCN to facilitate patient selection for surgical referral and, particularly, to determine in which patients a thyroidectomy rather than a lobectomy should be the initial surgery.

Follicular thyroid carcinoma (FTC) is the second most common thyroid malignancy and accounts for approximately 10% of all thyroid malignancies.' Lymph node metastases are uncommon, and distant pulmonary or bony metastases are more common in patients with FTC than papillary thyroid carcinoma (PTC). Metastasis to the internal jugular vein (IJV) from a thyroid malignancy is not common, and most are direct invasions from the outside wall of the IJV. However, our case was a hematogenous intravascular metastasis that was easily diagnosed by sonographically guided fine-needle aspiration biopsy (FNAB).

Purpose The purpose of this study was to determine whether sonography (US) can usefully differentiate thyroid follicular adenoma (FA) and follicular carcinoma (FC). Methods This retrospective study included 60 pathologically proven FAs and 66 FCs in 123 consecutive patients (17 males and 106 females) with a mean age of 47 ± 13 years, (17–73 years) who underwent thyroid surgery. We analyzed US features of each nodule, including maximum diameter, echogenicity, composition, presence of calcification, margins, and presence of halo. The frequencies of each US feature were compared by using the χ2 test or Fisher's exact test between FAs and FCs. The relative risk of malignancy was evaluated by logistic regression analysis. Results Isohypoechoic echogenicity, predominantly solid or mixed echotexture, and presence of microcalcifications or rim calcifications were associated with FC (p < 0.05). Logistic regression analysis demonstrated that predominantly solid or mixed echotexture and microcalcifications or rim calcifications were associated with significant increases in relative risk for FC (odds ratio 8.1 and odds ratio 13.5, respectively, p < 0.01). Conclusions The US features of isohypoechoic echogenicity, predominantly solid or mixed echotexture, and microcalcifications or rim calcifications are more common in FC than in FA. © 2009 Wiley Periodicals, Inc. J Clin Ultrasound, 2009

Gliomatosis cerebri (GC) are extensively infiltrative glial tumors classified as astrocytic tumors in the current World Health Organization (WHO) classification scheme. In investigating the tumorigenesis of GC, we reviewed 28 cases of GC immunohistochemically and carried out array-based comparative genomic hybridization (CGH) in ten of those cases. In histological and immunohistochemical review, 18 cases (64%) were of astrocytic lineage, three (11%) were of oligodendroglial lineage, and seven (25%) were of uncommitted lineage. In the array-based CGH, 52 clones were frequently lost on 6p, 9p, and 9q in more than six cases, and six clones were frequently gained on 1p, 6q, 10q, and 21q in more than three cases. Some gained or lost genetic loci differed significantly between the histologically high-grade and low-grade GC (P < 0.05), but unsupervised hierarchical clustering failed to produce evidence of any clinical significance. These altered genetic foci are not known to be involved in the development of conventional glial tumors, including astrocytic tumors. In conclusion, despite the dominant astrocytic differentiation of GC histologically, novel genomic aberrations found in our GC cases were different from those of astrocytic tumors.

The detection of papillary microcarcinomas of the thyroid is increasing due to frequent use of ultrasound and fine-needle aspiration biopsy. Although most of the papillary microcarcinomas remain quiescent and follow an indolent clinical course, some behave aggressively and metastasize early, giving rise to clinically significant disease. There have been few studies concerning factors predictive of lymph node metastasis in papillary microcarcinomas. We analyzed the expression of S100A4, cyclin D1, p27 and MUC1, the presence of the BRAF V600E mutation and the clinicopathological features of the tumors, including patient age, tumor size (>or=5 vs

Summary Expression of excision repair cross-complementation group 1 (ERCC1) is important for resistance to platinum agents. Mutations of epidermal growth factor receptor (EGFR) are related to the responsiveness to tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC). This study was performed to determine if ERCC1 expression and EGFR are related to the prognosis of resected NSCLC, and to determine if ERCC1 expression and EGFR mutations are related. We used immunohistochemistry (IHC) to evaluate ERCC1 expression in tumors from 130 patients with curatively resected NSCLC. The median H -score was used as a cut-off for ERCC1 IHC. EGFR mutations were analyzed in exons 18, 19 and 21. ERCC1 expression was detected in tumors from 80 patients (61.5%). ERCC1 was expressed more frequently in smokers and in squamous cell carcinomas. Patients with a positive ERCC1 expression survived longer than ERCC1-negative patients (median overall survival 7.6 years for ERCC1-positive vs. 4.0 years for ERCC1-negative, P =0.046). Subsequent multivariate analysis suggested that ERCC1 expression is an independent prognostic marker of longer survival (hazard ratio: 0.598, 95% confidence interval: 0.357–1.001). EGFR mutations were found in 25 patients (19.2%) but did not affect overall survival. Interestingly, EGFR mutations were more frequent in ERCC1-negative tumors (12.5% in ERCC1-positive vs. 30% in ERCC1-negative tumors, P =0.014). In conclusion, ERCC1 expression was identified as a positive prognostic marker in resected NSCLC. In addition, EGFR mutations were more frequently found in ERCC1-negative tumors.

Pulmonary pleomorphic carcinoma is a rare tumor of the lung, which is believed to spread at an early stage and to have an aggressive clinical course. The efficacy of chemotherapy for advanced pulmonary pleomorphic carcinoma has not been defined. The objective of this study was to evaluate the efficacy of palliative chemotherapy for pulmonary pleomorphic carcinoma. Thirteen consecutive patients who received palliative chemotherapy for advanced pulmonary pleomorphic carcinoma were investigated. All 13 patients were treated using chemotherapy regimens known to be active for the treatment of advanced non-small cell lung cancer (NSCLC). Eleven patients (85%) had progressive disease and two (15%) had stable disease after first-line chemotherapy. No patient achieved an objective response (objective response rate, 0%; 95% confidence interval, 0-23%). Of the 13, eight were given second-line chemotherapy, and all had progressive disease after second-line chemotherapy (objective response rate, 0%; 95% CI, 0-32%). Median overall survival from the initiation of first-line palliative chemotherapy was only 5 months (range, 2-12) with a median follow-up of 16 months. Advanced pulmonary pleomorphic carcinoma showed poor response to chemotherapy regimens that provide active treatment for NSCLC. Novel treatment approaches are required for pulmonary pleomorphic carcinoma.

Although dipeptidyl peptidase IV (DPPIV) inhibitors are known to have renoprotective effects, the mechanism underlying these effects has remained elusive. Here we investigated the effects of DA-1229, a novel DPPIV inhibitor, in two animal models of renal injury including db/db mice and the adriamycin nephropathy rodent model of chronic renal disease characterized by podocyte injury. For both models, DA-1229 was administered at 300 mg/kg/day. DPPIV activity in the kidney was significantly higher in diabetic mice compared with their nondiabetic controls. Although DA-1229 did not affect glycemic control or insulin resistance, DA-1229 did improve lipid profiles, albuminuria and renal fibrosis. Moreover, DA-1229 treatment resulted in decreased urinary excretion of nephrin, decreased circulating and kidney DPPIV activity, and decreased macrophage infiltration in the kidney. In adriamycin-treated mice, DPPIV activity in the kidney and urinary nephrin loss were both increased, whereas glucagon-like peptide-1 concentrations were unchanged. Moreover, DA-1229 treatment significantly improved proteinuria, renal fibrosis and inflammation associated with decreased urinary nephrin loss, and kidney DPP4 activity. In cultured podocytes, DA-1229 restored the high glucose/angiotensin II-induced increase of DPPIV activity and preserved the nephrin levels in podocytes. These findings suggest that activation of DPPIV in the kidney has a role in the progression of renal disease, and that DA-1229 may exert its renoprotective effects by preventing podocyte injury.

This study reports an autopsy case of a 53 year-old male with rapidly progressive extra-nodal NK/T-cell lymphoma accompanied with unusual clinical and pathologic features. He was initially presented with localized swelling and tenderness in the right lower extremity and the biopsy from the calf muscle was interpreted as granulomatous myositis masquerizing lymphoma. The biopsy from erythematous skin lesion of trunk showed infiltration of medium sized atypical lymphoid cells with relatively plump cytoplasm and immunophenotype of CD30+, CD56+/- and surface CD3-, which lead to the diagnosis of CD30+ anaplastic large cell lymphoma. About 2 months later, nasal obstruction was developed and the nasal biopsy was done. After confirmation of EBV infection, he was finally diagnosed as extra-nodal NK/T-cell lymphoma with peculiar immunophenotype of CD3 dim+ and CD30+. Despite the chemotherapy, he was going rapidly downhill and died of respiratory and multi-organ failure 8 months after the onset of soft tissue lesion. At autopsy, disseminated angiocentric lymphoma was found all over the internal organs including the brain. This case emphasizes that extra-nodal NK/T-cell lymphoma should be considered as a cause of granulomatous myositis and can express CD30 positivity and CD3 weak positivity, which are unusual but rarely predominant feature of NK/T-cell lymphoma.

We report a typical case of nasal chondromesenchymal hamartoma (NCMH) of infancy, which extended to the orbit and intracranium through the skull base. The nasal mass was incidentally found in a 5-month-old otherwise healthy boy who had recently developed ptosis of the left eye. On neuroimaging, there were defects in the left ethmoid bone of the anterior cranial fossa and medial orbital wall. A round heterogeneous mass was found in the left nasal cavity. Solid portions were strongly enhanced. The preoperative diagnosis was nasal glioma or encephalocele. After frontal craniotomy, the mass was separated from the cranial basal dura. Through the transnasal approach, the mass was dissected from the left orbital content and removed. NCMH is a rare benign lesion and histopathological analogue of the mesenchymal hamartoma of the chest wall, having unique pathology: islands of hyaline cartilage, somewhat calcified or ossified hyalinized collagenous trabeculae and abundant myxoid stroma. Its occurrence in the nasal cavity was identified in 1998. The recognition of this entity is necessary to avoid misdiagnosis of the frozen section and for appropriate surgery.

INTRODUCTION 11C-Methionine (MET) PET and diffusion-weighted (DW) MRI are commonly used for evaluation of gliomas. We assessed the correlation between MET uptake and diffusion restriction measured on DW MRI in glioma. MATERIALS AND METHODS Thirty-one patients with gliomas, who were initially examined with MET PET and DW MRI, were enrolled retrospectively. MET PET and apparent diffusion coefficient (ADC) images were coregistered to each other, using rigid-body transformation. Tumor-to-normal count density ratio of the cortex (TNR) and normalized apparent diffusion coefficient (nADC) value were measured for each voxel on the MET PET and ADC map. The maximum TNR (TNRmax) and minimum nADC (nADCmin) were obtained for each tumor. Correlations between those parameters were evaluated. RESULTS The TNRmax and nADCmin values of a glioma were significantly correlated (r=-0.42). TNRmax and nADCmin were significantly correlated with glioma grades. Furthermore, TNRmax and nADCmin showed a trend for correlation with the Ki-67 index. We analyzed the correlation between voxel-based TNR and ADC within a tumor and observed no correlation between them. Regions with high MET uptake did not correspond with regions with low nADC. CONCLUSION We found a negative correlation between TNRmax and nADCmin for each glioma; however, MET uptake and ADC within a tumor were independent of each other and were heterogeneous. The two parameters represent different biological features; thus, as a comprehensive approach, MET PET and DW MRI might have a complementary role in the characterization of gliomas.

Acral lentiginous melanoma (ALM) is the most common type of cutaneous melanoma in Asian populations. Traditionally, ALM was believed to have a poorer prognosis than other subtypes of cutaneous melanoma because of its aggressive behavior. However, in Asians, there have been several unusual case reports that have shown only subtle melanocytic proliferation despite clinically malignant manifestations. We performed a retrospective study of 13 patients with ALM. We reviewed the clinical histories, histopathologies, and immunohistochemical staining from these patients. Clinically, the lesions were characterized by a brown to black pigmented patch with irregular borders and variegated pigmentation on the sole, heel, or finger. Histopathologically, most specimens revealed only bland scattered proliferation of atypical melanocytes without marked cellular atypia or dermal invasion. However, some of the lesions were suspected to progress to the invasive stage, into the papillary dermis after a long period of time. Although cytological atypia of the melanocytes is not sufficient to ALM in situ, the melanocytic proliferation pattern, dermal inflammation, and correlation with clinical presentation would suffice in making the correct diagnosis of ALM in situ. In these cases, more biopsies of other areas should be recommended for the precise diagnosis and early complete excision in accordance with ALM in situ.

Bone fixation systems made of biodegradable polymers are radiolucent, making post-operative diagnosis with X-ray imaging a challenge. In this study, to allow X-ray visibility, we separately prepared a radiopaque layer and attached it to a bioabsorbable bone plate approved for clinical use (Inion, Finland). We employed barium sulfate as a radiopaque material due to the high X-ray attenuation coefficient of barium (2.196 cm2/g). The radiopaque layer was composed of a fine powder of barium sulfate bound to a biodegradable material, poly(lactic-co-glycolic acid) (PLGA), to allow layer degradation similar to the original Inion bone plate. In this study, we varied the mass ratio of barium sulfate and PLGA in the layer between 3:1 w/w and 10:1 w/w to modulate the degree and longevity of X-ray visibility. All radiopaque plates herein were visible via X-ray, both in vitro and in vivo, for up to 40 days. For all layer types, the radio-opacity decreased with time due to the swelling and degradation of PLGA, and the change in the layer shape was more apparent for layers with a higher PLGA content. The radiopaque plates released, at most, 0.5 mg of barium sulfate every 2 days in a simulated in vitro environment, which did not appear to affect the cytotoxicity. The radiopaque plates also exhibited good biocompatibility, similar to that of the Inion plate. Therefore, we concluded that the barium sulfate-based, biodegradable plate prepared in this work has the potential to be used as a fixation device with both X-ray visibility and biocompatibility. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 103B:596–607, 2015.

Utilizing BRAFV600E mutation as a marker may reduce unnecessary prophylactic central neck dissection (pCND) in clinically nodal negative (cN0) neck for small (≤2 cm) classical papillary thyroid carcinoma (PTC). We aimed to assess whether BRAF is a significant independent predictor of occult central nodal metastasis (CNM) and its contribution to the overall prediction after adjusting for other significant preoperative clinical factors in small PTC. Primary tumor tissue (paraffin-embedded) from 845 patients with small classical cN0 PTC who underwent pCND was tested for BRAF mutation. Clinicopathologic factors were compared between those with and without BRAF. BRAF was evaluated to see if it was an independent factor for CNM. Prediction scores were generated using logistic regression models and their predictability was measured by the area under the ROC curve (AUC). The prevalence of BRAF was 628/845 (74.3%) while the rate of CNM was 285/845 (33.7%). Male sex (odds ratio (OR): 2.68, 95% CI: 1.71–4.20), large tumor size (OR: 2.68, 95% CI: 1.80–4.00), multifocality (OR: 1.49, 95% CI: 1.07–2.09), lymphovascular permeation (OR: 10.40, 95% CI: 5.18–20.88), and BRAF (OR: 1.65, 95% CI: 1.10–2.46) were significant independent predictors of CNM, while coexisting Hashimoto's thyroiditis (OR: 0.56, 95% CI: 0.40–0.80) was an independent protective factor. The AUC for prediction score based on tumor size and male sex was similar to that of prediction score based on tumor size, male sex, and BRAF status (0.68 vs 0.69, P=0.60). Although BRAF was an independent predictor of CNM, knowing its status did not substantially improve the overall prediction. A simpler prediction score based on male sex and tumor size might be sufficient.

SummaryObjective Follicular variant of papillary thyroid carcinoma (FVPTC) is a common variant of papillary thyroid carcinoma (PTC), but the association between BRAF mutation and the clinicopathological and ultrasonographical characteristics of FVPTC has not been well studied. The aim of this study was to determine the significance of BRAF mutation in FVPTC. Patients The medical records of the 137 patients with >5 mm FVPTCs and known BRAF mutation status in the interested nodule were reviewed. BRAF mutation analysis was performed routinely and prospectively by Sanger sequencing. Clinicopathological and ultrasonographical characteristics were compared between BRAF mutation-positive and BRAF mutation-negative groups. Results BRAF mutation was detected in 35 (25·5%) patients. The BRAF mutation-positive group was associated with smaller tumour size (P = 0·022), extrathyroidal extension (P = 0·001), multifocality (P = 0·046) and higher (III/IV) TNM stages (P = 0·005). In multivariable analysis, higher (III/IV) TNM stage was an independent predictive factor for BRAF mutation-positive status (adjusted OR 2·966, 95% CI 1·321–6·663). In diagnosis of FVPTC, the presence of BRAF mutation was associated with malignant features on ultrasonography (P

The purpose of this study was to identify the DNA methylation status of the mitogen-activated protein kinase (MAPK) signal-inhibiting genes dual-specificity phosphatase 4 (DUSP4) and 6 (DUSP6); and serpin peptidase inhibitor A member 5 (SERPINA5) in thyroid cancer.Using 76 papillary thyroid cancer(PTC) tissues and three thyroid cancer cell lines (TPC1, WRO82-1 and XTC), the expression of three genes and DNA methylation were determined by reverse transcription-PCR and methylation-specific PCR.In all cell lines, the expression of DUSP4 and DUSP6 increased; the corresponding gene promoters were unmethylated. However, SERPINA5 gene expression decreased and SERPINA5 DNA was methylated in the TPC1 cell line. With the de-methylating agent 5'-aza-2'-deoxycytidine, SERPINA5 gene expression was restored. In 82.9% of PTC tissues (63/76), the SERPINA5 DNA promoter was methylated, which was associated with a higher v-raf murine sarcoma viral oncogene homolog B1(BRAF) mutation rate in PTC tissues based on multivariate regression (odds ratio=3.573; 95% confidence interval=1.122-11.379; p=0.031).The expression of the MAPK signal-inhibiting gene SERPINA5 decreased in the TPC1 cell line, SERPINA5 expression was regulated by DNA methylation, which was associated with a higher BRAF mutation rate in PTC.

Follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) can often be challenging to diagnose using core needle biopsy (CNB) specimens. We have developed the histologic criteria for the CNB diagnosis of FN and validated the usefulness of CNB. We retrospectively reviewed 184 CNBs and 224 FNACs diagnosed with FN/SFN. CNBs were histologically classified into four subgroups, based on the histologic features of follicular proliferation, fibrous capsulation, and surrounding parenchyma. Among 184 CNBs, 103 (55.9%) had previous FNAC results of non-diagnostic or indeterminate. Overall malignancy rates in FNAC (48%) and CNB (46%) were nearly identical (p > 0.05), and the neoplasm rate was higher in CNB (88%) than FNAC (74%) (p = 0.007). There was no significant difference in the malignancy rates among the four histologic subgroups. Among the 40 nodules with simultaneous CNB and FNAC, only nine had the FNAC diagnosis of FN/SFN, and others were non-diagnostic, benign, or atypia of undetermined significance. Overall, CNB improved specimen adequacy and achieved better sensitivity of the FN/SFN diagnosis in thyroid nodules that were inconclusive by FNAC. In the preoperative diagnosis of FN/SFN, CNB has no advantage over FNAC in predicting the likelihood of malignancy, but helps to reduce the need for repeat biopsy.

The authors investigated the efficacy of photodynamic therapy against infantile hemangioma using a hemangioma animal model. Eighty-three hemangioma specimens from five children were implanted into nude mice. The gross and volume changes of the implants were evaluated for up to 13 weeks. The histological change of the implant was evaluated at 5 weeks after transplantation. Photodynamic therapy was performed between 6 and 10 weeks after transplantation. The photosensitizer uptake of the implant was evaluated at 24 h after photosensitizer administration. The implant response was evaluated at 0, 12, and 24 h after light delivery. The change in ATF3 levels, a transcription factor induced under severe hypoxic conditions, was investigated immediately after treatment. The implant volume increased slowly during the first 4 weeks and then involuted. At 5 weeks after transplantation, plump endothelial cells formed tightly packed sinusoidal channels, and the endothelial cells were positive for CD31 and GLUT1 expression. At 24 h after photosensitizer administration, confocal analysis showed that the photosensitizer was present within CD31-positive cells. The implant volume was significantly decreased in the treated implants compared with the untreated implants (p < 0.0001). At 24 h after light delivery, most cells had collapsed. ATF3 expression increased gradually and then reached a maximum level at 4 h after treatment. Photodynamic therapy was effective in the treatment of infantile hemangioma. Apoptosis, a major mechanism of hemangioma destruction in the early phase, might be caused by ischemic injury as well as direct effects of photodynamic therapy.

The aim of this study was to investigate the efficaciousness of histological tumor growth patterns in the prediction of lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC). All combinations of infiltrative tumor border, lateral tubular growth, and intraglandular dissemination were assessed for their ability to predict LNM in 229 patients. In addition, we analyzed their predictive value within subgroups based on the tumor size and number of tumor nodules. Each tumor growth pattern was significantly associated with LNM, as 11 of the 12 combinations of these 3 patterns were found to be independently predictive of LNM (P.05). Similar results were observed in both univariate and multivariate logistic regression analyses of PTCs, grouped according to the tumor size and number of tumor nodules. This study has shown that histological features suggestive of invasive tumor growth, including infiltrative tumor border and lateral tubular growth, may be used as independent predictive factors of LNM in PTC, and can improve treatment and follow-up strategies for PTC.

Objectives: A panel composed of three immunomarkers, cytokeratin 19, HBME-1 and galectin-3, is recommended for improving the accuracy of diagnosing papillary thyroid carcinoma (PTC), but the results are sometimes inconsistent and difficult to interpret. We used immunocytochemistry to assess the utility of chemokine CXC ligand 12 (CXCL12) as a novel diagnostic marker for PTC employing paraffin-embedded cell blocks. Methods: We analyzed the expression of CXCL12 using immunocytochemical staining in 82 cases of thyroid lesions (47 PTCs and 35 thyroid lesions other than PTC). To determine the optimal cut-off value for the assessment of CXCL12 positivity, we used receiver operating characteristics (ROC). Results: ROC curves showed that the optimum diagnostic cut-off was 10% (area under the curve 0.950, 95% confidence interval 0.891-1.008), with exclusive CXCL12 expression in PTC compared to other thyroid lesions (p < 0.001). In total, more than 90% of the PTCs were associated with CXCL12 immunohistochemical staining, while only up to 11.4% of thyroid lesions other than PTC were positive for CXCL12. The follicular variant PTC showed 90% CXCL12 expression compared to 10.5% positivity in follicular neoplasm. Conclusion: Our findings indicate that CXCL12 may be an effective supplementary diagnostic marker for PTC in preoperative fine-needle aspiration cytology using the cell block method.

Purpose: In this single repeated measures study, an examination was done on the effects of dialysate flow rate on dialysis adequacy and fatigue in patients receiving hemodialysis. Methods: This study was a prospective single center study in which repeated measures analysis of variance were used to compare Kt/V urea (Kt/V) and urea reduction ratio (URR) as dialysis adequacy measures and level of fatigue at different dialysate flow rates: twice as fast as the participant’s own blood flow, 500 mL/min, and 700 mL/min. Thirty-seven hemodialysis patients received all three dialysate flow rates using counterbalancing. Results: The Kt/V (M±SD) was 1.40±0.25 at twice the blood flow rate, 1.41±0.23 at 500 mL/min, and 1.46±0.24 at 700 mL/min. The URR (M±SD) was 68.20±5.90 at twice the blood flow rate, 68.67±5.22 at 500 mL/min, and 70.11±5.13 at 700 mL/min. When dialysate flow rate was increased from twice the blood flow rate to 700 mL/min and from 500 mL/min to 700 mL/min, Kt/V and URR showed relative gains. There was no difference in fatigue according to dialysate flow rate. Conclusion: Increasing the dialysate flow rate to 700 mL/min is associated with a significant nicrease in dialysis adequacy. Hemodialysis with a dialysate flow rate of 700 mL/min should be considered in selected patients not achieving adequacy despite extended treatment times and optimized blood flow rate.