Impact of Nrf2 overexpression on cholangiocarcinoma treatment and clinical prognosis

Purpose@#Nrf2 regulates antioxidant protein expression and protects against drug toxicity and oxidative stress, whereas Keap1 controls Nrf2 activity. The Keap1-Nrf2 pathway affects the prognosis of various cancers, however, its effect on cholangiocarcinoma chemoresistance and prognosis remains unclear. This study aimed to determine whether the Keap1-Nrf2 pathway affects chemoresistance and prognosis of distal cholangiocarcinoma. @*Methods@#We investigated the correlation between Nrf2 and Keap1 expression and clinical characteristics and prognosis in 91 patients with distal cholangiocarcinoma who underwent curative surgery. Immunohistochemical staining was performed on paraffin blocks using primary antibodies against Nrf2 and Keap1. The relationship between Keap1 and Nrf2 protein expression levels, and clinical characteristics and prognosis was examined. @*Results@#Nrf2 expression was not associated with overall survival in patients who did not receive adjuvant chemotherapy (P=0.994). Among patients receiving adjuvant chemotherapy, the Nrf2 low expression group had a significantly longer median overall survival than the Nrf2 high expression group in Kaplan-Meier survival analysis (P=0.019). In multivariate analysis, high expression of Nrf2 was confirmed as an independent poor prognostic factor in the group receiving adjuvant chemotherapy (P=0.041). @*Conclusion@#This study suggests that Nrf2 overexpression reduces the efficacy of adjuvant chemotherapy in distal cholangiocarcinoma.

Extramedullary Relapse of Acute Lymphoblastic Leukemia Involving the Parotid Gland: A Case Report and Literature Review

While extramedullary relapse of leukemia could occur, the parotid gland is a rare site of recurrence. Extramedullary relapse involving the parotid gland could be mistaken for other diseases. Moreover, the diagnosis of this disease is often delayed due to its rarity. Herein, we present a case of extramedullary relapse of acute lymphoblastic leukemia involving the parotid gland.

Intestinal Ganglioneuromatosis in a Pediatric Patient Presenting as Perforation: A Case Report and Literature Review

Intestinal ganglioneuromatosis is an extremely rare condition, particularly in pediatric patients, and the imaging features of the disease have been rarely reported before. Herein, we present a pediatric case of intestinal ganglioneuromatosis involving the transverse colon and splenic flexure with bowel perforation, which is a rare initial manifestation of the disease.

Histologically confirmed distant metastatic urothelial carcinoma from the urinary bladder: a retrospective review of one institution’s 20-year experience

Background@#Urothelial carcinoma (UC) accounts for roughly 90% of bladder cancer, and has a high propensity for diverse differentiation. Recently, certain histologic variants of UC have been recognized to be associated with unfavorable clinical outcomes. Several UC studies have also suggested that tumor budding is a poor prognostic marker. Distant metastasis of UC after radical cystectomy is not uncommon. However, these metastatic lesions are not routinely confirmed with histology. @*Methods@#We investigated the histopathologic features of 13 cases of UC with biopsy-proven distant metastases, with a special emphasis on histologic variants and tumor budding. @*Results@#Lymph nodes (6/13, 46%) were the most common metastatic sites, followed by the lung (4/13, 31%), liver (4/13, 31%), and the adrenal gland (2/13, 15%). The histologic variants including squamous (n=1), micropapillary (n=4), and plasmacytoid (n=1) variants in five cases of UC. Most histologic variants (4/5, 80%) of primary UCs appeared in the metastatic lesions. In contrast, high-grade tumor budding was detected in six cases (46%), including one case of non-muscle invasive UC. Our study demonstrates that histologic variants are not uncommonly detected in distant metastatic UCs. Most histologic variants seen in primary UCs persist in the distant metastatic lesions. In addition, high-grade tumor budding, which occurs frequently in primary tumors, may contribute to the development of distant metastasis. @*Conclusions@#Therefore, assessing the presence or absence of histologic variants and tumor budding in UCs of the urinary bladder, even in non-muscle invasive UCs, may be useful to predict distant metastasis.

Double cocktail immunostains with high molecular weight cytokeratin and GATA-3: useful stain to discriminate in situ involvement of prostatic ducts or acini from stromal invasion by urothelial carcinoma in the prostate

Background@#Distinguishing prostatic stromal invasion (PSI) by urothelial carcinoma (UC) from in situ UC involving prostatic ducts or acini with no stromal invasion (in situ involvement) may be challenging on hematoxylin and eosin stained sections. However, the distinction between them is important because cases with PSI show worse prognosis. This study was performed to assess the utility of double cocktail immunostains with high molecular weight cytokeratin (HMWCK) and GATA-3 to discriminate PSI by UC from in situ UC involvement of prostatic ducts or acini in the prostate. @*Methods@#Among 117 radical cystoprostatectomy specimens for bladder UCs, 25 cases showed secondary involvement of bladder UC in prostatic ducts/acini only or associated stromal invasion and of these 25 cases, seven cases revealed equivocal PSI. In these seven cases with equivocal PSI, HMWCK, and GATA-3 double immunohistochemical stains were performed to identify whether this cocktail stain is useful to identify the stromal invasion. @*Results@#In all cases, basal cells of prostate glands showed strong cytoplasmic staining for HMWCK and UC cells showed strong nuclear staining for GATA-3. In cases with stromal invasion of UC, GATA-3-positive tumor cells in the prostatic stroma without surrounding HMWCK-positive basal cells were highlighted and easily recognized. Among seven equivocal cases, two cases showed PSI and five in situ UC in the prostate. In two cases, the original diagnoses were revised. @*Conclusions@#Our study suggested that HMWCK and GATA-3 double stains could be utilized as an adjunct method in the distinction between PSI by UC from in situ UC involving prostatic ducts or acini.

14-3-3ζ Overexpression is Associated with Poor Prognosis in Ovarian Cancer

PURPOSE: 14-3-3ζ regulates cell signaling, cell cycle progression, and apoptosis, and its overexpression is associated with disease recurrence and poor clinical outcomes in some solid tumors. However, its clinicopathological role in ovarian cancer is unknown. Our goal was to investigate whether 14-3-3ζ is associated with ovarian cancer prognosis. MATERIALS AND METHODS: We examined 14-3-3ζ expression by immunohistochemistry in ovarian cancer tissues obtained from 88 ovarian cancer patients. The examined tissues were of various histologies and stages. 14-3-3ζ expression was also analyzed by western blot in seven ovarian cancer cell lines and a primary ovary epithelial cell line. Cell viability was measured using an MTS-based assay following cisplatin treatment. RESULTS: Among the ovarian cancer samples, 53.4% (47/88) showed high 14-3-3ζ expression, and 14-3-3ζ overexpression was positively correlated with more advanced pathologic stages and grades. 14-3-3ζ overexpression was also significantly associated with poor disease-free survival (DFS) and overall survival (OS) of ovarian cancer patients. Median DFS and OS were 1088 and 3905 days, respectively, in the high 14-3-3ζ expression group, but not reached in the low 14-3-3ζ expression group (p=0.004 and p=0.033, log-rank test, respectively). Downregulating 14-3-3ζ by RNA interference in ovarian cancer cells led to enhanced sensitivity to cisplatin-induced cell death. CONCLUSION: 14-3-3ζ overexpression might be a potential prognostic biomarker for ovarian cancer, and the inhibition of 14-3-3ζ could be a therapeutic option that enhances the antitumor activity of cisplatin.

GATA1 Expression in BCR/ABL1-negative Myeloproliferative Neoplasms

BACKGROUND: This study aimed to determine GATA1 expression levels to better characterize subgroups in BCR/ABL1-negative myeloproliferative neoplasms (MPNs). METHODS: This study enrolled 49 patients diagnosed as having BCR/ABL1-negative MPN on the basis of the 2016 World Health Organization classification : nine polycythemia vera (PV), 17 essential thrombocythemia (ET), 12 prefibrotic primary myelofibrosis (prePMF), and 11 overt primary myelofibrosis (PMF). Relevant clinical and laboratory data were retrieved from the medical records. The molecular analysis of CALR and MPL mutations and quantification of JAK2 V617F allele burden were performed. GATA1 expression was assessed by an immunohistochemical assay on bone marrow biopsy. GATA1 expression was analyzed serially in 18 patients. RESULTS: GATA1 expression decreased significantly in PMF compared with that in other subtypes, while no statistical difference was identified between ET and prePMF. GATA1 expression did not differ according to the mutation profiles or the allele burden of JAK2 V617F, but it decreased significantly in patients with overt fibrosis or leukemic transformation. CONCLUSIONS: Our results suggest that GATA1 expression is significantly low in PMF and decreases with progressive fibrosis and possibly with leukemic transformation, although our attempt to accurately distinguish between subgroups using GATA1 immunohistochemical approach did not achieve statistical significance. A large patient cohort with long term follow-up is required to evaluate the prognostic value of GATA1 expression.

Expression of CD44 according to Clinicopathologic Characteristics of Gastric Cancer / 이화의대지

OBJECTIVES: Cancer stem cells are defined as focal cluster of cells within a tumor that possess the capacity for self-renewal and differentiation into phenotypically heterogeneous cells. Cluster of differentiation 44 (CD44) is considered one of the gastric cancer stem cell markers. We aimed to investigate how the expression of CD44 varies according to the clinicopathologic characteristics in gastric cancer. METHODS: For this study, 157 patients who received an operation due to gastric cancer between May 1998 and December 2009 were selected. CD44 immunohistochemistry was reviewed using the semi-quantitative scoring of intensity and proportion. The sum of the intensity and proportion scores was calculated, and a score of 2 or less was deemed ‘CD44-negative’ and 3 or more as ‘CD44-positive.’ RESULTS: Among the final 143 subjects, 69 (48.3%) were CD44 positive. Older age, intestinal type gastric cancer, lymphatic invasion, and lymph node metastasis were significantly correlated with expression of CD44. In the multivariate analysis, older age was the only independent factor associated with CD44 expression (P=0.028). CD44 expression was correlated with overall survival, 5-year survival, and disease-free survival. In the multivariate analysis, older age, male gender, and lymphatic invasion were independent predictors of poor overall survival. Also, older age and lymphatic invasion were significant factors in 5-year survival, and lymphatic invasion was an independent factor of poor disease-free survival. CONCLUSION: Older age (≥60 years) was independently associated with CD44 expression in gastric cancer patients. Also, CD44 expression was correlated with poor prognosis in gastric cancer patients.

Anaplastic Large Cell Lymphoma with Massive Eosinophilia and Complex Karyotype Initially Misdiagnosed as Chronic Eosinophilic Leukemia

We report a patient with massive eosinophilia and a complex karyotype that was initially misdiagnosed as chronic eosinophilic leukemia (CEL), but later diagnosed as anaplastic large cell lymphoma (ALCL) masked by massive eosinophilia. The complex karyotype observed at initial diagnosis remained unchanged later, after the evidence of bone marrow involvement of ALCL was obtained. At diagnosis, genetic aberrations corresponding to metaphase cytogenetics were not identified by interphase fluorescence in situ hybridization, although abnormal results were noted at follow-up. Together, these observations indicate that the complex karyotype at initial work-up has been derived from a low proportion of lymphoma cells with high mitotic ability that were not identified by microscopy, rather than from massive eosinophils. These findings suggest that our patient had ALCL with secondary eosinophilia rather than CEL since initial diagnosis.

Effect of Necrosis on the miRNA-mRNA Regulatory Network in CRT-MG Human Astroglioma Cells / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Glioblastoma multiforme (GBM) is the most common adult primary intracranial tumor. The remarkable features of GBM include central necrosis. MicroRNAs (miRNAs) have been considered as diagnostic/prognostic biomarkers for many cancers, including glioblastoma. However, the effect of necrosis on the miRNA expression profile and predicted miRNA-mRNA regulatory information remain unclear. The purpose of this study is to examine the effect of necrotic cells on the modulation of miRNA and mRNA expression profiles and miRNA-mRNA network in CRT-MG cells. MATERIALS AND METHODS: We used human astroglioma cells, CRT-MG, treated with necrotic CRT-MG cells to examine the effect of necrosis on the modulation of miRNA and mRNA by next-generation sequencing. For preparation of necrotic cells, CRT-MG cells were frozen and thawed through cycle of liquid nitrogen–water bath. The putative miRNA-mRNA regulatory relationship was inferred through target information, using miRDB. RESULTS: The necrotic cells induced dysregulation of 106 miRNAs and 887 mRNAs. Among them, 11 miRNAs that had a negative correlation value of p < 0.05 by the hypergeometric test were screened, and their target mRNAs were analyzed by Gene Ontology enrichment analysis. Using the Kyoto Encyclopedia of Genes and Genomes database, we also found several necrotic cell treatment-activated pathways that were modulated by relevant gene targets of differentially expressed miRNAs. CONCLUSION: Our result demonstrated that dysregulation of miRNA and mRNA expression profiles occurs when GBM cells are exposed to necrotic cells, suggesting that several miRNAs may have the potential to be used as biomarkers for predicting GBM progression and pathogenesis.

A Case of Rheumatoid Vasculitis Involving Hepatic Artery in Early Rheumatoid Arthritis

Rheumatoid vasculitis is a rare, but most serious extra-articular complications of long-standing, seropositive rheumatoid arthritis (RA). Vasculitis of hepatic artery is an extremely rare but severe manifestation of rheumatoid vasculitis. A 72-year-old woman who presented with polyarthralgia for 2 months was diagnosed with early RA. Since she had manifestations of livedo reticularis, and liver dysfunction which was atypical for RA patients, a percutaneous needle liver biopsy was performed revealing arteritis of a medium-sized hepatic artery. Extensive investigations did not reveal evidences of other systemic causes such as malignancy or systemic vasculitis. The patient was diagnosed with rheumatoid vasculitis involving hepatic arteries based on Bacon and Scott criteria for rheumatoid vasculitis. With high dose corticosteroid and cyclophosphamide induction and methotrexate and tacrolimus maintenance treatment, she was successfully recovered. Association of rheumatoid vasculitis at very early stages of the disease may represent an early aggressive form of RA.

Skin metastases in ovarian clear cell adenocarcinoma: a case report and a review of the literature

Epithelial ovarian carcinoma is a high mortality neoplasm in gynecologic malignancy. It usually can metastasize to distant organs such as pleura, liver, lung, and lymph nodes. However, the skin metastases are not common and related to very poor prognosis. Here we report a 54-year-old patient with ovarian clear cell carcinoma with skin metastases on the anterior chest at 11 months after initial diagnosis. Although she received palliative chemotherapy, she expired due to disease progression 2 months later after the diagnosis of skin metastases.

Value of imaging study in predicting pelvic lymph node metastases of uterine cervical cancer

PURPOSE: To evaluate the diagnostic accuracy of computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography/computed tomography (PET/CT) in predicting pelvic lymph node (LN) metastases in patients with cervical cancer. MATERIALS AND METHODS: From January 2009 to March 2015, 114 patients with FIGO stage IA1-IIB uterine cervical cancer who underwent hysterectomy with pelvic lymphadenectomy and took CT, MRI, and PET/CT before surgery were enrolled in this study. The criteria for LN metastases were a LN diameter ≥1.0 cm and/or the presence of central necrosis on CT, a LN diameter ≥1.0 cm on MRI, and a focally increased FDG uptake on PET/CT. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for pelvic LN metastases were estimated. RESULTS: The sensitivity, specificity, PPV, NPV, and accuracy for detection of pelvic LN metastases were 51.4%, 85.9%, 41.3%, 90.1%, and 80.3% for CT; 24.3%, 96.3%, 56.3%, 86.8%, and 84.6% for MRI; and 48.6%, 89.5%, 47.4%, 90.0%, and 82.9% for PET/CT, respectively. The sensitivity of PET/CT and CT was higher than that of MRI (p=0.004 and p= 0.013, respectively). The specificity of MRI was higher than those of PET/CT and CT (p=0.002 and p=0.001, respectively). The difference of specificity between PET/CT and CT was not statistically significant (p=0.167). CONCLUSION: These results indicate that preoperative CT, MRI, and PET/CT showed low to moderate sensitivity and PPV, and moderate to high specificity, NPV, and accuracy. More efforts are necessary to improve sensitivity of imaging modalities in order to predict pelvic LN metastases.

Vaginal Brenner tumor with literature review: does this tumour originate from Walthard nests?

Vaginal Brenner tumor is extremely rare. Only five cases have been reported in the English literature to date. Here we report a vaginal Brenner tumor in a 76-year old postmenopausal woman, who presented with a 2.5cm-sized sessile vaginal polyp. Microscopically, it showed characteristic features of Brenner tumor consisting of three components; transitional islands, glands, and dense fibrous stroma. The epithelial tumor cells were positive for GATA-3, p63 and ER, but negative for PAX8. The origin of Brenner tumors in the vagina is unclear, but previous reports suggested of Müllerian origin. However, our case revealed that vaginal Walthard nests could be possible precursor lesions based on their immunohistochemical staining results.

Apoptosis and remodeling in adriamycin-induced cardiomyopathy rat model / 소아과

PURPOSE: The mechanism for the pathogenesis of adriamycin (ADR)-induced cardiomyopathy is not yet known. Different hypotheses include the production of free radicals, an interaction between ADR and nuclear components, and a disruption in cardiac-specific gene expression. Apoptosis has also been proposed as being involved in cardiac dysfunction. The purpose of this study was to determine if apoptosis might play a role in ADR-induced cardiomyopathy. METHODS: Male Sprague-Dawley rats were separated into 2 groups: the control group (C group) and the experimental group (ADR 5 mg/wk for 3 weeks through intraperitoneal injections; A group). Echocardiographic images were obtained at week 3. Changes in caspase-3, B-cell leukemia/lymphoma (Bcl)-2, Bcl-2-associated X (Bax), interleukin (IL)-6, tumor necrosis factor-α, brain natriuretic peptide (BNP), troponin I, collagen 1, and collagen 3 protein expression from the left ventricle tissues of C and A group rats were determined by Western blot. RESULTS: Ascites and heart failure as well as left ventricular hypertrophy were noted in the A group. Ejection fraction and shortening fraction were significantly lower in the A group by echocardiography. The expression of caspase-3, Bax, IL-6, BNP, collagen 1, and collagen 3 were significantly higher in the A group as compared with the C group. Protein expression of Bcl-2 decreased significantly in the A group compared with the C group. CONCLUSION: ADR induced an upregulation of caspase-3, Bax, IL-6, and collagen, as well as a depression in Bcl-2. Thus, apoptosis and fibrosis may play an important role in ADR-induced cardiomyopathy.

Progressive Pituitary Involvement in a Patient with Localized Granulomatosis with Polyangiitis / 이화의대지

Localized granulomatosis with polyangiitis (loc-GPA) is a milder disease state of GPA restricted to the respiratory tract. Transition from localized form to systemic/generalized disease is predicted to occur in approximately 10% of the patients. We report an unusual case of loc-GPA involving multiple cranial nerves, which in 3 years progressed into systemic disease involving pituitary gland. Initially antineutrophil cytoplasmic antibody (ANCA) was negative, but as symptoms of diabetes insipidus started, ANCA became positive. Clinical course of ANCA negative loc-GPA should be carefully monitored for development of systemic disease. ANCA may be a useful marker for detecting transition from localized to systemic disease.

Pancreatitis-Mimicking Pancreatic Cancer with Duodenal Obstruction: A Case Report

Pancreatic cancer tends to be delayed in diagnosis because of the lack of early symptom and less than 20% of patients present with resectable masses. A 95-year-old male visited due to recurrent abdominal pain and vomiting. About 2 years ago, a polypoid lesion was detected at the post-bulbar area on esophagogastroduodenoscopy for medical check-up. Endoscopic biopsy noted chronic inflammation with glandular atypia. On the CT scan, there was an intraluminal polypoid mass lesion with mixed hypodensity at the duodenal second portion. Ultrasound guided biopsy targeting the hypodense lesion was performed and revealed chronic pancreatitis. The vomiting persisted and the patient received a palliative gastrojejunostomy. Twenty-five days after gastrojejunostomy, jaundice occurred and an ill-defined mass at the pancreas head was noted on the CT. Pylorus preserving pancreatoduodenectomy was performed and a 3.5 cm sized, moderate to poorly differentiated ductal adenocarcinoma of pancreas head was diagnosed. Nineteen days after operation, the patient was discharged in good condition.

Changes in Caspase-3, B Cell Leukemia/Lymphoma-2, Interleukin-6, Tumor Necrosis Factor-alpha and Vascular Endothelial Growth Factor Gene Expression after Human Umbilical Cord Blood Derived Mesenchymal Stem Cells Transfusion in Pulmonary Hypertension Rat M

BACKGROUND AND OBJECTIVES: Failure of vascular smooth muscle apoptosis and inflammatory response in pulmonary arterial hypertension (PAH) is a current research focus. The goals of this study were to determine changes in select gene expressions in monocrotaline (MCT)-induced PAH rat models after human umbilical cord blood derived mesenchymal stem cells (hUCB-MSCs) transfusion. MATERIALS AND METHODS: The rats were separated into 3 groups i.e., control group (C group), M group (MCT 60 mg/kg), and U group (hUCB-MSCs transfusion) a week after MCT injection. RESULTS: TUNEL assay showed that the U group had significantly lowered positive apoptotic cells in the lung tissues, as compared with the M group. mRNA of caspase-3, B cell leukemia/lymphoma (Bcl)-2, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha and vascular endothelial growth factor (VEGF) in the lung tissues were greatly reduced at week 4 in the U group. Immunohistochemical staining of the lung tissues also demonstrated a similar pattern, with the exception of IL-6. The protein expression of caspase-3, Bcl-2 VEGF, IL-6, TNF-alpha and brain natriuretic peptide in the heart tissues were significantly lower in the U group, as compared with the M group at week 2. Furthermore, the protein expression of VEGF, IL-6 and BNP in the heart tissues were significantly lower in the U group at week 4. Collagen content in the heart tissues was significantly lower in the U group, as compared with M group at weeks 2 and 4, respectively. CONCLUSION: hUCB-MSCs could prevent inflammation, apoptosis and remodeling in MCT-induced PAH rat models.

Novel Germline Mutation of BRCA1 Gene in a 56-Year-Old Woman with Breast Cancer, Ovarian Cancer, and Diffuse Large B-Cell Lymphoma / Journal of the Korean Cancer Association, 대한암학회지

We report a case of a 56-year-old woman with breast cancer, ovarian cancer, and diffuse large B-cell lymphoma with a BRCA1 gene mutation. Evidence is mounting that there is a large increase in the risk for hematologic malignancies among patients with genetic changes in the BRCA pathways. The genomic analysis demonstrated a frameshift mutation in the BRCA1 gene: 277_279delinsCC (Phe93fs). It is a novel BRCA1 mutation that has never been reported, and caused malignant lymphoma as well as breast and ovarian cancer.

Cytomegalovirus-Associated Intussusception with Florid Vascular Proliferation in an Infant

No abstract available.