Recurrent KRAS mutations identified in papillary renal neoplasm with reverse polarity-a comparative study with papillary renal cell carcinoma.

Comprehensive molecular analyses revealed that papillary renal cell carcinoma (PRCC) is a heterogenous entity. Papillary renal neoplasm with reverse polarity (PRNRP) is a subset of PRCC with characteristic histomorphologies such as low-grade nuclear features, inverted nuclear location, eosinophilic cytoplasm, and indolent clinical behavior. We tried to define the molecular, clinicopathological, histologic, and immunohistochemical features of PRNRP by comparing them with type 1 PRCC (PRCC1) and type 2 PRCC (PRCC2). A cohort of 30 PRNRP, 23 PRCC1, and 26 PRCC2 cases was used. Targeted sequencing of 90 cancer-related genes including KRAS was performed in 26 PRNRP tumor samples. PNA-mediated clamping PCR of KRAS was performed using paired normal and tumor DNA from 30 PRNRP, 23 PRCC1, and 26 PRCC2 cases. Tissue microarray slides were made in three cores per tumor, which were stained with cytokeratin 7 (CK7), alpha-methylacyl-CoA racemase (AMACR), epithelial membrane antigen (EMA), E-cadherin, vimentin, and CD10. Recurrent mutations in KRAS were detected in 28 of the 30 PRNRPs. However, there were no KRAS mutations in any PRCC1 or PRCC2 cases. PRNRP exhibited distinct clinicopathological features: small tumor size, lower pathologic T stage, and no disease-specific death during the follow-up period. Histologically, peritumoral lymphoid aggregation, prominent papillary architecture (>80% of tumor), hyalinized papillae, inverted nuclear location, and lower nuclear grade were observed. PRNRP was usually positive for CK7, AMACR, EMA, and E-cadherin, and negative for CD10. The findings suggest that PRNRP is a subtype of papillary renal neoplasm that is different from PRCC1 or PRCC2 in terms of molecular, clinicopathological, histological, and immunohistochemical features.

Pituitary Adenylate Cyclase-activating Polypeptide Inhibits Pacemaker Activity of Colonic Interstitial Cells of Cajal.

This study aimed to investigate the effect of pituitary adenylate cyclase-activating peptide (PACAP) on the pacemaker activity of interstitial cells of Cajal (ICC) in mouse colon and to identify the underlying mechanisms of PACAP action. Spontaneous pacemaker activity of colonic ICC and the effects of PACAP were studied using electrophysiological recordings. Exogenously applied PACAP induced hyperpolarization of the cell membrane and inhibited pacemaker frequency in a dose-dependent manner (from 0.1 nM to 100 nM). To investigate cyclic AMP (cAMP) involvement in the effects of PACAP on ICC, SQ-22536 (an inhibitor of adenylate cyclase) and cell-permeable 8-bromo-cAMP were used. SQ-22536 decreased the frequency of pacemaker potentials, and cell-permeable 8-bromo-cAMP increased the frequency of pacemaker potentials. The effects of SQ-22536 on pacemaker potential frequency and membrane hyperpolarization were rescued by co-treatment with glibenclamide (an ATP-sensitive K(+) channel blocker). However, neither N (G)-nitro-L-arginine methyl ester (L-NAME, a competitive inhibitor of NO synthase) nor 1H-[1,2,4]oxadiazolo[4,3-α]quinoxalin-1-one (ODQ, an inhibitor of guanylate cyclase) had any effect on PACAP-induced activity. In conclusion, this study describes the effects of PACAP on ICC in the mouse colon. PACAP inhibited the pacemaker activity of ICC by acting through ATP-sensitive K(+) channels. These results provide evidence of a physiological role for PACAP in regulating gastrointestinal (GI) motility through the modulation of ICC activity.

Extracellular acidity­induced expression of Kallikrein­related peptidases 7 and 8 is involved in increased invasiveness of gastric cancer cells.

In several cancers, the acidic microenvironment of cancer cells has been implicated in enhanced malignancy and metastasis. In the present study, it was observed that gastric cancer cell lines, SNU601 and AGS, exposed to an acidic medium had increased invasiveness, as assessed using Matrigel­coated Transwell analysis. The factors regulating such acidity­mediated enhancement of invasiveness were investigated and it was revealed that a low­pH environment markedly increased kallikrein­related peptidase 7 (KLK7) and kallikrein­related peptidase 8 (KLK8) expression. Gene silencing assays confirmed that these peptidases were involved in acidity­promoted invasion. Acidic conditions also increased the expression of cyclooxygenases (COX), key regulatory enzymes in the catalytic pathway of prostaglandin production. Notably, these enzymes appeared to be involved in the acidity­mediated expression of KLK7 and KLK8, as revealed using COX inhibitors. Therefore, it was indicated that tumor invasion enhancement by extracellular acidity is regulated at least in part through the induction of the COX/KLK7 and KLK8 axis in gastric cancer cells.

Amyloidosis of seminal vesicles and ejaculatory ducts: a histologic analysis of 21 cases among 447 prostatectomy specimens.

To investigate the incidence of amyloidosis of seminal vesicles and ejaculatory system including ejaculatory ducts and vasa deferentia, we reviewed the whole mount sections of 447 radical prostatectomy specimens removed for prostatic cancer, including 273 cases from the United States and 174 cases from Korea. Of these, 21 cases (4.7%) showed amyloidosis in seminal vesicles, vasa deferentia, and in ejaculatory ducts. Ten of these (3.7%) cases were from the United States and 11 cases (6.3%) from Korea. The patients' age ranged from 51 to 79 years (mean, 66.1 years). Amyloid deposition was found in 5 patients in the sixth decade (3.4%), 9 patients in the seventh decade (4.7%), and 7 patients in the eighth decade (9.3%). At the seventh decade of life, the Korean patients showed a higher incidence (8.3%) than American patients (2.5%), but other age groups showed no difference. All cases showed bilateral involvement of the seminal vesicles and ejaculatory systems. The deposits of amyloid tended to be nodular and affected the subepithelial region of seminal vesicles, vasa deferentia, and ejaculatory ducts. There was no amyloid deposit around blood vessels or in the prostatic parenchyma. Localized amyloidosis of the ejaculatory system involves not only the seminal vesicles but also the vasa deferentia and the ejaculatory ducts. The vessels or prostatic stroma are not part of this process. Amyloidosis develops subepithelially spreading to include the wall of these organs and appears to be related to advanced age. The incidence of amyloidosis of the ejaculatory system in Korean patients was higher than in US patients.

Andrographolide induces apoptotic and non-apoptotic death and enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in gastric cancer cells.

Andrographolide, a natural compound isolated from Andrographis paniculata, has been reported to possess antitumor activity. In the present study, the effect of andrographolide in human gastric cancer (GC) cells was investigated. Andrographolide induced cell death with apoptotic and non-apoptotic features. At a low concentration, andrographolide potentiated apoptosis and reduction of clonogenicity triggered by recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL). Exposure of GC cells to andrographolide altered the expression level of several growth-inhibiting and apoptosis-regulating proteins, including death receptors. It was demonstrated that activity of the TRAIL-R2 (DR5) pathway was critical in the development of andrographolide-mediated rhTRAIL sensitization, since its inhibition significantly reduced the extent of apoptosis induced by the combination of rhTRAIL and andrographolide. In addition, andrographolide increased reactive oxygen species (ROS) generation in a dose-dependent manner. N-acetyl cysteine prevented andrographolide-mediated DR5 induction and the apoptotic effect induced by the combination of rhTRAIL and andrographolide. Collectively, the present study demonstrated that andrographolide enhances TRAIL-induced apoptosis through induction of DR5 expression. This effect appears to involve ROS generation in GCs.

Epithelial-myoepithelial carcinoma arising from the subglottis: a case report and review of the literature.

BACKGROUND: Epithelial-myoepithelial carcinoma is an extremely rare disease that usually occurs in the parotid gland but can occur in a variety of sites such as the nasal cavity, paranasal sinus, and base of the tongue. CASE PRESENTATION: We report a rare case of epithelial-myoepithelial carcinoma, which developed in the subglottic region. A 78-year-old Korean woman visited our hospital complaining of hoarseness, which had developed 1 month previously. Flexible laryngoscopy showed a round mass that blocked approximately 80 % of the tracheal diameter. Complete excision of the mass was carried out under general anesthesia, using a transoral approach. Epithelial-myoepithelial carcinoma was diagnosed following immunohistochemical analysis. CONCLUSIONS: We report a rare case of epithelial-myoepithelial carcinoma that occurred in the subglottic region. To the best of our knowledge, only one other case has been reported since this disease was first identified approximately 40 years ago.

Involvement of DR4/JNK pathway-mediated autophagy in acquired TRAIL resistance in HepG2 cells.

Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, a number of cancer cells demonstrate TRAIL resistance. To date, various molecular targets leading to TRAIL resistance have been elucidated by many researchers, but the mechanisms involved are still not fully understood. In the present study, we obtained TRAIL-resistant cells from the human hepatocellular carcinoma cell line HepG2 by exposing cells to recombinant human TRAIL (rhTRAIL), and determined a mechanism for TRAIL resistance. The selected TRAIL-resistant cells (HepG2-TR) were insensitive to rhTRAIL and triggered autophagy in response to rhTRAIL. The inhibition of autophagy by 3-methyladenine or the knockdown of ATG5 partially restored rhTRAIL-induced apoptosis and cytotoxicity, indicating that protective autophagy occurred in the cells. Notably, rhTRAIL-induced autophagy was mediated through DR4 in HepG2-TR cells, but not in parental HepG2 cells. In addition, the c-Jun N-terminal kinase was involved in DR4-mediated autophagy in HepG2-TR cells. Our results suggest a novel mechanism of TRAIL resistance which is regulated through alterations in DR4 function, which may extend our understanding of the mechanisms of TRAIL resistance.

Bilateral variations of musculocutaneous nerves with rare pattern in a Korean female cadaver.

Bilateral variations in the formation and branching of brachial plexus are rare. Variations between median and musculocutaneous nerves were observed on both sides during the dissection of an 87-year-old Korean female cadaver, whose cause of death was cholangiocarcinoma. The variations found were bilateral, in which each musculocutaneous nerve did not pierce the coracobrachialis muscle. The musculocutaneous nerve was rudimentary in the right arm and all branches arose from the median nerve separately, which corresponds to previous classification type 0-2. In the case of the left arm, the musculocutaneous nerve originated from the lateral cord, but had connections between median and musculocutaneous nerves below the coracobrachialis muscle, which corresponds to previous classification type 1-B-2. To the best of our knowledge, the bilateral variations between median and musculocutaneous nerves in this case have different features from other previous reports. Awareness of the possible variations between median and musculocutaneous nerves is important to both anatomists and clinicians.

Ewing's Sarcoma of the Stomach; Rare Case of Ewing's Sarcoma and Suggestion of New Treatment Strategy.

Ewing's sarcoma is a neoplasm of the undifferenciated small round cells, which generally affects the bone and deep soft tissues of children and adolescents. We present a case of gastric Ewing's sarcoma; a 35-year-old female who had no symptoms. While she was at a routine medical checkup, a protruding mass in her gastric antrum was incidentally found on esophagogastroduodenoscopy. Endoscopic ultrasonogram showed a submucosal mass on the same lesion and a laparosopic wedge resection was done. Pathologic gross findings showed a granular grape appearance tissue and histoloigc examination revealed a small round cell tumor with CD 99 immunoexpression positive. In general, a combined modality therapy for Ewing's sarcoma such as surgical resection with chemotherapy, is accepted as an effective method. However, this patient had no adjuvant chemotherapy after surgery and she has no recurrence for eleven months.

Primary paratesticular osteosarcoma: A case report.

Extraosseous osteosarcoma originating from paratesticular soft tissue is an extremely rare type of malignant tumor. With the exception of the present study, only one other case of osteosarcoma originating from paratesticular soft tissue has previously been reported. A 52-year-old man presented with a painless scrotal swelling and palpable mass. The patient underwent left orchiectomy with the diagnosis of testicular tumor. Pathological examination was suggestive of osteosarcoma without any different histological components. The postoperative course of the patient was uneventful, and the patient is currently free of disease.

Capsaicin-induced apoptosis is regulated by endoplasmic reticulum stress- and calpain-mediated mitochondrial cell death pathways.

Capsaicin, a pungent compound found in hot chili peppers, induces apoptotic cell death in various cell lines, however, the precise apoptosis signaling pathway is unknown. Here, we investigated capsaicin-induced apoptotic signaling in the human breast cell line MCF10A and found that it involves both endoplasmic reticulum (ER) stress and calpain activation. Capsaicin inhibited growth in a dose-dependent manner and induced apoptotic nuclear changes in MCF10A cells. Capsaicin also induced degradation of tumor suppressor p53; this effect was enhanced by the ER stressor tunicamycin. The proteasome inhibitor MG132 completely blocked capsaicin-induced p53 degradation and enhanced apoptotic cell death. Capsaicin treatment triggered ER stress by increasing levels of IRE1, GADD153/Chop, GRP78/Bip, and activated caspase-4. It led to an increase in cytosolic Ca(2+), calpain activation, loss of the mitochondrial transmembrane potential, release of mitochondrial cytochrome c, and caspase-9 and -7 activation. Furthermore, capsaicin-induced the mitochondrial apoptotic pathway through calpain-mediated Bid translocation to the mitochondria and nuclear translocation of apoptosis-inducing factor (AIF). Capsaicin-induced caspase-9, Bid cleavage, and AIF translocation were blocked by calpeptin, and BAPTA and calpeptin attenuated calpain activation and Bid cleavage. Thus, both ER stress- and mitochondria-mediated death pathways are involved in capsaicin-induced apoptosis.

Intraprostatic adipose tissue: a study of 427 whole mount radical prostatectomy specimens.

Prostatic adenocarcinoma is the most frequently diagnosed cancer in American men. Tumor Gleason grade and stage provide extremely valuable prognostic information and play an important role in therapeutic decision making and patient counseling. A biopsy or radical prostatectomy specimen revealing carcinoma extending into extraprostatic tissue permits a T3 classification. This is most easily recognized, particularly in a needle biopsy, when tumor is seen to invade the adipose tissue. The existence of intraprostatic adipose tissue is somewhat controversial. To investigate this, formalin-fixed paraffin-embedded whole-mount radical prostatectomy specimens from 427 patients with adenocarcinoma were evaluated for intraprostatic adipose tissue. It was defined as any collection of adipocytes amid or internal to the most peripheral glands. The amount, anatomic location, and relationship to normal structures were also recorded. Intraprostatic adipose tissue was identified in 17 (3.98%) of cases. It consisted of small microscopic foci composed of 5 to 20 adipocytes. In 13 cases, the fat was intimately associated with benign glands. In another 2 cases, it was associated with small nerves, and in 2 cases was random with no specific localization. Intraprostatic adipose tissue was located in the peripheral zone in 15 cases and in the central zone in 2. Intraprostatic adipose tissue, although uncommon, does exist. Therefore, caution must be exercised in diagnosing extraprostatic extension based only upon identification of fat invasion, especially in a needle biopsy. The small size of foci of adipose tissue and its admixture with benign glands are useful morphologic clues in distinguishing it from extraprostatic fat.

Mantle cell lymphoma, blastoid variant, diagnosed on the basis of cytomorphology and flow cytometric immunophenotyping of the lymph node aspirate and peripheral blood.

Mantle cell lymphoma, blastoid variant (B-MCL), is a very rare type of non-Hodgkin's lymphoma exhibiting an aggressive clinical course. We describe a case of B-MCL showing generalized lymphadenopathy and leukemic conversion in a 62-yr-old man. The case was diagnosed and subclassified as B-MCL on the basis of cyto-morphology and immunophenotype. Microscopic examination of the peripheral blood (PB) showed a spectrum of cells ranging from small mature lymphocytes to medium- and large-sized lymphocytes with blast-like chromatin and prominent nucleoli. The lymphoma cells were monoclonal B cells with moderately intense surface IgM. They were CD5 positive, cyclin D1 positive, CD10 negative, and CD23 negative. The flow cytometric immunophenotyping and DNA ploidy analysis of the PB and material obtained by aspiration cytology supported the diagnosis of B-MCL. These findings underline the utility of aspiration cytology in diagnosing B-MCL when cytomorphologic examination is combined with flow cytometric analysis of immuno-phenotype and demonstration of proliferation markers.