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Bevacizumab-containing chemotherapy constitutes an important salvage treatment for recurrent/refractory glioblastoma(r/rGBM).We retrospectively collected the data of r/rGBM patients treated with the combination of bevacizumab and irinotecan (BEV+IRI) as their salvage treatment from July 2013 and December 2021 in Konkuk Medical Center of Korea. Patients with available results from molecular diagnostic tests were eligible, and markers of interest were examined including the presence of MGMT methylation, IDH1/2 mutation, or 1p/19q co-deletion. Efficacy of BEV+IRI and its potential biomarker was explored.Among 21 patients, 38.1% demonstrated European Cooperative Oncology Group-Performance scale (ECOG-PS) ≥3. The majority (71.4%) received BEV+IRI as their second-line chemotherapies, and the median dose was 5 (range=1-25). Objective response rate (ORR) was 33.3% and disease-control rate (DCR) was 85.7%. Irrespective of objective response, early clinical response was achieved in 14(66.7%) patients. During the median follow-up of 16.4 months for survivors, median progression-free survival (PFS) and overall survival (OS) were 3.6 and 6.8 months, respectively. ECOG PS≥3 and TP53 loss were independent predictors of an unfavorable OS, while prompt clinical improvement could predict favorable OS. Any molecular aberration was associated with OS or PFS in the study.Salvage BEV+IRI treatment in r/rGBM conferred comparable clinical benefit. ECOG PS ≥3, TP53 loss, and lack of prompt clinical improvement after the treatment were significantly associated with an unfavorable OS.

Glioneuronal and neuronal tumors (GNTs) are rare heterogeneous central nervous system tumors characterized by slow growth and favorable outcomes, but are often associated with diagnostic difficulties. A thorough analysis of three rare and recently recognized GNTs was performed in the context of clinicopathological features and molecular genetic characterization. The current spinal diffuse leptomeningeal glioneuronal tumor (DLGNT) was characterized with oligodendroglioma-like tumor with chromosome 1p/19q codeletion without IDH mutations and KIAA1549:BRAF fusion. The current occipital multinodular and vacuolating neuronal tumor (MVNT) was characteristic of the variable-sized vague nodules consisted of gangliocytic tumor cells with intracytoplasmic and pericellular vacuolation and the next-generation sequencing (NGS) revealed MAP2K1 p.Q56_V60del. A diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC) of the amygdala was characterized by oligodendroglia-like cells and nuclear clusters, and monosomy 14. From the current cases and literature review, we found that DLGNT commonly occurs in the spinal cord and can make mass and more commonly have KIAA1549:BRAF fusion; MVNT is a neoplasm rather than malformation and MAP2K1 deletion is one of the hallmarks of this tumor; although DGONC may require a methylation profile, we can reach a diagnosis through its unique histology, monosomy 14, and exclusion diagnosis without a methylation profile.

Spinal cord hemangioblastoma (HBL) is a highly vascularized tumor that occurs sporadically or in relation to von Hippel-Lindau disease. Sporadic-type HBLs in the spinal cord usually present as single lesions that are potentially curable by complete surgical resection, with a low rate of recurrence. We report a case of a totally excised sporadic-type spinal cord HBL with multiple recurrences observed 10 years after surgery. Long-term follow-up may be necessary for spinal cord HBL, even in cases of complete resection.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis and a lack of targeted therapy. Overexpression ofFirst, using different web-based bioinformatics platforms (TIMER 2.0, UALCAN, and GEPIA 2), the expression ofThe expression of

Purpose Triple-negative breast cancer (TNBC) represents a major clinical challenge due to its aggressive and metastatic behavior and the lack of available targeted therapies. Therefore, therapeutic strategies are needed to improve TNBC patient management. Recently, atezolizumab and nab-paclitaxel chemotherapy has been approved by the Food and Drug Administration for the first-line treatment of patients with locally advanced and metastatic TNBC. The programmed death-ligand 1 (PD-L1) immunohistochemical SP142 assay was also approved as a companion diagnostic device for selecting TNBC patients for atezolizumab treatment. This study aimed to evaluate and compare the analytical performance of the PD-L1 22C3/SP263 assays in comparison with the SP142 assay for ≥ 1% immune cells (ICs). Methods Immunohistochemical expression for the PD-L1 22C3/SP263 assays, in comparison with the SP142 assay, was analyzed for the ≥ 1% ICs in 95 TNBCs. Results At the 1% cut-off value, the proportions of positive cases were 52.6% for the SP142 assay in infiltrating ICs and 50.5% and 52.6% for the 22C3 and SP263 assays in tumor cells, respectively. The PD-L1 SP263 assay had the highest while the PD-L1 22C3 assay had the lowest total positive expression rate at all cut-off values. The concordance rate between the assays was highest at a 1% cut-off value and decreased when the cut-off value increased. The concordance rate between the SP142 and SP263 assays at 1% cut-off was high, while in comparison, the concordance rate between the SP142 and 22C3 assays at 1% cut-off was relatively lower. Conclusion This study demonstrates that although the 22C3 assay at a 1% cut-off value compared with the PD-L1 SP142 assay at the clinically relevant cut-off shows comparable but not interchangeable analytical performance, the analytical performance of the SP263 assay at a 1% cut-off value shows interchangeable performance with the PD-L1 SP142 assay at the clinically relevant cut-off.

Due to the rare occurrence of young-onset bladder cancer (YBC), its genomic characteristics remain largely unknown. Twenty-nine biopsy-proven YBC cases were collected using a nation-wide search for bladder cancer diagnosed at 20 years or younger. Whole exome sequencing and RNA sequencing were carried out in 21 and 11 cases, respectively, and compared with those of adult bladder cancer (ABC) cases obtained from public databases. Almost all YBCs were low grade, non-invasive papillary tumors. YBC had a low mutation burden and less complex copy number alterations. All cases harbored putative driver mutations. Mutations were most commonly found in HRAS (10 cases), with a preference for exon 5. FGFR3 gene fusions were noted with various partner genes (7 cases). The alterations on HRAS and FGFR3 occurred in a mutually exclusive manner. Others included KRAS mutations (2 cases), chromosomes 4p and 10q arm-level deletions (1 case), and ERCC2 mutation (1 case). There were no point mutations in TP53 and FGFR3. The gene expression profiles of YBC were similar to those of the ABC group with good prognosis. None of the YBCs and ABCs with YBC-like mutations showed progression to muscle-invasive tumors. Our results suggest that bladder cancer with YBC-like mutations represents an indolent bladder tumor, regardless of age.

Clinical attention to gluten-related disorders, such as celiac disease and nonceliac gluten sensitivity, is on the rise. However, identifying the pathophysiological mechanisms of gluten-related disorders remains elusive. Gliadin, a component of gluten, is known to play a major role in gluten toxicity. Caenorhabditis elegans has been widely used as the predominant experimental animal model to study toxicity and stress response in biomedical research. We investigated the stress response induced by gliadin intake in C. elegans to evaluate its toxicity and found brood size, body bending, and pumping rates to be significantly altered in response to gliadin. Notably, reactive oxygen species (ROS) production and Pgst-4::GFP transgene expression, an indicator of the oxidative-stress response, were significantly increased after gliadin intake. Reduced pumping rates were most likely caused by gliadin-induced oxidative stress, since pumping rates in oxidative stress-sensitive mev-1 mutants were more severely reduced than in oxidative stress-resistant daf-2 mutants following gliadin intake. Our results indicated that gluten/gliadin intake in C. elegans triggered ROS production and induced an oxidative stress response that reduced pumping rates and decreased brood size. We suggest C. elegans to be a useful model system for studying gluten/gliadin toxicity.

Background Histologic grade is the most important predictor of the clinical outcome of non-muscle invasive (Ta, T1) papillary urothelial carcinoma (NMIPUCa), but its ambiguous criteria diminish its power to predict recurrence/progression for individual patients. We attempted to find an objective and reproducible histologic predictor of NMIPUCa that correlates well with the clinical outcome. Methods A total of 296 PUCas were collected from the Departments of Surgical Pathology of 11 institutions in South Korea. The clinical outcome was grouped into no event (NE), recurrence (R), and progression (P) categories. All 25 histological parameters were numerically redefined. The clinical pathology of each case was reviewed individually by 11 pathologists from 11 institutions based on the 2004 WHO criteria and afterwards blindly evaluated by two participants, based on our proposed parameters. Univariate and multivariate logistic regression analyses were performed using the R software package. Results The level of mitoses was the most reliable parameter for predicting the clinical outcome. We propose a four-tiered grading system based on mitotic count (> 10/10 high-power fields), nuclear pleomorphism (smallest-to-largest ratio of tumor nuclei >20), presence of divergent histology, and capillary proliferation (> 20 capillary lumina per papillary core). Conclusions The level of mitoses at the initial bladder biopsy and transurethral resection (TUR) specimen appeared to be an independent predictor of the Ta PUCa outcome. Other parameters include the number of mitoses, nuclear pleomorphism, divergent histology, and capillary proliferation within the fibrovascular core. These findings may improve selection of patients for a therapeutic strategy as compared to previous grading systems. Electronic supplementary material The online version of this article (doi:10.1186/s13000-017-0639-y) contains supplementary material, which is available to authorized users.

Background: The BRAFV600E mutation in papillary thyroid carcinoma (PTC) is particularly prevalent in Korea, and a considerable number of wild-type BRAF PTCs harbor RAS mutations. In addition, subsets of other genetic alterations clearly exist, but their prevalence in the Korean population has not been well studied. Recent increased insight into noninvasive encapsulated follicular variant PTC has prompted endocrine pathologists to reclassify this entity as “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” (NIFTP). This study analyzed the genetic alterations among the histologic variants of PTC, including NIFTP. Methods: Mutations of the BRAF and RAS genes and rearrangement of the RET/PTC1, NTRK1, and ALK genes using 769 preoperative fine-needle aspiration specimens and resected PTCs were analyzed. Results: Molecular alterations were found in 687 (89.3%) of 769 PTCs. BRAFV600E mutation (80.8%) was the most frequent alteration, followed by RAS mutation and RET/PTC1, NTRK1, and AL...

Objectives: Androgen receptor splice variants (AR-Vs), especially androgen receptor splice variant 7 (AR-V7), are considered as important factors in developing castration-resistance of prostate can...

BACKGROUND/PURPOSE High-intensity focused ultrasound (HIFU) has been used for skin tightening. However, there is a rising concern of irreversible adverse effects. Our aim was to evaluate the depth of thermal injury zone after HIFU energy passes through different condition. MATERIALS AND METHODS To analyze the consistency of the HIFU device, phantom tests were performed. Simulations were performed on ex vivo porcine tissues to estimate the area of the thermal coagulation point (TCP) according to the applied energy and skin condition. The experiment was designed in three orientations: normal direction (from epidermis to fascia), reverse direction (from fascia to epidermis), and normal direction without epidermis. RESULTS The TCP was larger and wider depending on the applied fluence and handpieces (HPs). When we measured TCP in different directions, the measured area in the normal direction was more superficially located than that in the reverse direction. The depth of the TCP in the porcine skin without epidermis was detected at 130% deeper than in skin with an intact epidermis. CONCLUSION The affected area by HIFU is dependent on the skin condition and the characteristics of the HP and applied fluence. Considerations of these factors may be the key to minimize the unwanted adverse effects.

// Seung Eun Lee 1 , Seong-Hwan Chang 2 , Wook Youn Kim 1 , So Dug Lim 1 , Wan Seop Kim 1 , Tea Sook Hwang 1 and Hye Seung Han 1 1 Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea 2 Department of Surgery, Konkuk University School of Medicine, Seoul, Korea Correspondence to: Hye Seung Han, email: // Keywords : TERT, CTNNB1, hepatocellular carcinoma, intratumoral genetic heterogeneity, Pathology Section Received : May 05, 2016 Accepted : September 12, 2016 Published : September 19, 2016 Abstract Genetic alterations of TERT and CTNNB1 have been documented in hepatocellular carcinoma. TERT promoter mutations are the earliest genetic events in the multistep process of hepatocarcinogenesis related to cirrhosis. However, analyses of TERT promoter and CTNNB1 mutations in hepatocellular carcinoma tumor samples have not been performed in the Korean population, where hepatitis B virus-related hepatocellular carcinoma is prevalent. In order to identify the role of TERT promoter and CTNNB1 mutations in the hepatocarcinogenesis and pathogenesis of recurrent hepatocellular carcinoma, we performed the sequence analyses in 140 hepatocellular nodules (including 107 hepatocellular carcinomas), and 8 pairs of matched primary and relapsed hepatocellular carcinomas. TERT promoter and CTNNB1 mutations were only observed in hepatocellular carcinomas but not in precursor lesions. Of 109 patients with hepatocellular carcinoma, 41 (39.0%) and 15 (14.6%) harbored TERT and CTNNB1 mutations, respectively. TERT promotermutations were significantly more frequent in hepatocellular carcinomas related to hepatitis C virus infection (5/6; 83.3%) compared to tumors of other etiologies ( P = 0.001). In two cases, discordance in TERT promoter mutation status was observed between the primary and the corresponding recurrent hepatocellular carcinoma. The two patients with discordant cases had early relapses. In conclusion, we identified TERT promoter and CTNNB1 mutations as the most frequent somatic genetic alterations observed in hepatocellular carcinoma, indicating its pivotal role in hepatocarcinogenesis. Furthermore, we suggest the possibility of intratumoral genetic heterogeneity of TERT promoter mutations in hepatocellular carcinoma as indicated by the discordance in TERT promoter mutations between primary and corresponding recurrent hepatocellular carcinoma.

Background/Aims: Immunoglobulin A nephropathy (IgAN) is a generally progressive disease, even in patients with favorable prognostic features. In this study, we aimed to investigate the antiproteinuric effect and tolerability of low-dose valsartan (an angiotensin II receptor blocker) therapy in normotensive IgAN patients with minimal proteinuria of less than 0.5 to 1.0 g/day. Methods: Normotensive IgAN patients, who had persistent proteinuria with a spot urine protein-to-creatinine ratio of 0.3 to 1.0 mg/mg creatinine, were recruited from five hospitals and randomly assigned to either 40 mg of valsartan as the low-dose group or 80 mg of valsartan as the regular-dose group. Clinical and laboratory data were collected at baseline, and at 4, 8, 12, and 24 weeks after valsartan therapy. Results: Forty-three patients (low-dose group, n = 23; regular-dose group, n = 20) were enrolled in the study. Proteinuria decreased significantly not only in the regular-dose group but also in the low-dose group. The change in urine protein-to-creatinine ratio at week 24 was −41.3% ± 26.1% (p < 0.001) in the regular-dose group and −21.1% ± 45.1% (p = 0.005) in the low-dose group. In the low-dose group, blood pressure was constant throughout the study period, and there was no symptomatic hypotension. In the regular-dose group, blood pressure decreased at weeks 8 and 12. No significant change in glomerular filtration rate, serum creatinine level, or serum potassium level was observed during the study period. Conclusions: Our results suggest that low-dose valsartan can significantly reduce proteinuria without causing any intolerability in normotensive IgAN patients with minimal proteinuria.

Presacral ganglioneuromas are extremely rare benign tumors and fewer than 20 cases have been reported in the literature. Ganglioneuromas are difficult to be differentiated preoperatively from tumors such as schwannomas, meningiomas, and neurofibromas with imaging modalities. The retroperitoneal approach for resection of presacral ganglioneuroma was performed for gross total resection of the tumor. Recurrence and malignant transformation of these tumors is rare. Adjuvant chemotherapy or radiation therapy is not indicated because of their benign nature. We report a case of a 47-year-old woman with a presacral ganglioneuroma.

Rationale Fat embolism syndrome (FES) is characterized by the classical triad of cerebral, respiratory, and cutaneous manifestations. In contrast, cerebral fat embolism (CFE), corresponding to incomplete pure type FES, is much rarer and usually follows trauma. CFE typically shows a "starfield" pattern on diffusion-weighted magnetic resonance imaging due to the involvement of multiple small arteries. We report 2 unusual cases of CFE that showed a nontraumatic etiology and the involvement of a single dominant cerebral artery. Patient concerns Case 1 was a 33-year-old woman without a history of trauma who visited the emergency room due to hemiparesis and hemisensory deficits. She was a heavy smoker and had used oral contraceptives for several years. Most importantly, she had 2 experiences of autologous fat grafting 2 months previously. Magnetic resonance angiography (MRA) revealed acute occlusion of the right middle cerebral artery. Case 2 was an 80-year-old man suddenly presented with dizziness, ataxia, and left-sided sensorimotor dysfunction. He had a history of hypertension, untreated atrial fibrillation, and chronic alcoholism. MRA demonstrated the occlusion of the distal basilar artery. Diagnosis Case 1: Microscopic findings demonstrated variable sized fat vacuoles intermixed with moderate amounts of thrombi. Case 2: Histologically, mature adipocytes were intermingled with fibrin, blood cells, and a fragment of entrapped soft tissue resembling the vessel wall. Intervention Case 1 and 2 underwent aspirational thrombectomy guided by transfemoral cerebral angiography. Outcome Case 1 recovered well but Case 2 still suffers from gait ataxia. Lessons CFE can rarely occur in various nontraumatic conditions, with or without evident etiology. Furthermore, it may not show characteristic clinicopathological manifestations. Therefore, careful follow up of those who have undergone procedures that are likely to trigger FES or who have hemodynamic or hypercoagulable risk factors is needed.

Rationale: Poroid hidradenoma (PH) is a rare variant of benign sweat gland neoplasm without connection to the epidermis. This tumor presents clinically as a solitary lesion with a cystic component located in the subcutaneous layer abutting the skin. On ultrasound, it appears as a circumscribed complex cystic and solid mass abutting the dermis. The occurrence of PH in the breast is very rare. Its features overlap with intraductal papilloma and papillary carcinoma. Patient concerns: A 66-year-old woman presented with a palpable lump in her right breast. Diagnoses: Clinical examination revealed dark bluish dome-shaped nodule which presented as circumscribed round isodense mass on mammography and oval complex cystic and solid mass abutting the dermis on ultrasound. Clinically, a papillary neoplasm was suspected. Interventions: The patient underwent En bloc surgical excision including the overlying epidermis and the surrounding adipose tissue to prevent recurrence. Outcomes: A well-demarcated, non-encapsulated grayish white mass composed of a partly solid and partly cystic area was completely removed and histopathologically confirmed as PH. At the 12-month follow-up, no recurrence was evident. Lessons: PH should be considered in the differential diagnosis of a slowly growing breast mass that is bluish, cystic, and solid and abuts the dermis.

Poststreptococcal glomerulonephritis (PSGN) is one of the most well-known and important infectious renal diseases resulting from a prior infection with group A β-hemolytic streptococcus. The typical clinical characteristics of the disease reflect acute onset with gross hematuria, edema, hypertension and moderate proteinuria after the antecedent streptococcal infection. In children, usually PSGN is healed spontaneously but if it combines with fast progressing glomerulonephritis, it would be developed to chronic renal failure. Therefore, it is important to make a fast diagnosis and treatment by simple tools to predict the course and the prognosis of disease. Sonography is a simple tool for diagnosis but there is no typical renal sonographic finding in PSGN, so it is difficult to predict the course and the prognosis of disease by sonographic findings. In comparison between two cases of renal sonographic findings in PSGN, a patient who showed more increased echogenicity in more extended area of renal sonography had the severe results of renal pathology, prolonged treatment period and low serum C3 level. Here, we report the different findings of renal sonography and pathology depending on the degree of severity between two patients. Thus, it is necessary to gather more information from further studies to make a consensus about the relationship between the renal sonography and the prognosis of disease in PSGN.

Peroxisome proliferator-activated receptor gamma (PPAR-γ), a ligand-activated transcription factor has been investigated as the target for cancer treatment as well as metabolic disorders. Recent studies have demonstrated that PPAR-γ ligands are anti-tumorigenic in prostate cancer due to anti-proliferative and pro-differentiation effects. The aim of this study was to validate PPAR-γ expression in malignant and benign prostate tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (PCR). A total of 730 prostatic adenocarcinomas (PCAs) including 63 whole sections from radical prostatectomy specimens and tissue microarrays containing 667 PCAs were subject to immunostaining for two PPAR-γ antibodies. Twenty-five benign prostate tissues and PCAs were selected for investigating mRNA expression by quantitative real-time PCR. 10.7% of PCAs (78/730) showed cytoplasmic immunoreactivity of PPAR-γ and no nuclear immunoreactivity was noted in PCAs. Most benign prostatic glands showed negative immunoreactivity of PPAR-γ except for variable weak cytoplasmic staining in some glands. Nuclear immunoreactivity of PPAR-γ was noted some central zone and verumontanum mucosal epithelium. The constitutive PPAR-γ mRNA showed significantly lower level in PCAs compared to that in the benign tissues. There was no difference of PPAR-γ mRNA expression between low (≤7) and high (>7) Gleason score groups. There was no association of PPAR-γ mRNA level or cytoplasmic immunostaining with Gleason grade or pathologic stage. Our study supported the evidence of extra-nuclear localization and nongenomic actions of PPAR-γ. Further studies are needed to assess the functional role of PPAR-γ and to validate its therapeutic implication in prostate cancer. Graphical Abstract Keywords: Prostatic Neoplasms, PPAR gamma, Immunohistochemistry, Real-Time Polymerase Chain Reaction INTRODUCTION Prostate cancer is the second most frequently diagnosed cancer affecting male adults and the sixth most common cause of cancer associated death in men across the world (1). The major risk factors for prostate cancer are old age, race, inherited susceptibility and environmental and behavioral factors such as diets (2, 3). Treatment options of prostate cancer include active surveillance, surgical resection, androgen ablation therapy, radiotherapy, and cryotherapy variously depending on risk grouping, medical comorbidities and age at the diagnosis of the patients (4, 5, 6). Prostate cancer is heterogeneous in terms of clinical behaviors, histological and molecular features, and treatment options (4, 5, 6, 7). Although most patients with low and intermediate-risk prostate cancer follow an indolent clinical course and are potentially curative by surgical resection or radiotherapy, patients with high-risk prostate cancer have higher rate of cancer related death and conventional chemotherapy and radiation therapy are of limited effectiveness for them (2, 4, 5, 6, 8). Androgen deprivation therapy has good efficacy for advanced disease to lead to either a partial or complete remission initially. However most patients evolve towards an androgen-independent state within a few years and result in death due to widespread metastasis (6). Therefore, more improved treatments and novel biomarkers are strongly needed in order to overcome metastasis and lethal recurrence for advanced prostate cancer as well as unpredictable cases of low or intermediate risk groups. Peroxisome proliferator-activated receptors (PPARs) are a group of 50-kDa ligand-dependent transcription factors localized at human chromosome 3p25 and belong to a member of the nuclear hormone receptor superfamily such as steroid and thyroid hormones (9, 10, 11). They are composed of three isoforms (PPAR-α, PPAR-γ, and PPAR-δ/β) and require heterodimerization with the retinoid X receptor for optimal DNA binding to specific response elements, termed to as peroxisome proliferator response elements (PPREs), in the promoter of the various target genes (9, 10, 11). The nuclear receptor superfamily was named because they show prominent nuclear localization. Among the subtypes, PPAR-γ is known to play a prominent role in adipocyte differentiation, the inflammatory response and peripheral glucose utilization (9, 11). Recent studies have suggested that PPAR-γ play a key role in tumorigenesis as a tumor suppressor and PPAR-γ agonists showed antiproliferative and proapoptotic actions in cancers (8, 12, 13). Currently PPAR-γ agonists including the most active natural ligand, 15-deoxy-D-12, 14-prostaglandin J2 (15-dPGJ2) and the most specific PPAR-γ synthetic agonists, the thiazolidinediones (TZDs) are used for enhancing insulin sensitivity in type II diabetes patients (9). And they have been introduced in clinical trials for treatment of several malignancies such as colorectal and esophageal cancers (9, 14). Many in vivo or in vitro studies have shown antineoplastic effect of PPAR-γ ligands in prostate cancers (15, 16). It has been reported that exposure to the TZDs has been shown to increase apoptotic activity in LNCaP, C4-2, and PC-3 prostate cancer cells and a combination therapy using histone deacetylases inhibitors and PPAR-γ agonists decrease invasiveness of the prostate adenocarcinoma cells in vivo (13, 15, 16). Efatutazone is recently introduced as a novel third-generation TZD PPAR-γ agonist, which is at least 500-fold more potent than the other TZDs such as troglitazone and pioglitazone (17). Therefore, PPAR-γ and its agonists have recently drawn more attention and promise in terms of chemoprevention and chemotherapy for cancer treatment and it has been also considered as a promising molecular target for anticancer targeted therapy development in prostate cancers (18). However, there is little or controversial information on PPAR-γ expression and clinical implications in the clinical specimen of prostate cancers (18, 19, 20). Whereas Nakamura et al. (19) reported PPAR-γ expression showed an inverse correlation with worse clinical parameters including pT stage and serum PSA levels, Rogenhofer et al. (20) reported PPAR-γ protein and mRNA expression were found to be significantly higher in advanced prostate cancers than in localized cancer. Therefore, further studies are needed to obtain a better understanding of the clinical roles of PPAR-γ in human prostate cancers for considering a potential trial of PPAR-γ ligands therapy for the patients. The aim of this study was to validate PPAR-γ expression in malignant and benign prostate tissues of a clinically well-characterized prostatectomy cohort by immunohistochemistry and quantitative real-time PCR in a Korean population.

The BRAFMutations of the BRAF and RAS genes and rearrangement of the RET/PTC1, NTRK1, and ALK genes using 769 preoperative fine-needle aspiration specimens and resected PTCs were analyzed.Molecular alterations were found in 687 (89.3%) of 769 PTCs. BRAFGenetic alterations in PTC vary among its different histologic variants and seem to be different in each ethnic group.

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening hyperinflammatory syndrome characterized by activated macrophages engulfing erythrocytes, leukocytes, platelets, and their precursor cells in bone marrow, liver, spleen, or lymph nodes. We report a case of Epstein-Barr virus (EBV)-associated HLH unusually presenting as an ileal mass. A 23-year-old man presented initially with persistent fever unresponsive to antibiotics and pancytopenia. A bone marrow aspiration and biopsy were used to diagnose the patient with aplastic anemia and HLH. A relatively well-defined low-density mass was radiologically noted in the terminal ileum, along with enlarged lymph nodes, and was suspected to be malignant lymphoma or an abscess. The ileocecectomy specimen revealed a transmural hemorrhagic infarction with numerous activated macrophages phagocytosing erythrocytes, plasma cells, and lymphocytes, and he was diagnosed with EBV-associated HLH. The patient received an allo-unrelated peripheral blood stem-cell transplantation and expired due to graft-versus-host disease following liver failure. The present case is very unique, in that EBV-associated HLH presented with an unusual ileal mass resulting from hemorrhagic infarction in a patient with aplastic anemia, suggesting variability in the biological behavior of EBV-associated disease.

A primary ductal adenocarcinoma (PDA) of the lacrimal gland is a rare distinct subtype of an epithelial tumor arising in the lacrimal gland. PDA is the counterpart of salivary duct carcinoma (SDC) resembling an invasive ductal carcinoma (IDC) of the breast. In our case, PDA revealed histopathological and immunohistochemical results corresponding to SDC. Interestingly, the tumor cells showed intracytoplasmic vacuoles containing dense eosinophilic hyaline globules at light microscopy. Ultrastructurally, the tumor cells exhibited microvilli-lined intracytoplasmic lumen containing homogenous electron-dense secretory products. A previous study demonstrated that numerous intracytoplasmic lumens of tumor cells are favored breast malignant tumor, similar to the histopathology of PDA, rather than benign lesion. This characteristic finding may be meaningful to diagnose high grade epithelial tumors including PDA.

Brain metastasis occurs in 3.9-24% of patients with renal cell carcinoma (RCC), with an average interval from nephrectomy to brain metastasis of 1 to 3 years. A few cases have been reported where brain metastasis occurred after a delay of more than 10 years from the initial onset of renal cell carcinoma. This long interval for central nervous system metastasis from the primary cancer has been recognized as an indicator of better prognosis. Histopathological confirmation and aggressive treatment must be considered in these delayed brain metastases cases, since the patients usually show long survival and good prognosis. We present a case of a 76-year-old woman who developed extremely late multiple brain metastases 18 years after a nephrectomy for RCC.

We evaluated p53, KRAS, BRAF and CTNNB1 mutation and p53, WT1, p16 and beta-catenin expression in 31 ovarian high-grade serous adenocarcinoma. Twenty-five (80.6%) tumors contained functional mutations of p53; three frameshift, four nonsense and 19 missense mutations. None of the tumors showed KRAS, BRAF or CTNNB1 mutation. In all 18 tumors with missense mutations, ≥60% of tumor cells were strongly positive for p53 immunostaining whereas all tumors with frameshift or nonsense mutations were completely negative. Missense mutation was correlated with diffuse and strong imunoreaction and frameshift/nonsense mutation was correlated with completely negative immunoreaction (P = 0.000). Tumors with wild-type p53 revealed a wide range of immunostaining patterns. In 27 (87.1%) and 18 (58.1%) tumors, ≥50% of tumor cells were moderate to strongly positive for WT1 and p16, respectively. A considerable intratumoral heterogeneity for p16 expression was present. None of the tumors demonstrated nuclear beta-catenin expression. p53 mutations appear to be a powerful molecular marker for ovarian high-grade serous adenocarcinoma. Using p53 with an appropriate interpretation criteria together with WT1, p16 and beta-catenin, most of the high-grade serous adenocarcinoma could be distinguished from other ovarian tumors.

Follicular variants of papillary thyroid carcinoma (FVPTC), particularly the encapsulated subtype, often cause a diagnostic dilemma. Therefore, many FVPTCs are interpreted as "indeterminate" in preoperative fine-needle aspiration (FNA). The aim of this study was to analyze the genotypic changes in BRAF codons 600 and 601, as well as the N, H, and KRAS codons 12, 13, and 61 in FVPTCs and investigate the usefulness of preoperative BRAF and RAS mutation analysis as an adjunct diagnostic tool along with routine FNA. Surgically resected thyroid nodules were reviewed to establish the histological diagnosis of FVPTC. All preoperative FNA diagnoses were categorized according to the Bethesda Reporting System. Mutations in BRAF codons 600 and 601, and N, H, KRAS codons 12, 13, and 61 were analyzed by pyrosequencing. Of 132 cases, 81 (61.4 %) had a point mutation in one of the BRAF V600E, BRAF K601E, or RAS oncogenes; BRAF V600E in 43(32.6 %), BRAF K601E in three (2.3 %), and RAS in 35 (26.5 %) cases. All mutations were mutually exclusive. Of 78 cases with an FNA indeterminate category diagnosis, 51 (65.4 %) were positive for mutations: 24 for BRAF V600E, 3 for BRAF K601E, and 24 for the RAS gene. The KRAS mutation was more frequently found than the HRAS mutation, comprising 22.9 % of the RAS mutations, and all KRAS mutations were located at codon 61. This study demonstrated that either BRAF or RAS mutations were present in two thirds of FVPTCs and these mutations were mutually exclusive.

Medulloblastoma (MB) is a clinically and biologically heterogeneous group of tumors, and currently classified into four molecular subgroups (Wnt, Shh, Group 3 and Group 4). Intracellular signaling of the Wnt pathway has been divided into two classes: the "canonical" and the "non-canonical" signaling pathway. The canonical signaling pathway is a well-established, β-catenin-dependent signaling pathway in MB. In contrast, very little research about the non-canonical WNT signaling pathway in MB exists. In order to identify the roles of Wnt-5a and Ror2, two non-canonical WNT pathway-related genes, we studied 76 cases of MB with immunohistochemistry and quantitative real-time PCR and correlated the results with clinicopathological and other molecular parameters and prognosis. Wnt5a and Ror2 were immunopositive in 20 (29.4%) and 35 (51.5%) of 68 cases, respectively. There were positive associations among protein expressions of Wnt5a, Ror2 and β-catenin. Ror2 mRNA levels were well correlated with immunoexpression. Ror2 mRNA expression was significantly associated with CTNNB1 mutation. High Ror2 mRNA expression was an independent favorable prognostic factor. In conclusion, our study demonstrates the first attempt to identify Wnt5a and Ror2 as additional mechanisms contributing to dysregulation of the non-canonical WNT signaling pathway in MB. Ror2 may play a role as an oncosuppressor in MB.

DNA extraction from microdissected cells has become essential for handling clinical specimens with advances in molecular pathology. Conventional methods have limitations for extracting amplifiable DNA from specimens containing a small number of cells. We developed an ammonium sulfate DNA extraction method (A) and compared it with two other methods (B and C). DNA quality and quantity,β-globin amplification, and detectability of two cancer associated gene mutations were evaluated. Method A showed the best DNA yield, particularly when the cell number was very low. Amplification of theβ-globin gene using DNA from the SNU 790 cell line and papillary thyroid carcinoma (PTC) cells extracted with Method A demonstrated the strongest band.BRAFV600Emutation analysis using ethanol-fixed PTC cells from a patient demonstrated both a “T” peak increase and an adjacent “A” peak decrease when 25 and 50 cells were extracted, whereas mutant peaks were too low to be analyzed using the other two methods.EGFRmutation analysis using formalin-fixed paraffin-embedded lung cancer tissues demonstrated a mutant peak with Method A, whereas the mutant peak was undetectable with Methods B or C. Method A yielded the best DNA quantity and quality with outstanding efficiency, particularly when paucicellular specimens were used.

In patients with colorectal cancer (CRC), the BRAF V600E mutation has been reported to be associated with several clinicopathological features and poor survival. However, the prognostic implications of BRAF V600E mutation and the associated clinicopathological characteristics in CRCs remain controversial. Therefore, we reviewed various clinicopathological features, including BRAF status, in 349 primary CRCs and analyzed the relationship between BRAF status and various clinicopathological factors, including overall survival. Similar to previous studies conducted in Eastern countries, the incidence of the BRAF V600E mutation in the current study was relatively low (5.7%). BRAF-mutated CRC exhibits distinct clinicopathological features from wild-type BRAF-expressing cancer independent of the microsatellite instability (MSI) status. This mutation was significantly associated with a proximal tumor location (P = 0.002); mucinous, signet ring cell, and serrated tumor components (P < 0.001, P = 0.003, and P = 0.008, respectively); lymphovascular invasion (P = 0.004); a peritumoral lymphoid reaction (P = 0.009); tumor budding (P = 0.046); and peritoneal seeding (P = 0.012). In conclusion, the incidence of the BRAF V600E mutation was relatively low in this study. BRAF-mutated CRCs exhibited some clinicopathological features which were also frequently observed in MSI-H CRCs, such as a proximal location; mucinous, signet ring cell, and serrated components; and marked peritumoral lymphoid reactions.

Ethylene glycol (EG) is a sweet-tasting, odorless organic solvent found in many agents, such as anti-freeze. EG is composed of four organic acids: glycoaldehyde, glycolic acid, glyoxylic acid and oxalic acid in vivo. These metabolites are cellular toxins that can cause cardio-pulmonary failure, life-threatening metabolic acidosis, central nervous system depression, and kidney injury. Oxalic acid is the end product of EG, which can precipitate to crystals of calcium oxalate monohydrate in the tubular lumen and has been linked to acute kidney injury. We report a case of EG-induced oxalate nephropathy, with the diagnosis confirmed by kidney biopsy, which showed acute tubular injury of the kidneys with extensive intracellular and intraluminal calcium oxalate monohydrate crystal depositions.

Although the hippocampus is considered an important site of seizures in mesial temporal lobe epilepsy (mTLE), the amygdala may also have a significant role. Amygdala enlargement is occasionally found in patients with mTLE, and volumetric detection of amygdala enlargement has been documented in "image-negative" patients with TLE. However, only limited data have been reported on the clinical features, surgical outcomes, and pathological characteristics in patients with mTLE with amygdala enlargement. We recruited 12 patients who had undergone surgical treatment for refractory epilepsy with radiological evidence of amygdala enlargement, and 11 became seizure free. All patients showed homogenously increased amygdala volumes on MRI without enhancement and underwent surgical treatment for mTLE. Pathology results revealed that eight patients had focal cortical dysplasia (FCD), two had ganglioglioma, one had oligodendroglioma, and one had astrocytoma. The clinical features and MRI findings were largely indistinguishable between the patients with brain tumors and those with FCD, but the patients with brain tumors tended to be younger at the time of seizure onset. Our study shows that surgical treatment of epilepsy in patients with amygdala enlargement usually has a favorable outcome. FCD was the most frequent pathological diagnosis in these patients. However, a brain tumor should be considered in the differential diagnosis, especially in young patients, because it is often difficult to differentiate FCD from a brain tumor on radiological features.

The purposes of this study were to assess chronologic changes in normal growth plate after radiofrequency-induced thermal injury and to evaluate the feasibility of MRI for revealing alteration of the growth plate.Radiofrequency ablation was performed on the right proximal tibia of 13 8-week-old New Zealand White rabbits. An 18-gauge cooled-tip electrode with a 5-mm active tip was placed distal to the physis under fluoroscopic guidance. MRI, including T1- and T2-weighted images, gradient-recalled echo images, and contrast-enhanced T1-weighted images, was performed 2, 4, and 12 weeks after ablation. Rabbits were sacrificed 2 (n = 4), 4 (n = 4), and 12 weeks (n = 5) after ablation. The sequential changes in the ablated zone, the injured physis, and the nonablated portion of the physis were correlated between MRI features and histologic results.Diameter of the nonenhancing lesion on MR images strongly correlated with the size of the region of coagulation necrosis at gross examination. The intraclass correlation coefficients were 0.98 and 0.94 for the long and short axes (p0.001). On gradient-recalled echo images, physial conspicuity was less in the injured physis than in the nonablated portion and less in the ablated than the control tibia. Physial conspicuity was graded for comparison with physial thickness at microscopic examination. The thickness of the physis was less in the ablated than in the control tibia 4 and 12 weeks after treatment (p0.05, paired Student t test). The cartilage column of the injured physis was delaminated 2 weeks after treatment, and a bone bridge through the injured physis was detected at 4 weeks.Radiofrequency-induced thermal injury causes early closure of the physis. MRI can depict the extent of radiofrequency-induced thermal injury and alterations in the physis that lead to early closure.

OBJECTIVE: To evaluate effect of postbiopsy hemorrhage on detection of peripheral zone (PZ) prostate cancer by multiparametric MR imaging according to Gleason score and tumor volume. METHODS: This retrospective study included 54 biopsy-proven prostate cancer patients (median age, 67.0 years) who underwent multiparametric MR imaging. Two independent readers evaluated each sextant of the PZ using the PI-RADS v2. One reader recorded the presence or absence of hemorrhage per sextant on T(1) weighted MR images. Areas under the receiver operating characteristic curves (AUCs) were used to evaluate cancer detection accuracy. RESULTS: Postbiopsy hemorrhage was noted in 122 (37.7%) of 324 sextants of all patients. There was no significant difference in the AUC for detection of cancer with Gleason score ≥3 + 4 or volume ≥0.5 ml between sextants with and without hemorrhage (with hemorrhage, reader 1, 0.83 for Gleason score ≥3 + 4, 0.84 for tumor volume ≥0.5 ml; reader 2, 0.74 for Gleason score ≥3 + 4, 0.77 for tumor volume ≥0.5 ml; without hemorrhage, reader 1, 0.86 for Gleason score ≥3 + 4, 0.88 for tumor volume ≥0.5 ml; reader 2, 0.79 for Gleason score ≥3 + 4, 0.83 for tumor volume ≥0.5 ml; p > 0.2 for all). CONCLUSION: Postbiopsy hemorrhage did not negatively affect the detection of clinically significant PZ prostate cancer on multiparametric MR imaging. ADVANCES IN KNOWLEDGE: Under influence of postbiopsy hemorrhage, multiparametric MR can be useful for the detection of clinically significant PZ prostate cancer.

Occipital neuralgia is a form of headache that involves the posterior occiput in the greater or lesser occipital nerve distribution. Pain can be severe and persistent with conservative treatment. We present a case of intractable occipital neuralgia that conventional therapeutic modalities failed to ameliorate. We speculate that, in this case, the cause of headache could be the greater occipital nerve entrapment by the obliquus capitis inferior muscle. After steroid and local anesthetic injection into obliquus capitis inferior muscles under fluoroscopic and sonographic guidance, the visual analogue scale was decreased from 9-10/10 to 1-2/10 for 2-3 weeks. The patient eventually got both greater occipital neurectomy and partial resection of obliquus capitis inferior muscles due to the short term effect of the injection. The successful steroid and local anesthetic injection for this occipital neuralgia shows that the refractory headache was caused by entrapment of greater occipital nerves by obliquus capitis inferior muscles.

Renal angiomyolipoma (AML) is a benign but progressive tumor that occasionally requires non-surgical therapy and there appears to be a possibility that epidermal growth factor (EGF) is associated with pathogenesis of renal AML. The response to gefitinib, anti-epidermal growth factor receptor (EGFR) agent and a prime example of target therapy, reportedly has been correlated with the presence of mutations within the tyrosine kinase (TK) domain of EGFR or the expression of its truncated form, EGFR variant III. Therefore the purpose of the present paper was to investigate EGFR protein expression and gene mutations in exons 18, 19 and 21 in 40 renal AML. No EGFR gene mutations of TK domain were detected in any of the 40 cases studied and strong immunostaining was found in 5% of the renal AML cases. The present findings indicate that in renal AML, anti-EGFR treatment may not be promising but that there is a possibility that EGFR is associated with renal AML pathogenesis.

Angiomyolipomas are benign tumors of the kidney which express phenotypes of smooth muscle, fat, and melanocytes. These tumors appear with increased frequency in the autosomal dominant disorder tuberous sclerosis and are the leading cause of morbidity in adults with tuberous sclerosis. While benign, these tumors are capable of provoking life threatening hemorrhage and replacement of the kidney parenchyma, resulting in renal failure. The histogenesis of these tumors is currently unclear, although currently, we believe these tumors arise from “perivascular epithelioid cells” of which no normal counterpart has been convincingly demonstrated. Recently, stem cell precursors have been recognized that can give rise to smooth muscle and melanocytes. These precursors have been shown to express the neural stem cell marker NG2 and L1. In order to determine whether angiomyolipomas, which exhibit smooth muscle and melanocytic phenotypes, express NG2 and L1, we performed immunocytochemistry on a cell line derived from a human angiomyolipoma, and found that these cells are uniformly positive. Immunohistochemistry of human angiomyolipoma specimens revealed uniform staining of tumor cells, while renal cell carcinomas revealed positivity only of angiogenic vessels. These results support a novel histogenesis of angiomyolipoma as a defect in differentiation of stem cell precursors.

The study aimed to verify the prognostic utility, therapeutic application and clinical benefits of tumor substaging and HER2 status in papillary non-muscle invasive bladder cancer (NMIBC). Select NMIBC transurethral resection specimens from 141 patients were used to construct tissue microarrays for assessing the substaging, HER2 protein expression by immunohistochemistry (HER2-IHC) and gene amplification by dual-color silver in situ hybridization (HER2-SISH). Substages were identified by the differing depth of tumor invasion (pTa / pT1a / pT1b / pT1c). HER2 protein expression was semiquantitatively analyzed and grouped into negative (score 0, 1+) and positive (score 2+, 3+). Other clinicopathological variables were also investigated. For NMIBC, HER2-IHC and HER2-SISH showed positive results in 6/141 (4.3%) and 4/141 (2.8%) respectively, which correlated well with tumor substaging. In multivariate analysis, substaging, HER2-IHC, and HER2-SISH were found to be independent predictors of progression-free survival (P < 0.001, P < 0.001, P = 0.031). HER2-IHC was the sole independent predictor of recurrent free survival in NMIBC (P = 0.017). It is suggested that tumor substaging and HER2 status are independent predictive markers for tumor progression or recurrence, and thus could be included in diagnostic and therapeutic management for NMIBC. Graphical Abstract

Follicular variant of papillary thyroid carcinoma (FVPTC), particularly the encapsulated subtype, often causes a diagnostic dilemma. We reconfirmed the molecular profiles in a large number of FVPTCs and investigated the efficacy of the preoperative mutational analysis in indeterminate thyroid nodules. BRAF V600E/K601E and RAS mutational analysis was performed on 187 FVPTCs. Of these, 132 (70.6%) had a point mutation in one of the BRAF V600E (n=57), BRAF K601E (n=11), or RAS (n=64) genes. All mutations were mutually exclusive. The most common RAS mutations were at NRAS codon 61. FNA aspirates from 564 indeterminate nodules were prospectively tested for BRAF and RAS mutation and the surgical outcome was correlated with the mutational status. Fifty-seven and 47 cases were positive for BRAF and RAS mutation, respectively. Twenty-seven RAS-positive patients underwent surgery and all except one patient had FVPTC. The PPV and accuracy of RAS mutational analysis for predicting FVPTC were 96% and 84%, respectively. BRAF or RAS mutations were present in more than two-thirds of FVPTCs and these were mutually exclusive. BRAF mutational analysis followed by N, H, and KRAS codon 61 mutational analysis in indeterminate thyroid nodules would streamline the management of patients with malignancies, mostly FVPTC.

BACKGROUND Connexins have their traditional function as part of gap junction (GJ) structures, but have recently been shown to have GJ-independent roles. Although GJs and their connexin subunits are thought to be down-regulated in cancer, depending on the connexin examined, many times the expression level is preserved or even increased. This is further apparent by the importance of GJs in “by-stander effects” of radiation and viral targeting treatments. METHODS We surveyed connexin isoforms in prostate cancer cell lines and tissue with RT-PCR and immunohistochemistry. Upon modulating GJ function, we observed prostate epithelial cell behaviors. RESULTS Advanced cells within PC-3 and LNCaP prostate cancer progression models exhibit elevated connexin 26 (Cx26) levels—a trend validated in clinical samples. When GJs were inhibited, adhesion was not affected, but invasion and migration were strikingly decreased. A link between the expression of Cx26 and integrin adhesion-linked functions are suggested by Cx26's direct interaction with focal adhesion kinase (FAK). CONCLUSIONS These results suggest a novel mechanism for adhesion regulation by a GJ-independent Cx26 function that correlates with prostate disease progression. The increased Cx26 expression during prostate cancer progression plays a role in adhesion regulation possibly through its interaction with FAK. © 2005 Wiley-Liss, Inc.