Acute hydrocephalus caused by a colloid cyst - a case report.

BACKGROUND: Colloid cysts are rare benign, slowly growing intracranial tumors of endodermal origin. Most colloid cysts are found incidentally and are asymptomatic, but rarely, they can lead to sudden death. CASE PRESENTATION: A 73-year-old female patient was admitted to our emergency department with complaints of dizziness, nausea, vomiting, fatigue, walking difficulties, and behavioral changes. CT imaging revealed acute obstructive hydrocephalus attributable to a third ventricular colloid cyst. The patient was immediately transferred to a tertiary center where she underwent successful neurosurgical resection of the mass. Pathology results of the lesion confirmed the diagnosis of colloid cyst. CONCLUSION: The case we present emphasizes the critical importance of prompt identification of warning signs, complex thinking, and evaluation. Establishing the right diagnostic approach early on can facilitate accurate diagnosis.

Burnout and occupational stress among Hungarian radiographers working in emergency and non-emergency departments during COVID-19 pandemic.

INTRODUCTION: The increased workload caused by the coronavirus pandemic may have had a significant impact on the mental health of radiographers. The aim of our study was to investigate burnout and occupational stress in radiographers working in emergency departments (ED) and non-emergency departments (NED). METHODS: Quantitative, cross-sectional, descriptive research was carried out among radiographers working in the public health sector in Hungary. Due to the cross-sectional nature of our survey, there was no overlap between the ED and NED groups. For data collection, we used simultaneously the Maslach Burnout Inventory (MBI), the Effort-Reward Imbalance questionnaire (ERI), and our self-designed questionnaire. RESULTS: We excluded incomplete questionnaires from our survey; finally, 439 responses were evaluated. Significantly higher scores for depersonalisation (DP; 8.43 (SD = 6.69) vs. 5.63 (SD = 4.21) and emotional exhaustion (EE; 25.07 (SD = 11.41) vs. 19.72 (SD = 11.72)) were observed in radiographers working in ED (p = 0.001; p = 0.001) when compared to NED. Male radiographers working in ED aged 20-29 and 30-39 years with experience of 1-9 years were more affected by DP (p ≤ 0.05). Worrying about one's own health had a negative effect on DP and EE (p ≤ 0.05). Having close friend with a COVID-19 infection had a negative effect on EE (p ≤ 0.05); not being infected with coronavirus, not being quarantined and relocating within the workplace had a positive effect on personal accomplishment (PA); radiographers who were 50 years or older with 20-29 years of experience were more affected by depersonalisation (DP); and those who worried about their health had significantly higher stress scores (p ≤ 0.05) in both ED and NED settings. CONCLUSION: Male radiographers at the beginning of their careers were more affected by burnout. Employment in EDs had a negative impact on DP and EE. IMPLICATIONS FOR PRACTICE: Our results support the implementation of interventions to counter the effects of occupational stress and burnout among radiographers working in ED.

Increased expression of claudin-1 and claudin-7 in liver cirrhosis and hepatocellular carcinoma.

Claudins have been reported to be differentially regulated in malignancies and implicated in the process of carcinogenesis and tumor progression. Claudin-1 has been described as key factor in the entry of hepatitis C virus (HCV) into hepatocytes and as promoter of epithelial-mesenchymal transition in liver cells. The objective of the current study was to characterize claudin expression in hepatocellular carcinoma (HCC) as well as HCC-surrounding and normal liver samples with respect to cirrhosis and HCV infection. Expression of claudin-1, -2, -3, -4, and -7 was measured by morphometric analysis of immunohistochemistry, and Western blotting in 30 HCCs with 30 corresponding non-tumorous tissues and 6 normal livers. Claudin-1 and -7 protein expression was found significantly elevated in cirrhosis when compared with non-cirrhotic liver. HCCs developed in cirrhotic livers showed even higher expression of claudin-1 contrary to decreased claudin-7 expression when compared with cirrhosis. With reference to HCV status, HCCs or surrounding livers of HCV-infected samples did not show significant alterations in claudin expression when compared with HCV-negative specimens. Cirrhotic transformation associates with elevated claudin-1 and -7 expressions in both non-tumorous liver and HCC. The fact that no significant differences in claudin expression were found regarding HCV-positivity in our sample set suggests that HCV infection alone does not induce a major increase in the total amount of its entry co-factor claudin-1. Increased expression of claudin-1 seems to be a consequence of cirrhotic transformation and might contribute to a more effective HCV entry and malignant transformation.

Transitional cell and clear cell renal carcinoma: differentiation of distinct histological types with multiphase CT.

BACKGROUND: Transitional cell carcinoma (TCC) may mimic renal cell carcinoma (RCC) when it develops in a similar location, therefore, differentiation with imaging techniques might be challenging. Preoperative differentiation may have a significant role indicating the type of surgical treatment (nephrectomy vs. ureteronephrectomy). PURPOSE: To retrospectively analyze the differences in the contrast enhancement of TCC and RCC. MATERIAL AND METHODS: Images of 20 RCC and 12 TCC (mean ages, 62.3 ± 14.1 and 67.4 ± 12.0 years, respectively) were analyzed from patients who underwent multiphase computed tomography (CT) examinations following 1.5 mL/kg non-ionic contrast agent administration. Unenhanced corticomedullary (30-45 s), nephrographic (70-90 s), and excretory (300-480 s) phases were imaged. The attenuation characteristics of RCC and TCC were compared to the attenuation of the normal renal cortex. RESULTS: Significant differences were found in the attenuation ratios between RCC or TCC in the corticomedullary (P = 0.040) and nephrographic (P = 0.004) phases using three regions of interest (ROIs) of 10 mm(2) size. If measuring ROIs comprising the complete tumor lesion instead of three small ROIs, no significant difference was observed in the attenuation ratios between RCC in TCC in any phases. CONCLUSION: Our study reports significant attenuation differences between RCC and TCC in the corticomedullary and nephrographic phases by multiphase CT. The findings underscore the importance of multiphase CT in the differentiation of these two different entities. Using multiple small (three) ROIs is more accurate than measuring the whole tumor attenuation.

High frequency of brachiocephalic trunk stent fractures does not impair clinical outcome.

OBJECTIVE: Stenting is the preferred, minimally invasive treatment for innominate artery (IA) stenosis or occlusion. Stent fractures in the IA have not been assessed in larger cohorts. In this retrospective study, we examined the frequency and risk factors of IA stent fractures. METHODS: The final analysis included 32 patients (15 women; mean age, 59.4 ± 12.0 years) with 32 balloon-expandable stents (2000 to 2009). In 2010, the patients were asked to come back for a fluoroscopic examination of the implanted stents. Stent fractures and their relationship to atherosclerotic risk factors, lesion characteristics, postprocedural symptoms, and in-stent restenosis were analyzed. Fisher exact test and univariate Cox regression analysis were used in the statistical evaluation. RESULTS: Lesions were >20 mm in 14 patients (44%) or heavily calcified in 13 (41%). The mean follow-up time was 33.4 ± 21.0 months. Postprocedural symptoms were noted in nine patients (28%). Significant restenosis was detected in 22% of the implanted stents, and 11 stent fractures (34%) were found. The prevalence of heavily calcified lesions, postprocedural symptoms, and in-stent restenosis did not differ significantly between groups with and without fracture. Long lesions were associated with an increased incidence of stent fracture (hazard ratio, 5.09; 95% confidence interval, 1.33-19.48; P = .017). No correlation was observed between stent fractures and old age (≥70 years), female gender, smoking, hypertension, hyperlipidemia, or diabetes mellitus. CONCLUSIONS: IA stent fractures are common but seem to have no effect on symptoms and in-stent restenosis rates.

A clinical feasibility study to evaluate the safety and efficacy of PEOT/PBT implants for human donor site filling during mosaicplasty.

UNLABELLED: Mosaicplasty has become a well-accepted treatment modality for articular cartilage lesions in the knee. Postoperative bleeding remains potentially concerning. This study evaluates the porous poly(ethylene oxide)terephthalate/poly(butylene terephthalate) (PEOT/PBT) implants used for donor site filling. Empty donor sites were the controls. After 9 months, MRI, macroscopical and histological analysis were carried out. Treated defects did not cause postoperative bleeding. No adverse events or inflammatory response was observed. PEOT/PBT implants were well integrated. Empty controls occasionally showed protrusion of repair tissue at the defect margins. Surface stiffness was minimally improved compared to controls. Existing polymer fragments indicated considerable biodegradation. Histological evaluation of the filled donor sites revealed congruent fibrocartilaginous surface repair with proteoglycan-rich domains and subchondral cancellous bone formation with interspersed fibrous tissue in all implanted sites. The PEOT/PBT implants successfully reduce donor site morbidity and postoperative bleeding after mosaicplasty. LEVEL OF EVIDENCE: II.

Loss of c-Met accelerates development of liver fibrosis in response to CCl(4) exposure through deregulation of multiple molecular pathways.

HGF/c-Met signaling plays a pivotal role in hepatocyte survival and tissue remodeling during liver regeneration. HGF treatment accelerates resolution of fibrosis in experimental animal models. Here, we utilized Met(fl/fl);Alb-Cre(+/-) conditional knockout mice and a carbon tetrachloride(CCl(4))-induced liver fibrosis model to formally address the role of c-Met signaling in hepatocytes in the context of chronic tissue injury. Histological changes during injury (4weeks) and healing phase (4weeks) were monitored by immunohistochemistry; expression levels of selected key fibrotic molecules were evaluated by western blotting, and time-dependent global transcriptomic changes were examined using a microarray platform. Loss of hepatocyte c-Met signaling altered hepatic microenvironment and aggravated hepatic fibrogenesis. Greater liver damage was associated with decreased hepatocyte proliferation, excessive stellate cell activation and rapid dystrophic calcification of necrotic areas. Global transcriptome analysis revealed a broad impact of c-Met on critical signaling pathways associated with fibrosis. Loss of hepatocyte c-Met caused a strong deregulation of chemotactic and inflammatory signaling (MCP-1, RANTES, Cxcl10) in addition to modulation of genes involved in reorganization of the cytoskeletal network (Actb, Tuba1a, Tuba8), intercellular communications and adhesion (Adam8, Icam1, Itgb2), control of cell proliferation (Ccng2, Csnk2a, Cdc6, cdk10), DNA damage and stress response (Rad9, Rad52, Ercc4, Gsta1 and 2, Jun). Our study demonstrates that deletion of c-Met receptor in hepatocytes results in pronounced changes in hepatic metabolism and microenvironment, and establishes an essential role for c-Met in maintaining the structural integrity and adaptive plasticity of the liver under adverse conditions.

2012 provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative.

The objective of this study was to develop EULAR/ACR classification criteria for polymyalgia rheumatica (PMR). Candidate criteria were evaluated in a 6-month prospective cohort study of 125 patients with new onset PMR and 169 non-PMR comparison subjects with conditions mimicking PMR. A scoring algorithm was developed based on morning stiffness >45 minutes (2 points), hip pain/limited range of motion (1 point), absence of RF and/or ACPA (2 points), and absence of peripheral joint pain (1 point). A score ≥4 had 68% sensitivity and 78% specificity for discriminating all comparison subjects from PMR. The specificity was higher (88%) for discriminating shoulder conditions from PMR and lower (65%) for discriminating RA from PMR. Adding ultrasound, a score ≥5 had increased sensitivity to 66% and specificity to 81%. According to these provisional classification criteria, patients ≥50 years old presenting with bilateral shoulder pain, not better explained by an alternative pathology, can be classified as having PMR in the presence of morning stiffness>45 minutes, elevated CRP and/or ESR and new hip pain. These criteria are not meant for diagnostic purposes.

2012 Provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative.

The objective of this study was to develop European League Against Rheumatism/American College of Rheumatology classification criteria for polymyalgia rheumatica (PMR). Candidate criteria were evaluated in a 6-month prospective cohort study of 125 patients with new-onset PMR and 169 non-PMR comparison subjects with conditions mimicking PMR. A scoring algorithm was developed based on morning stiffness >45 minutes (2 points), hip pain/limited range of motion (1 point), absence of rheumatoid factor and/or anti-citrullinated protein antibody (2 points), and absence of peripheral joint pain (1 point). A score ≥4 had 68% sensitivity and 78% specificity for discriminating all comparison subjects from PMR. The specificity was higher (88%) for discriminating shoulder conditions from PMR and lower (65%) for discriminating RA from PMR. Adding ultrasound, a score ≥5 had increased sensitivity to 66% and specificity to 81%. According to these provisional classification criteria, patients ≥50 years old presenting with bilateral shoulder pain, not better explained by an alternative pathology, can be classified as having PMR in the presence of morning stiffness >45 minutes, elevated C-reactive protein and/or erythrocyte sedimentation rate, and new hip pain. These criteria are not meant for diagnostic purposes.

Patient-reported outcomes in polymyalgia rheumatica.

OBJECTIVE: To prospectively evaluate the disease course and the performance of clinical, patient-reported outcome (PRO) and musculoskeletal ultrasound measures in patients with polymyalgia rheumatica (PMR). METHODS: The study population included 85 patients with new-onset PMR who were initially treated with prednisone equivalent dose of 15 mg daily tapered gradually, and followed for 26 weeks. Data collection included physical examination findings, laboratory measures of acute-phase reactants, and PRO measures. Ultrasound evaluation was performed at baseline and Week 26 to assess for features previously reported to be associated with PMR. Response to corticosteroid treatment was defined as 70% improvement in PMR on visual analog scale (VAS). RESULTS: At baseline, 77% had hip pain in addition to shoulder pain and 100% had abnormal C-reactive protein or erythrocyte sedimentation rate. On ultrasound, 84% had shoulder findings and 32% had both shoulder and hip findings. Response to corticosteroid treatment occurred in 73% of patients by Week 4 and was highly correlated with percentage improvement in other VAS measures. Presence of ultrasound findings at baseline predicted response to corticosteroids at 4 weeks. Factor analysis revealed 6 domains that sufficiently represented all the outcome measures: PMR-related pain and physical function, an elevated inflammatory marker, hip pain, global pain, mental function, and morning stiffness. CONCLUSION: PRO measures and inflammatory markers performed well in assessing disease activity in patients with PMR. A minimum set of outcome measures consisting of PRO measures of pain and function and an inflammatory marker should be used in practice and in clinical trials in PMR.

Follow-up findings in young females with high-grade squamous intraepithelial lesion papanicolaou test results.

CONTEXT: New guidelines discourage cervical screening and procedures in young females, given available human papillomavirus vaccines, concerns regarding procedure-associated harms, and the rarity of cervical cancers. OBJECTIVE: To analyze histopathologic follow-up data on a large number of young females with high-grade squamous intraepithelial lesion (HSIL) Papanicolaou (Pap) test results. DESIGN: Hospital records were searched for HSIL Pap test results in females 20 years or younger between January 2002 and December 2007. Histopathologic and Pap test follow-up, age group variations, and impact of Pap test transformation zone/endocervical sampling were analyzed. RESULTS: Four hundred seventy-four females aged 20 years or younger had HSIL Pap test results during the study period. Three hundred thirty-five young females with at least one cervical biopsy were included. The average age was 18.6 years (range, 13-20 years). The average follow-up period was 24 months (range, 0.1-75 months), with a median of 22 months. Histopathologic detection rates were 44.2% for cervical intraepithelial neoplasia (CIN) 2/3 and 47.8% for CIN 1. The average period between the HSIL Pap test result and an initial diagnosis of CIN 2/3 was 5 months (range, 0.1-62 months), with a median of 2 months. Neither invasive carcinoma nor adenocarcinoma in situ was identified. Presence or absence of a transformation zone/endocervical sample did not significantly impact CIN 2/3 risk (44.5% versus 38.9%, P = .64). CONCLUSIONS: Histopathologic CIN 2/3 was documented in 148 of 335 (44%) of biopsied young females with HSIL Pap results, likely reflecting both the reported high likelihood of HSIL regression in younger females and the challenge of colposcopic sampling of relatively short-lived smaller CIN 2/3 lesions. Although no cases of invasive carcinoma were identified in this study, updated guidelines pose new risks for maturing females with undetected cervical precancer.

Loss of c-Met disrupts gene expression program required for G2/M progression during liver regeneration in mice.

BACKGROUND: Previous work has established that HGF/c-Met signaling plays a pivotal role in regulating the onset of S phase following partial hepatectomy (PH). In this study, we used Met(fl/fl);Alb-Cre(+/-) conditional knockout mice to determine the effects of c-Met dysfunction in hepatocytes on kinetics of liver regeneration. METHODOLOGY/PRINCIPAL FINDING: The priming events appeared to be intact in Met(fl/fl);Alb-Cre(+/-) livers. Up-regulation of stress response (MAFK, IKBZ, SOCS3) and early growth response (c-Myc, c-Jun, c-Fos, DUSP1 and 6) genes as assessed by RT-qPCR and/or microarray profiling was unchanged. This was consistent with an early induction of MAPK/Erk and STAT3. However, after a successful completion of the first round of DNA replication, c-Met deficient hepatocytes were blocked in early/mid G2 phase as shown by staining with phosphorylated form of histone H3. Furthermore, loss of c-Met in hepatocytes diminished the subsequent G1/S progression and delayed liver recovery after partial hepatectomy. Upstream signaling pathways involved in the blockage of G2/M transition included lack of persistent Erk1/2 activation and inability to up-regulate the levels of Cdk1, Plk1, Aurora A and B, and Mad2 along with a defective histone 3 phosphorylation and lack of chromatin condensation. Continuous supplementation with EGF in vitro increased proliferation of Met(fl/fl);Alb-Cre(+/-) primary hepatocytes and partially restored expression levels of mitotic cell cycle regulators albeit to a lesser degree as compared to control cultures. CONCLUSION/SIGNIFICANCE: In conclusion, our results assign a novel non-redundant function for HGF/c-Met signaling in regulation of G2/M gene expression program via maintaining a persistent Erk1/2 activation throughout liver regeneration.

[Comparative genomic classification of human hepatocellular carcinoma]. / Az emberi májrák komparatív genomikai osztályozása.

Global transcriptome analysis has been successfully applied to characterize various human tumors, including hepatocellular carcinomas. This novel technology can facilitate early diagnosis, as well as prognostic and therapeutic diversification of cancer patients. To enhance access to the genomic information buried in archived pathology samples, we assessed RT-PCR amplification rates in paraffin-embedded tissues preserved in three different fixatives. Reliable amplification could be achieved from all paraffin-embedded specimens, when the amplicon size did not exceed 225 bp. A longer amplicon size resulted in rapid decrease of yield and reproducibility. In addition, formalin provided superior morphology and better reactivity with claudin-4 and -7 immunohistochemistry. Amplification of the initial sample is often required before transcriptome analysis of clinical specimens could be performed. We introduced a random nonamer primed T3 polymerase reaction into the conventional linear RNA amplification protocol. The modified T3T7 method generated a sense strand product ideal for synthesizing indirectly labeled cDNA templates. Microarray analysis of amplified frozen and laser-microdissected Myc and Myc/TGFalpha mouse liver tumors confirmed good reproducibility (r=0.9) of the reaction and conservation of original transcriptional patterns (r=0.78). Finally, we tested the utility of expression profiling for the classification of human HCC samples. By comparing expression data from HGF-treated c-Met conditional knock-out and control primary mouse hepatocytes, we identified 690 HGF/c-Met target genes. Functional analysis of the significant gene set implicated c-Met as key regulator of hepatocyte motility and oxidative homeostasis. Cross comparison of the c-Met-induced transcription signature with human HCC expression profiles revealed a group of tumors (27%) with potentially activated c-Met signaling (MET+). These tumors were characterized by higher vascular invasion rate, increased microvessel density, and shortened survival. A prediction model based on 111 cross-species conserved c-Met signature genes was able to diversify HCC patients into good and bad prognostic groups with 83-95% accuracy. Our results therefore demonstrate that careful experimental design and state-of-the-art laboratory methods could open the way for global expression profiling of archived and limited availability pathologic samples. Comparative functional genomics based analysis of the cancer transcriptome could lead to novel molecular classification systems which are essential for the introduction of individualized cancer therapeutics.

Central role of c-Myc during malignant conversion in human hepatocarcinogenesis.

Hepatocarcinogenesis is a multistage process in which precursor lesions progress into early hepatocellular carcinomas (eHCC) by sequential accumulation of multiple genetic and epigenetic alterations. To decode the molecular events during early stages of liver carcinogenesis, we performed gene expression profiling on cirrhotic (regenerative) and dysplastic nodules (DN), as well as eHCC. Although considerable heterogeneity was observed at the regenerative and dysplastic stages, overall, 460 differentially expressed genes were detected between DN and eHCC. Functional analysis of the significant gene set identified the MYC oncogene as a plausible driver gene for malignant conversion of the DNs. In addition, gene set enrichment analysis revealed global activation of the MYC up-regulated gene set in eHCC versus dysplasia. Presence of the MYC signature significantly correlated with increased expression of CSN5, as well as with higher overall transcription rate of genes located in the 8q chromosome region. Furthermore, a classifier constructed from MYC target genes could robustly discriminate eHCC from high-grade and low-grade DNs. In conclusion, our study identified unique expression patterns associated with the transition of high-grade DNs into eHCC and showed that activation of the MYC transcription signature is strongly associated with the malignant conversion of preneoplastic liver lesions.

Hepatocyte-specific c-Met deletion disrupts redox homeostasis and sensitizes to Fas-mediated apoptosis.

The hepatocyte growth factor and its receptor c-Met direct a pleiotropic signal transduction pathway that controls cell survival. We previously demonstrated that mice lacking c-Met (Met-KO) in hepatocytes were hypersensitive to Fas-induced liver injury. In this study, we used primary hepatocytes isolated from Met-KO and control (Cre-Ctrl) mice to address more directly the protective effects of c-Met signaling. Loss of c-Met function increased sensitivity to Fas-mediated apoptosis. Hepatocyte growth factor suppressed apoptosis in Cre-Ctrl but not Met-KO hepatocytes concurrently with up-regulation of NF-kappaB and major antiapoptotic proteins Bcl-2 and Bcl-xL. Intriguingly, Met-KO hepatocytes exhibited intrinsic activation of NF-kappaBas well as Bcl-2 and Bcl-xL. Furthermore, unchallenged Met-KO cells displayed oxidative stress as evidenced by overproduction of reactive oxygen species, which was associated with greater NADPH and Rac1 activities, was blocked by the known NADPH oxidase inhibitors, and was paralleled by increased lipid peroxidation and reduced glutathione (GSH) content. N-Acetylcysteine, an antioxidant and GSH precursor, significantly reduced Jo2-induced cell death. Conversely, the GSH-depleting agent buthionine sulfoximine completely abolished the protective effects of N-acetylcysteine in Met-KO hepatocytes. In conclusion, genetic inactivation of c-Met in mouse hepatocytes caused defects in redox regulation, which may account for the increased sensitivity to Fas-induced apoptosis and adaptive up-regulation of NF-kappaB survival signaling. These data provide evidence that intact c-Met signaling is a critical factor in the protection against excessive generation of endogenous reactive oxygen species.

Loss of hepatocyte growth factor/c-Met signaling pathway accelerates early stages of N-nitrosodiethylamine induced hepatocarcinogenesis.

Hepatocyte growth factor (HGF) has been reported to have both positive and negative effects on carcinogenesis. Here, we show that the loss of c-Met signaling in hepatocytes enhanced rather than suppressed the early stages of chemical hepatocarcinogenesis. c-Met conditional knockout mice (c-metfl/fl, AlbCre+/-; MetLivKO) treated with N-nitrosodiethylamine developed significantly more and bigger tumors and with a shorter latency compared with control (w/w, AlbCre+/-; Cre-Ctrl) mice. Accelerated tumor development was associated with increased rate of cell proliferation and prolonged activation of epidermal growth factor receptor (EGFR) signaling. MetLivKO livers treated with N-nitrosodiethylamine also displayed elevated lipid peroxidation, decreased ratio of reduced glutathione to oxidized glutathione, and up-regulation of superoxide dismutase 1 and heat shock protein 70, all consistent with increased oxidative stress. Likewise, gene expression profiling done at 3 and 5 months after N-nitrosodiethylamine treatment revealed up-regulation of genes associated with cell proliferation and stress responses in c-Met mutant livers. The negative effects of c-Met deficiency were reversed by chronic p.o. administration of antioxidant N-acetyl-L-cysteine. N-acetyl-L-cysteine blocked the EGFR activation and reduced the N-nitrosodiethylamine-initiated hepatocarcinogenesis to the levels of Cre-Ctrl mice. These results argue that intact HGF/c-Met signaling is essential for maintaining normal redox homeostasis in the liver and has tumor suppressor effect(s) during the early stages of N-nitrosodiethylamine-induced hepatocarcinogenesis.

Detection of HER-2/neu gene amplification in breast carcinomas using quantitative real-time PCR - a comparison with immunohistochemical and FISH results.

The aim of our study was to evaluate the value of quantitative real-time-PCR (qPCR) in the determination of HER-2/neu amplification status of human breast carcinomas by comparing qPCR, FISH and immunohistochemistry results from the same samples. A total of 210 breast carcinomas were examined. Ready-to-use CB11 antibody was applied to detect HER-2/neu oncoprotein expression. In 76 out of 210 cases FISH was performed, and 162 cases were investigated with qPCR. Seventy-five tumors were 2+ or 3+ positive with immunohistochemistry, while 135 samples were either completely negative or 1+. In 45 cases results from all three methods were available. Out of these, in twenty negative and sixteen positive cases both FISH and qPCR led to similar results. The mean qPCR amplification ratio in the concordant positive cases was 5.424 while in the qPCR+/FISH- group the mean ratio was 2.765. Out of 121 samples with scores of 0 or 1+ immunohistochemical result, analyzed also with qPCR, 26 showed HER-2/neu gene amplification. In these cases the mean amplification ratio was 2.53. Comparison of FISH and qPCR together with immunohistochemistry shows that qPCR is more sensitive to detect HER-2/neu gene amplification in tumors scored as 2+ with immunohistochemistry, but the diagnostic cut-off ratio should be defined above 2.7 to avoid high number of false positive cases. Amongst the immunohistochemistry score 2+ cases, 10 of 18 showed gene amplification by qPCR while 10 of 26 by FISH. In conclusion, a well calibrated HER-2/neu qPCR assay may serve as useful alternative to FISH in breast cancer patients.

[Polymyalgia rheumatica]. / Polymyalgia rheumatica.

Polymyalgia rheumatica is a disorder that affects people over 50 years of age. The etiology of the disease has not been hitherto clarified exactly. Its incidence among people over 50 is in the range of 0.1-0.5%. The incidence rate peaks in the age group of 60-70 years. It is also found in younger people, but far less frequently. The diagnosis is based primarily on locomotor complains--namely on pronounced pain, morning stiffness of the shoulder girdle, pelvic girdle and neck. Complaints relating to the arms and legs (such as muscular weakness, oedema, tendonitis etc.) are also observed, however, in one third of the cases. The diagnostic criteria are defined empirically. Polymyalgia rheumatica was formerly considered to be a form of elderly onset rheumatoid arthritis. The progressive erosion process is absent in the case of polymyalgia rheumatica unlike in the case of rheumatoid arthritis. Numerous factors are known, which point to a link between polymyalgia rheumatica and giant cell vasculitis, arthritis, but the precise nature of this relationship remains unknown. Both conditions affect the same age group in the general population and they are even found--not infrequently--in the same patient. Polymyalgia rheumatica can be found in 40% of the patients suffering from arthritis while the histological examination detected mild vasculitis in approximately 10% of the patients suffering for "isolated" polymyalgia rheumatica. The response to be given to the acute phase is similar in both disorders. Scandinavian authors consider polymyalgia rheumatica as the appearance of generalised arthritis. Arthroscopic, nuclear magnetic resonance imaging as well as isotopic studies show unequivocally, that in the background of the osteo-muscular symptoms, complaints, inflammation is to be found partly of the joints but primarily that of the periarticular synovial structures. The above mentioned--dominant--proximal symptoms can often mask the distal locomotor disorders (pitting oedema of the hands and feet, tendonitis, tendosynovitis, carpal tunnel syndrome). The disorder may be accompanied by atypical generalised symptoms (loss of appetite, weight loss, fever, fatigue). An excellent indicators of the acute phase reactions are erythrocyte sedimentation rate, C-reactive protein and interleukin-6. These are suitable for monitoring the effectiveness of the therapy, for indicating a relapse/recurrence. It should be noted, that polymyalgia rheumatica may also be present if the erythrocyte sedimentation rate and C-reactive protein values are low. This disorder is also characterised by fast and effective response to corticosteroid, which should be administered for 1-2 years. In some individual cases a different dosage regime may be necessary: steroid administered in low dosage over a longer period of time. Administration of methotrexate and anti-tumor necrotic factor-alpha may also be considered as alternative or adjuvant therapy for lowering the quantity of corticosteroid. Further multicenter, double blind studies should, however, be performed on large number of patients in this regard.

Oncogene-specific gene expression signatures at preneoplastic stage in mice define distinct mechanisms of hepatocarcinogenesis.

We applied a genome-wide microarray analysis to three transgenic mouse models of liver cancer in which targeted overexpression of c-Myc, E2f1, and a combination of the two was driven by the albumin promoter. Although gene expression profiles in HCC derived in all three transgenic lines were highly similar, oncogene-specific gene expression signatures were identified at an early dysplastic stage of hepatocarcinogenesis. Overexpression of E2f1 was associated with a strong alteration in lipid metabolism, and Srebp1 was identified as a candidate transcription factor responsible for lipogenic enzyme induction. The molecular signature of c-Myc overexpression included the induction of more than 60 genes involved in the translational machinery that correlated with an increase in liver mass. In contrast, the combined activity of c-Myc and E2f1 specifically enhanced the expression of genes involved in mitochondrial metabolism--particularly the components of the respiratory chain--and correlated with an increased ATP synthesis. Thus, the results suggest that E2f1, c-Myc, and their combination may promote liver tumor development by distinct mechanisms. In conclusion, determination of tissue-specific oncogene expression signatures might be useful to identify conserved expression modules in human cancers.

Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype.

Identification of specific gene expression signatures characteristic of oncogenic pathways is an important step toward molecular classification of human malignancies. Aberrant activation of the Met signaling pathway is frequently associated with tumor progression and metastasis. In this study, we defined the Met-dependent gene expression signature using global gene expression profiling of WT and Met-deficient primary mouse hepatocytes. Newly identified transcriptional targets of the Met pathway included genes involved in the regulation of oxidative stress responses as well as cell motility, cytoskeletal organization, and angiogenesis. To assess the importance of a Met-regulated gene expression signature, a comparative functional genomic approach was applied to 242 human hepatocellular carcinomas (HCCs) and 7 metastatic liver lesions. Cluster analysis revealed that a subset of human HCCs and all liver metastases shared the Met-induced expression signature. Furthermore, the presence of the Met signature showed significant correlation with increased vascular invasion rate and microvessel density as well as with decreased mean survival time of HCC patients. We conclude that the genetically defined gene expression signatures in combination with comparative functional genomics constitute an attractive paradigm for defining both the function of oncogenic pathways and the clinically relevant subgroups of human cancers.