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OBJECTIVES Patients with advanced ampullary carcinoma (AC) who are unsuitable for surgery are most likely to have poor outcomes. The role of endoscopic radiofrequency ablation (RFA) in this population has not been fully defined. We aimed to assess the short- and long-term outcomes of RFA in a large cohort of AC patients. METHODS In this retrospective study, data of consecutive patients with pathologically proven AC who underwent successful endobiliary RFA and/or stent placement were collected. All patients did not undergo surgical resection. The primary outcome was overall survival (OS). The secondary outcomes included clinical success and adverse events. RESULTS A total of 85 patients, 50 in the RFA plus stenting group and 35 in the stenting alone group, were identified. The median OS was significantly longer in the RFA group than in the stenting alone group (16.9 vs. 9.8 months, P

Large, multinodular ( 3 nodules and/or 3 cm) hepatocellular carcinoma (HCC) is not an indication for liver resection based on the Barcelona Clinic Liver Cancer (BCLC) staging classification. We hypothesize that microvascular invasion (MVI) is a strong indication for surgery in these patients.Between December 2009 and December 2010, a retrospective cohort of the patients with BCLC intermediate stage HCC undergoing surgical resection at Eastern Hepatobiliary Surgery Hospital was analyzed. Propensity score matching (PSM) was conducted to balance the patients with regard to their baseline characteristics. Survival analysis was performed according to the Kaplan-Meier method. Logistic regression was conducted to identify the predictors of MVI. Risk factors were evaluated using the Cox proportional hazards model.Among 323 patients, the MVI-negative group (26.0%) had a more favorable prognosis than did the MVI-positive group (5-year recurrence-free survival: 25.2% vs. 7.8%; 5-year overall survival: 49.5% vs. 24.0%). Similar results were identified after PSM. Compared with MVI-negative patients, MVI-positive patients experienced more early recurrence ( 2 years, P = 0.006), multinodular recurrence (P = 0.004), and extrahepatic recurrence (P = 0.026). Total bilirubin levels 17.1 μmol/L, alpha fetal protein levels 400 ng/mL, the presence of 2 nodules, and the lack of a capsule were independent predictors of MVI.In BCLC intermediate stage HCC, MVI predicted an adverse recurrence pattern and poor prognosis and has the potential to be used as a reference index when deciding whether to operate. Factors predictive of MVI could assist in choosing preoperative treatment and postoperative surveillance.

Background Mantle cell lymphoma (MCL) is derived from naïve CD5+ B-cells with the cytogenetic hallmark translocation 11;14. The presence of additional abnormalities is associated with blastoid variants in MCL (BMCL) and confers a poor prognosis. Many of these tumors also show deletion or loss of heterozygosity (LOH) of the ATM gene and biallelic ATM inactivation show significantly higher chromosomal imbalances. Case presentation Here we report a 52 year-old male who presented to the clinic with worsening dyspnea, fever, chills, diffuse lymphadenopathy, splenomegaly and leukocytosis with blastoid cells circulating in blood. The bone marrow aspirate showed about 40% abnormal blast-looking cells and biopsy revealed a remarkable lymphoid infiltrate. The patient was diagnosed with blastoid variant mantle cell lymphoma (BMCL). Chromosome analysis on bone marrow showed a complex karyotype. FISH analysis from B-cell lymphoma panel showed bi-allelic amplification of ATM gene. Other abnormalities were present including CCND1/IGH fusion, confirming the MCL diagnosis, in addition to RB1 and p53 deletion. High resolution SNP-microarray studies showed complex copy number changes, especially on chromosomes 7 and 11, consistent with chromoanagenesis. Microarray studies also showed LOH at the ATM locus indicating the amplification seen on FISH is not biallelic. Conclusion To the best of our knowledge, ATM gene amplification is not previously reported in BMCL and our case suggests a novel mechanism of ATM inactivation caused by chromoanagenesis resulting in mutant allele specific imbalance with copy number gain.

Cat scratch disease (CSD) is an infectious disease process of generally immunocompetent children and young adults. This infection can be introduced through skin trauma by direct exposure to the saliva of an infected kitten or cat. CSD is typically associated with constitutional symptoms and self-limited regional lymphadenopathy. In the sole presence of swollen lymph nodes, however, the differential diagnosis for CSD is relatively broad, including an active infection, an ongoing inflammatory process, and a metastatic process. CSD can present as axillary lymphadenopathy without typical constitutional symptoms. With proper clinical and laboratory investigation, CSD can be accurately identified and correctly diagnosed, as demonstrated in this case series featuring five symptomatic young adults with axillary lymphadenopathy. Breast imaging clinic specializes in lymph node assessment because metastatic lymphadenopathy is one of the most common presenting signs of breast cancer. Most isolated axillary lymphadenopathy without breast mass is benign reactive lymphadenopathy, but biopsy is necessary to exclude malignancies, such as metastatic lymphadenopathy or lymphoma.

Identification of the functional impact of mutated and altered genes in cancer is critical for implementing precision oncology and drug repurposing. In recent years, the emergence of multiomics data from large, well-characterized patient cohorts has provided us with an unprecedented opportunity to address this problem. In this study, we investigated survival-associated genes across 26 cancer types and found that these genes tended to be hub genes and had higher K-core values in biological networks. Moreover, the genes associated with adverse outcomes were mainly enriched in pathways related to genetic information processing and cellular processes, while the genes with favorable outcomes were enriched in metabolism and immune regulation pathways. We proposed using the number of survival-related neighbors to assess the impact of mutations. In addition, by integrating other databases including the Human Protein Atlas and the DrugBank database, we predicted novel targets and anticancer drugs using the drug repurposing strategy. Our results illustrated the significance of multidimensional analysis of clinical data in important gene identification and drug development.

Surgical resection of huge hepatocellular carcinoma (HCC, ≥ 10 cm) is potentially curative. More adjuvant treatments are needed to reduce relapses in these patients. We evaluated the influence of postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) on the prognosis of huge HCC.Data from consecutive patients who underwent curative resection for huge HCC in our center were retrospectively collected. Recurrence-free survival (RFS) and overall survival (OS) were compared between patients who did and did not undergo PA-TACE. Propensity score matching (PSM) was used.Among the 255 enrolled patients, 93 underwent PA-TACE. The clinical outcomes were significantly better in the PA-TACE group than those in the non PA-TACE group (5-year RFS rate: 33.5% vs. 18.0%; 5-year OS rate: 47.0% vs. 28.0%, all P 0.001). After PSM, similar results were obtained (5-year RFS rate: 28.8% vs. 17.6%, P 0.001; 5-year OS rate: 42.5% vs. 25.0%, P = 0.004). PA-TACE decreased the possibility of early recurrence ( 2 years, crude cohort: P 0.001, PSM cohort: P 0.001) but not late recurrence (≥ 2 years, crude cohort: P = 0.692, PSM cohort: P = 0.325). Multivariable Cox regression analysis suggested that PA-TACE was an independent protective factor prolonging early RFS, RFS and OS.PA-TACE is a safe intervention for huge HCC patients after liver resection and improves outcomes.

Background: Chronic neutrophilic leukemia (CNL) is an extremely rare myeloproliferative neoplasm (MPN). Due to the difficulty in its diagnosis, the diagnostic criterion was just recently revised in 2016. CNL is defined as: A clonal disorder with sustained primary neutrophilia, with normal neutrophil maturation, that does not meet other MPN criteria, as well as no identifiable mutations of the PDGFRA, PDGFRB or FGFR1 or PCM1-JAK2 genes, and, either, the presence of a CSF3R mutation, or if absent, the presence of sustained neutrophilia (> 3 months), splenomegaly and no other identifiable cause of reactive neutrophilia including the absence of a plasma cell neoplasm, or, if present, demonstration of myeloid cell clonality by cytogenetics. Only about 200 cases have been reported. Case Presentation: We report a 61-year-old Caucasian male patient who initially presented with unexplained leukocytosis. An outpatient work-up was planned to rule out a myeloproliferative disorder but the patient was acutely admitted for MRSA septic shock. The patient was stabilized prior bone marrow work-up and was then diagnosed with an atypical type of CNL (JAK2 positive, CSF3R negative). The patient refused further treatment due to social circumstances and requested palliative care instead. Conclusion: This case aims to present atypical findings of an extremely rare MPN. Even though a recent revision has been made to help in its diagnosis, atypical findings must still be considered. This, in turn, will help to further improve the current CNL diagnostic criteria.

Background: To identify the impact of tumor number on Barcelona Clinic Liver Cancer (BCLC) early-stage hepatocellular carcinoma (HCC) and the impact of microvascular invasion (MVI) on multinodular HCC (MHCC). Methods: We retrospectively analyzed 1,548 patients who had early-stage HCC [solitary HCC (SHCC, n=1,481) and MHCC (n=67)], according to the BCLC classification, after curative resection. Recurrence-free survival (RFS) and overall survival (OS) were compared. Propensity score matching (PSM) was used to balance potential confounding factors. Results: Both before and after PSM, significant differences were noted between the MHCC group and the SHCC group in RFS but not in OS. For the PSM cohort, the 5-year RFS rates were 7.5% and 41.2% for the MVI-positive MHCC group and the SHCC group, respectively (P

We report a case of type I cryoglobulinemic glomerulonephritis in a patient with chronic hepatitis C who presented with acute renal failure. The renal biopsy revealed membranoproliferative GN (MPGN) due to cryoglobulinemia with unexpected monoclonal Kappa restriction on immunofluorescence microscopy, suggesting an underlying hematopoietic malignancy. The bone marrow biopsy revealed presence of marginal zone lymphoma. Our case raises awareness regarding possibility of monoclonality in the renal biopsy of HCV-infected patients and exemplifies the crucial role the renal biopsy plays in detecting lymphoid malignancies where clinical features are ambiguous.

Atypical marginal zone hyperplasia (AMZH) is a recently described disease entity seen mainly in children. AMZH most commonly affects tonsils and appendices. Cutaneous AMZH is rare. The authors report here a recurrent AMZH in the lip of a 9-year-old child who presented originally with a lip swelling for approximately 3 months. The lip lesion recurred after each incomplete excision for 4 times. Pathologically, the lesion demonstrated marginal zone B-cell hyperplasia with kappa monoclonality by flow cytometry and immunohistochemistry studies. Lymphoepithelial lesions were noted with involvement of minor salivary glands. Polymerase chain reaction for immunoglobulin heavy-chain gene rearrangement has been repeatedly negative. Polymerase chain reaction for Borrelia species DNA was negative on both paraffin-embedded tissue and plasma. Serum antibodies IgG and IgM for Helicobacter Pylori were positive. A diagnosis of AMZH was made. Two courses of anti H. Pylori therapy did not improve the lip lesion, which completely regressed after a course of prednisone therapy. With differential diagnosis of cutaneous marginal zone lymphoma, the case illustrated diagnostic challenges, especially with recurrent lesions. This is the first case of recurrent cutaneous AMZH that has uncharacteristic kappa light-chain restriction. AMZH should be considered in children with mucocutaneous lesions with features of marginal zone lymphoma.

Generalized polypoid lesions of the gallbladder (PLG) refer to all the protruding lesions on the mucosal surface of the gallbladder, the incidence of which is 3–7% in a healthy population and 2–12% in cholecystectomy specimens [1]. GP can be divided into two major categories, pseudo and true GP. Pseudo-polyps include cholesterol polyps, adenomatoid polys, etc., and true polyps include adenoma and adenocarcinoma [2] or polypoid gallbladder lymphoma in some cases [3].

The rate of extrahepatic biliary benign tumors is very low, accounting for less than one tenth the rate of malignant biliary tumors, and the diameter of the tumor varies from several milimeters to centimeters; thus, intrabiliary growth often leads to stenosis of the bile ducts resulting in obstructive jaundice, of which adenoma is the most common type which accounts for about 75% of all benign tumors of extrahepatic bile duct.

Sentinel lymph nodes (SLNs) of melanoma patients show evidence of tumor-induced immune dysfunction. Our previous works have shown that IL-10 and IFNγ co-regulate indoleamine-2,3-dioxygenase (IDO)-expressing immunosuppressive dendritic cells (DCs) in melanoma SLNs. The goal of this study is to examine the relationship between melanoma SLN tumor burden and the degree of SLN immune dysfunction as a model to study tumor-induced immune dysfunction. We hypothesize that SLN tumor burden correlates with the degree of SLN immune dysfunction.Patients undergoing SLN biopsy for clinical stages I and II melanomas were enrolled in the study under an IRB-approved protocol. During the SLN biopsy, non-hot and non-blue portion of the SLN was harvested, flash-frozen in liquid nitrogen, and mRNA was extracted. By using quantitative real-time PCR, gene expressions of cytokines (IL-4, IL-10, IFNγ, TGFβ, GM-CSF) and the surrogates of immunosuppressive regulatory and effector cells (IDO-expressing DCs and Foxp3-expressing T-regs, respectively) were measured and correlated against the SLN tumor burden (MART1) and against each other. The data were log transformed for normalization. Statistical test used Student's t-test and stepwise multivariate regression analysis. Statistical significance was determined at P 0.05.SLNs of 74 patients were analyzed in this analysis. Ten of seventy-four patients (13.5%) had tumor-positive SLNs. MART1 gene expression showed a significant difference between the SLN (+) and SLN (-) groups (P = 0.04). Among the various cytokines, multivariate analysis showed that only IFNγ gene expression correlated independently with MART1 gene expression (P 0.0001, r = 0.91). Similar multivariate analyses show that IFNγ (P 0.0001, r = 0.78), IL-10 (P = 0.0037, r = 0.60), and TGFβ (P 0.0001, r = 0.95) gene expressions correlated independently with IDO gene expression. IFNγ (P 0.0001, r = 0.87) and GM-CSF (P = 0.042, r = 0.76) gene expressions correlated independently with Foxp3 gene expression. MART1 gene expression showed independent correlation with IDO (P = 0.0002, r = 0.75) and Foxp3 (P = 0.0002, r = 0.75) gene expressions.SLN tumor burden correlates with immunosuppressive IDO and Foxp3 expressions within the SLNs of melanoma patients. Our data are consistent with our theory that melanoma induces expressions of specific cytokines, which in turn, stimulate immune suppressors within the SLN. This study also supports our previous finding that IL-10 and IFNγ co-regulate IDO within the SLN. In our data, IFNγ is the sole cytokine that correlates with the SLN tumor burden and seems to play a central role in tumor-induced immunological changes in the SLN immune microenvironment.

Pancreatitis and sinusitis as presentations of Burkitt lymphoma are uncommon and rarely described in children. We describe here the case of a child who presented with symptoms suggestive of sinusitis unresponsive to antibiotics, with subsequent development of abdominal symptoms due to pancreatitis. He was eventually diagnosed with Burkitt lymphoma.

Hepatocellular adenoma (HCA) is a benign hepatocyte-derived tumor commonly seen in reproductive-aged women with long-term use of oral contraceptives (OCs) in European and North American countries. Accordingly, HCA is currently classified into four molecular subtypes as adopted by the World Health Organization. The present study was firstly to characterize and determine the genetic alterations and clinicopathological features of the largest series of HCAs in China. We reviewed 189 patients with HCA who underwent hepatectomies at our liver center from January 1984 to January 2012, among which 36 HCAs were randomly selected for the sequencing of HNF1α, β-catenin and gp130 genes, and 60 HCAs were randomly selected for detecting microsatellite instability (MSI). Compared with Western studies, our data showed distinctive findings including male (69.8%) and overweight/obese (50.3%) predominance. Only 3.5% of female patients had a documented history of OCs use for 2-4 years. All 36 sequenced HCAs showed HNF1α mutations (72% missense, 28% synonymous), 2 hotspot polymorphisms of HNF1α (I27L: rs1169288 and S487N: rs2464196) were seen in 17 (47%) and 10 (27.8%) cases, respectively, and a novel single nucleotide polymorphism site (rs1169304) in intron 9 of HNF1α was detected in 32 (88%) cases, but no β-catenin or gp130 gene mutation was detected, and no nuclear β-catenin staining was detected by immunohistochemistry. The frequency of MSI was 75% for D12S1398 (HNF1α inactivated pathway) and 78.5% for D6S1064 (HIPPO signaling pathway) in 34 overweight/obese patients with HCA. Our results firstly indicate that patients with HCA in China frequently occur in male overweigh and obese adult population, lack an association with OCs use and exhibit unique genetic alterations. Taken together, these observations suggest that alternative pathogenetic pathways involve in HCA tumorigenesis in Chinese patients.

We report a case of a 43-year-old male who presented with a large soft-tissue neck mass 7 years ago. A diagnosis of giant cell angiofibroma (GCA) was made on the basis of light microscopy and immunohistochemical studies. Chromosome analysis showed a male karyotype with t(12;17)(q15;q23),del(18)(q21) in all 20 cells analyzed. This cytogenetic abnormality in GCA is different from the t(17;22)(q22;q13) found in related lesions, such as giant cell fibroblastoma and solitary fibrous tumor, none of which has a specific chromosomal abnormality. Our case is the second case of GCA with chromosomal aberrations. To the best of our knowledge, this is the first case of GCA with t(12;17) occurring as an extra-orbital mass.

Pyruvate kinase (PK) deficiency is the commonest enzyme deficiency in the glycolytic pathway leading to hemolytic anemia secondary to decreased Adenosine Triphosphate (ATP) synthesis in the red cells. synthesis. PK deficiency due to mutations in the PKLR (1q21) gene leads to highly variable clinical presentation ranging from severe fetal anemia to well compensated anemia in adults. We describe dyserythropoiesis in the bone marrow of a child with transfusion dependent anemia and unilateral multicystic dysplastic kidney (MCDK) mimicking Congenital Dyserythropoietic Anemia type I (CDA type I). Persistently low erythrocyte PK levels and double heterozygous mutations present in the PKLR gene confirmed the diagnosis of PK deficiency.

Cardiac ischemia causes beat-to-beat fluctuation in action potential duration (APD) alternans, which leads to T wave alternans and arrhythmias. Occurrence of APD alternans that is out of phase at two sites is especially important, but most APD alternans studies have involved rapid pacing of normal myocardium rather than ischemia. To determine the spatial features of APD alternans during ischemia, blood-perfused rabbit hearts were stained with 4-{β-[2(di- n-butylamino)-6-napthyl]vinyl}pyridinium (di-4-ANEPPS) and imaged with a high-resolution camera. Hearts were perfused with oxygenated Tyrode solution at 37°C for staining and then switched to a 50:50% blood/Tyrode mixture. Hearts were paced from the right ventricle at 3/s, and made ischemic by stopping flow for 6 min. Images of 10,000 pixels were obtained at 300 frames/s. Motion artifact was controlled by immobilization and by manual selection of undistorted single-pixel records. Upstroke propagation and conduction isochrones were displayed by computerized image processing. APD alternans was demonstrated in six of seven hearts, and was out of phase in different regions of the image in three hearts. The largest spatial variation in the onset of depolarization to 50% repolarization (APD50) was 155%. This caused beat-to-beat reversal of repolarization. An alternans map could be constructed for well-immobilized portions of the image. There were discrete regions of APD alternans separated by a boundary, as occurs with intracellular Ca2+ concentration alternans. Pixels as close together as 1.1 mm showed an APD alternans that was out of phase. The out-of-phase APD alternans was not due to conduction alternans, as shown by upstroke intervals and conduction isochrones. This contrasts with rapid pacing, where a causal relationship appears to exist. These new observations suggest distinct mechanisms for the genesis of arrhythmias during ischemia.

Hepatitis C virus (HCV) involves both the liver and extra hepatic organs. The aim of this study was to retrospectively evaluate the association between HCV genotypes and lymphomas. Lymphoma cases were retrieved from our surgical pathology and hematopathology archives from January 2005 to April 2012. Patients who had positive HCV serology with subsequent viral genotyping were selected. Patients with positive Human immunodeficiency virus (HIV)serology were excluded. We identified 17 lymphoma cases with associated HCV infection. Eleven out of 14 (79%) patients had genotype 1 HCV. Diffuse large B cell lymphoma (DLBCL) was the most common lymphoma (6 out of 17 cases) and all cases of DLBCL had genotype 1. Genotype 2 was detected in only three patients (21%) with the diagnoses of follicular lymphoma, splenic marginal zone lymphoma, and classical Hodgkin lymphoma (CHL). CHL was diagnosed in three cases and peripheral T-cell lymphoma in one case.Twelve of 17 (71%) patients were incarcerated in the Texas Department of Criminal Justice system. All 11 genotype 1 patients were male, 4 of 11 (36%) were African American, 4 of 11 (36%) were Caucasian and 3 of 11 (27%) were Hispanic.We concluded that HCV genotype 1 was more common than genotype 2 while no other genotype was detected.

To assess the impact of preanalytical variables of time and temperature on prothrombin time (PT), activated partial thromboplastin time (aPTT), dilute Russell viper venom time (DRVVT), activated protein C resistance (APCR), and d-dimer, samples from 23 healthy individuals and 18 patients having coagulopathy with known abnormal PT and aPTT were collected. Plasma from each individual was separately pooled and aliquoted; the first 2 aliquots were stored at room temperature then analyzed at 2 hours (baseline) and 4 hours postcollection. The remaining aliquots were stored at −20°C and thawed for analysis at 48 hours, 1, and 2 weeks. In both healthy participants and participants with coagulopathy, PT, aPTT, APCR, DRVVT, and D-dimer had no significant changes at 4 and 48 hours, and 1 and 2 weeks postcollection compared to baseline, or the changes were less than 10%. The results indicate PT, aPTT, DRVVT, APCR, and d-dimer can be stored for 2 weeks at −20°C without compromising clinical interpretation in both healthy individuals and individuals with coagulopathy. Increasing storage time will facilitate sample processing from off-site clinics.

Precursor T-lymphoblastic lymphoma (pre-TLL) is a high-grade lymphoma that is invariably fatal if not treated [1]. The presence of precursor T-lymphoblasts outside of the bone marrow and thymus is ...

Pyruvate kinase (PK) deficiency is the commonest enzyme deficiency in the glycolytic pathway leading to hemolytic anemia secondary to decreased Adenosine Triphosphate (ATP) synthesis in the red cells. synthesis. PK deficiency due to mutations in the PKLR (1q21) gene leads to highly variable clinical presentation ranging from severe fetal anemia to well compensated anemia in adults. We describe dyserythropoiesis in the bone marrow of a child with transfusion dependent anemia and unilateral multicystic dysplastic kidney (MCDK) mimicking Congenital Dyserythropoietic Anemia type I (CDA type I). Persistently low erythrocyte PK levels and double heterozygous mutations present in the PKLR gene confirmed the diagnosis of PK deficiency.

Myeloproliferative neoplasms (MPNs) are traditionally separated intoBCR-ABL-positive chronic myeloid leukemia (CML), and BCR-ABL-negative MPNs including primary myelofibrosis (PMF), essential thrombocythemia (ET), and so forth. One of the diagnostic requirements for PMF and ET is the absence of the Philadelphia chromosome, while its presence is almost universally indicative of CML. However, a diagnostic dilemma arises when Philadelphia chromosome-positive MPNs lack the majority of the typical features seen in CML. Some of these classic CML features include basophilIa, marked leukocytosis, neutrophils left-shift with myelocytes bulge, and “dwarf” megakaryocytes. Presented here is a case of a 32-year-old pregnant patient who did not have typical morphologic findings for CML, and yet the Philadelphia chromosome was positive. The patient demonstrated some pathologic features that are commonly presented in PMF that included bone marrow reticulin fibrosis, leukoerythroblastosis, splenomegaly, and increased serum lactate dehydrogenase.

Pro-tumorigenic function of the p38 kinase plays a critical role in human cholangiocarcinogenesis. However, the underlying mechanism remains incompletely understood. Here, we report that c-Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF), contributes to the pro-tumorigenic ability of p38 in human cholangiocarcinoma cells. Both p38 and c-Met promote the proliferation and invasion of human cholangiocarcinoma cells. Importantly, inhibition or knockdown of p38 decreased the basal activation of c-Met. Tyrosine phosphatase inhibitor studies revealed that p38 promotes the activity of c-Met, at least in part, by inhibiting dephosphorylation of the receptor. Moreover, density enhanced phosphatase-1 (DEP-1) is involved in p38-mediated inhibiting dephosphorylation of c-Met. Furthermore, p38 inhibits the degradation of c-Met. Taken together, these data provide a potential mechanism to explain how p38 promotes human cholangiocarcinoma cell proliferation and invasion. We propose that the link between p38 and c-Met is implicated in the progression of human cholangiocarcinoma.

Acute promyelocytic leukemia (APL) is a well-defined subtype of acute myeloid leukemia (AML) specifically characterized by the t(15;17)(q22;q12) translocation. The t(15;17) results in the fusion of the promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARA) genes. Rare cryptic fusions often associated with small genomic insertions can best be detected by reverse transcriptase-polymerase chain reaction (RT-PCR) although conventional chromosomal studies or even fluorescence in situ hybridization (FISH) analyses appear normal. We report here an APL clone with a cryptic PML-RARA fusion that returned negative results by both karyotyping and fluorescence in situ hybridization (FISH), but returned positive results by RT-PCR analysis. A single nucleotide polymorphism (SNP) microarray analysis was used in this case to help resolve the discordance, revealing a 49-kilobase intragenic PML gene duplication. A dual color dual fusion PML-RARA FISH probe set identified a small, extra PML signal in a chromosome other than 15 or 17. Although coinsertion of a RARA sequence could be detected by neither FISH nor array, the RT-PCR positivity is consistent with this fusion "ectopic" to the natural gene loci. The findings highlight the clinical utility of microarray in cases of cryptic PML-RARA fusion.

c-Met, the tyrosine-kinase receptor for hepatocyte growth factor, plays a critical role in the tumorigenesis of hepatocellular carcinoma (HCC). However, the underlying mechanism remains incompletely understood. The mature c-Met protein p190Met(αβ) (consists of a α subunit and a β subunit) is processed from pro-Met. Here we show that pro-Met is processed into p190Met(NC) by sarco/endoplasmic reticulum calcium-ATPase (SERCA) inhibitor thapsigargin. p190Met(NC) compensates for the degradation of p190Met(αβ) and protects human HCC cells from apoptosis mediated by endoplasmic reticulum (ER) stress. In comparison with p190Met(αβ), p190Met(NC) is not cleaved and is expressed as a single-chain polypeptide. Thapsigargin-initiated p190Met(NC) expression depends on the disturbance of ER calcium homeostasis. Once induced, p190Met(NC) is activated independent of hepatocyte growth factor engagement. p190Met(NC) contributes to sustained high basal activation of c-Met downstream pathways during ER calcium disturbance-mediated ER stress. Both p38 MAPK-promoted glucose-regulated protein 78 (GRP78) expression and sustained high basal activation of PI3K/Akt and MEK/ERK are involved in the cytoprotective function of p190Met(NC). Importantly, the expression of p190Met(NC) is detected in some HCC cases. Taken together, these data provide a potential mechanism to explain how c-Met promotes HCC cells survival in response to ER stress. We propose that context-specific processing of c-Met protein is implicated in HCC progression in stressful microenvironments.

Background & Aims Hepatocellular carcinoma (HCC) is believed to arise from tumor-initiating cells (T-ICs), although little is known about their stem cell–like properties. Methods We quantified levels of p28 GANK (Gankyrin), OV6, and Oct4 in 130 human HCC samples using immunohistochemistry. Magnetic-activated cell sorting was used to isolate OV6 + HCC cells. T-IC properties were evaluated by quantitative reverse-transcription polymerase chain reaction, flow cytometry, and spheroid formation. We used a coimmunoprecipitation assay to study interactions among p28 GANK , Oct4, and WWP2. Tumorigenicity and pulmonary metastasis were examined in nonobese diabetic and severe combined immunodeficient mice. Results In HCC samples, high levels of p28 GANK correlated with expansion of OV6 + tumor cells; the combination of high levels of p28 GANK and OV6 was associated with progression of HCC. p28 GANK was predominantly expressed in liver T-ICs, isolated by magnetic sorting, and undifferentiated primary HCC spheroids. Increased levels of p28 GANK in T-ICs increased their percentages in HCC samples, expression of stem cell genes, self-renewal potential, chemoresistance in vitro, and tumorigenicity and ability to develop into pulmonary metastases in mice. Conversely, knockdown of p28 GANK reduced their T-IC properties. p28 GANK likely activates liver T-ICs by impeding ubiquitination and degradation of the transcription factor Oct4 by WWP2. In support of this concept, levels of p28 GANK correlated with those of Oct4 in HCC samples. Conclusions p28 GANK activates and maintains liver T-ICs in HCCs by preventing degradation of Oct4. Inhibitors of p28 GANK might therefore be developed to inactivate T-ICs and slow tumor progression.

Lymphoma is the most frequent malignant tumor of the ocular adnexa with the most common histologic type being extranodal marginal zone B-cell lymphoma (EMZL) of mucosa-associated lymphoid tissue (MALT lymphoma). Here we report a case of a 28 year-old male who presented with a left conjunctival mass of one year duration. A diagnosis of primary MALT lymphoma of the conjunctiva was made based on morphologic and immunopheno-typic studies. Chromosome analysis revealed a male karyotype with a translocation t (5;11) (q33;p11.2) as the primary chromosomal abnormality, which, to the best of our knowledge, is the first reported translocation in MALT lym-phomas and ocular MALT lymphomas as well.

The peritumoral environment has been implicated to be important in the process of metastasis and recurrence in hepatocellular carcinoma (HCC). Our aims were to assess the prognostic value of proline-rich tyrosine kinase 2 (Pyk2) in HCC and investigate related molecular mechanism. Expression of Pyk2 was tested by immunohistochemistry in tissue microarrays containing 141 paired HCC samples. Correlation between Pyk2 and vascular endothelial growth factor (VEGF) expression in clinical samples was analyzed by Spearman rank correlation. Matrigel invasion, anchorage-independent growth assay and immunoblotting were performed to study the effect of Pyk2 on the invasion and progression of HCC cells and phosphoinositide 3-kinase (PI3K)/AKT pathway activation. Higher Pyk2 density in both tumor and peritumor was associated with lower overall survival (P = 0.044; P = 0.041, respectively), serum AFP levels > 1,000 ng/ml (P = 0.013; P = 0.032, respectively) and postoperative distant metastasis (both P

The overall survival of patients with hepatocellular carcinoma (HCC) remains poor, and the molecular mechanisms underlying HCC progression and aggressiveness are unclear. Here, we report that increased expression of p28GANK (Gankyrin, PSMD10, or p28) in human HCC predicts poor survival and disease recurrence after surgery. Patients with HCC who have large tumors, with vascular invasion and intrahepatic or distant metastasis, expressed high levels of p28GANK. Invasive tumors overexpressing p28GANK were featured by active epithelial-mesenchymal transition (EMT), and exhibited increased angiogenesis associated with vascular endothelial growth factor overexpression, whereas silencing p28GANK expression attenuated EMT and motility/invasion of tumor cells. The p28GANK activates phosphoinositide 3-kinase (PI3K)–V-akt Murine Thymoma Viral Oncogene Homolog (AKT)–hypoxia-inducible factor 1α (HIF-1α) signaling to promote TWIST1, vascular endothelial growth factor, and metalloproteinase 2 expression. Suppression of the PI3K–AKT–HIF-1α pathway interfered with p28GANK-mediated EMT and invasion. Consistently, we detected a significant correlation between p28GANK expression and p-AKT levels in a cohort of HCC biopsies, and the combination of these two parameters is a more powerful predictor of poor prognosis. Conclusion: These results present novel mechanistic insight into a critical role of p28GANK in HCC progression and metastasis. (HEPATOLOGY 2011)

We described a combined multiple clustering approach to automatically identify chronic lymphocytic leukemia neoplastic population by flow cytometry immunophenotyping. Flow cytometry data from various specimens were preprocessed by data cross-linking and subset selection before undergoing subspace and consensus clustering. This approach was implemented as a Server-side application, with results comparable to those performed by manual gating on commercial software.

It has been shown that oncoprotein p28(GANK), which is consistently overexpressed in human hepatocellular carcinoma (HCC), plays a critical role in tumorigenesis of HCC. However, the underlying mechanism remains unclear. Here, we demonstrated that p28(GANK) inhibits apoptosis in HCC cells induced by the endoplasmic reticulum (ER) stress. During ER stress, p28(GANK) enhances the unfolded protein response, promotes ER recovery from translational repression, and thereby facilitates cell's ability to cope with the stress conditions. Furthermore, p28(GANK) upregulates glucose-regulated protein 78 (GRP78), a key ER chaperone protein, which subsequently enhances the ER folding capacity and promotes recovery from ER stress. We also demonstrated that p28(GANK) increases p38 mitogen-activated protein kinase and Akt phosphorylation, and inhibits nuclear factor kappa B (NF-kappaB) activation under ER stress, which in turn contributes to GRP78 upregulation. Taken together, our results indicate that p28(GANK) inhibits ER stress-induced apoptosis in HCC cells, at least in part, by enhancing the adaptive response and GRP78 expression. We propose that p28(GANK) has potential implications for HCC progression under the ER stress conditions.

An online decision support system for hematopoietic neoplasm based on virtual flow has been developed. Rules were implemented via eXtensible Markup Language (XML). 153 cases representing 28 different hematopoietic neoplasms were correctly classified. Further testing for unknown cases is undergoing.

The authors used high-resolution optical recording technique to study the mechanism of protective zone during electrical induction of ventricular fibrillation (VF). Using programmed-stimulation, VF can be induced and terminated with successive stimuli. "Break activation" in virtual electrode mechanism appeared to be responsible for both the onset and cessation of VF.