Dilsa Mizrak

Genome-Wide Transcriptional Reorganization Associated with Senescence-to-Immortality Switch during Human Hepatocellular Carcinogenesis

Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage. It contributes strongly to tissue aging and serves as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become “immortal”) by inactivating growth control genes such as TP53 and CDKN2A. They also reactivate telomerase reverse transcriptase. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by genome-wide transcriptional modifications. This appears to happen during hepatocellular carcinoma (HCC) development in patients with liver cirrhosis, however, the accompanying transcriptional changes are virtually unknown. We investigated genome-wide transcriptional changes related to the senescence-to-immortality switch during hepatocellular carcinogenesis. Initially, we performed transcriptome analysis of senescent and immortal clones of Huh7 HCC cell line, and identified genes with significant differential expression to establish a senescence-related gene list. Through the analysis of senescence-related gene expression in different liver tissues we showed that cirrhosis and HCC display expression patterns compatible with senescent and immortal phenotypes, respectively; dysplasia being a transitional state. Gene set enrichment analysis revealed that cirrhosis/senescence-associated genes were preferentially expressed in non-tumor tissues, less malignant tumors, and differentiated or senescent cells. In contrast, HCC/immortality genes were up-regulated in tumor tissues, or more malignant tumors and progenitor cells. In HCC tumors and immortal cells genes involved in DNA repair, cell cycle, telomere extension and branched chain amino acid metabolism were up-regulated, whereas genes involved in cell signaling, as well as in drug, lipid, retinoid and glycolytic metabolism were down-regulated. Based on these distinctive gene expression features we developed a 15-gene hepatocellular immortality signature test that discriminated HCC from cirrhosis with high accuracy. Our findings demonstrate that senescence bypass plays a central role in hepatocellular carcinogenesis engendering systematic changes in the transcription of genes regulating DNA repair, proliferation, differentiation and metabolism.

A potential link between endothelial function, cardiovascular risk, and metabolic syndrome in patients with Non-alcoholic fatty liver disease

BackgroundAsymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide (NO) synthetase. Elevated ADMA reduces NO formation and is associated with endothelial dysfunction. The aims of this study were to evaluate endothelial function and the cardiovascular risk (CVR) profile in patients with non-alcoholic fatty liver disease (NAFLD), and to determine whether or not an association with metabolic syndrome (MS) increases these parameters.MethodsA total of 100 consecutive patients with NAFLD, who were seen in Liver Disease Outpatient clinic and 45 age- and sex-matched controls were included. Endothelial function was evaluated based on the serum ADMA level measured using a validated ELISA kit (DLD Diagnostika GMBH, Hamburg, Germany) and flow-mediated vasodilatation (FMV) measured via high-resolution external ultrasonography. The CVR profile was calculated according to the Framingham equation.ResultsAt baseline there weren’t any significant differences in brachial artery diameter between the NAFLD and control groups (3.7 ± 0.6 mm vs. 3.6 ± 0.6 mm, respectively). FMV and flow-independent vasodilatation in response to sublingual nitroglycerin did not differ between the NAFLD and control groups (mean: 16% ± 9.4% vs. 17.9% ± 12.4%, and 21.4% ± 14% vs. 17.8% ± 11.3%, respectively, p > 0.05). No significant difference in the serum ADMA concentration between the NAFLD and control groups was observed (mean: 0.8 ± 0.07 μmol L-1 vs. 0.74 ± 0.2 μmol L-1, respectively). The CVR profile was significantly higher in the NAFLD group than in the control group (mean: 9% ± 6.9% vs. 4.6% ± 3.8%, P = 0.000). MS associated with NAFLD significantly increased the CVR profile (mean: 11.2% ± 7.4%, P = 0.000). An abnormal serum alanine aminotransferase level (>37 IU L-1) and the presence of fibrosis did not increase the CVR profile (p > 0.05).ConclusionsThe risk of cardiovascular events is increased in patients with NAFLD. The association with MS is further increased such risk.

Lower folate levels in gastric cancer: Is it a cause or a result?

Folate deficiency and its association with cancer have been studied in the literature, but its clinical impact is still unknown. Folate deficiency and its result on gastric cancer is a mysterious part of oncology, with ongoing studies hopefully clarifying its impact on gastric cancer management. Lee et al studied folate deficiency and its impact on staging and clinical results. Here we try to contribute to the field by expressing our own thoughts about the paper.

Lymphoproliferative disorders in individuals with chronic hepatitis b and C in the Turkish population

The aims of this cohort study were to evaluate the association of malignant lymphoproliferative disorders in patients with chronic viral hepatitis and to compare the results with those in individuals with non‐alcoholic fatty liver disease. A total of 3,873 patients with chronic liver disease who were seen consecutively in the Liver Disease Outpatient Clinic between January 2001 and July 2007 were assessed retrospectively. The frequency of malignant lymphoproliferative disorders including non‐Hodgkins lymphoma, Hodgkins lymphoma, and chronic lymphocytic leukemia in these patients was investigated. Of the total, 1,999 patients had chronic hepatitis B infection (male/female: 1,226/773, mean age: 45.1 ± 13.2 years), 978 had chronic hepatitis C infection (male/female: 437/541, mean age: 53.8 ± 13.7 years), and the remaining 896 had non‐alcoholic fatty liver disease (male/female: 450/446, mean age: 50.8 ± 11.2 years). A malignant lymphoproliferative disorder was identified in 13 patients (male/female: 9/4, mean age: 52.8 ± 16.8 years) with chronic viral hepatitis, while no case of malignant lymphoproliferative disorder was identified in individuals with non‐alcoholic fatty liver disease (P = 0.048). Among the patients with malignant lymphoproliferative disorders, seven had chronic hepatitis B infection and six had chronic hepatitis C infection; 11 had non‐Hodgkins lymphoma and two had chronic lymphocytic leukemia. All non‐Hodgkins lymphoma cases were B‐cell lymphoma. Based on the data obtained in this investigation, the association with malignant lymphoproliferative disorders in chronic viral hepatitis seems to be high as compared to that occurring in individuals with non‐alcoholic fatty liver disease. J. Med. Virol. 83:974–980, 2011.

Docetaxel-induced pericardial effusion

Hypersensitivity reactions, cumulative fluid retention, and neurotoxicity are frequently seen toxicities related to docetaxel. Fluid retention may be present as edema, weight gain, or third place fluid collection. Pericardial effusion is rarely seen with docetaxel treatment. We report a 58-year-old female patient who was presented with pericardial tamponade after three cycles of docetaxel therapy.

Aflibercept-related nasal septum perforation

Hypertension, cytopenia and diarrhea are the most common side effects of aflibercept. Rarely thromboembolism, hemorrhage, fistulization and reversible posterior leukoencephalopathy have been reported. Here we report a patient experiencing nasal septum perforation during aflibercept therapy.

The more we use, the more we lose

We have read the study by Meattini et al. [1] with great interest. Nausea and vomiting (NV) are the most common chemotherapy-induced toxicities and constitute an important part of oncology practice. Aprepitant, in addition to 5HT3 inhibitors, made chemotherapy regimens more tolerable. The efficacy in highly emetogenic regimens has been confirmed in moderately emetogenic regimens, and more widely usage has provided more NM control. Fluorouracil, epirubicin, and cyclophosphamide (FEC) combination is important in breast cancer management, and grades 3–4 NM ranges between 9.9 and 20.5 % in clinical trials [2, 3]. The addition of aprepitant to steroid and setron combination provided better NV results in the study by Meattini et al. However, multidrug therapies are like a double-edged sword, and drug interactions should be cautiously checked. The addition of aprepitant to FEC regimen can result in other toxicities and even change the expected therapy results. Aprepitant inhibits CYP450 3A4, and coadministration of aprepitant with drugs metabolized with CYP450 3A4 can result in increased levels of the target drug. Pharmacokinetics of cyclophosphamide can be effected with aprepitant, and this can cause unexpected toxicities while preventing NV. Another issue in this multidrug regimen is the increased incidence of QT prolongation in both palonosetron and epirubicin. This cardiac side effect is another toxicity that must be followed cautiously. In oncology practice, our aim was to treat patients with minimum toxicity and maximum efficacy. While doing this, drug interactions must be checked, and expected toxicities and interactions should be cautiously followed.

Osteogenesis Imperfecta, Pseudoachalasia, and Gastric Cancer

Osteogenesis imperfecta (OI) is a rare, inherited skeletal disorder characterized by abnormalities of type 1 collagen. Malignancy is rarely reported in patients with OI and it was suggested that this disease can protect against cancer. Here, we report a 41-year-old woman with symptoms of achalasia where repeated treatment of pneumatic dilation and stent replacement was unsuccessful; therefore, surgery was performed. Pathology showed gastric adenocarcinoma unexpectedly. Chemotherapy was given after assessing dihydropyrimidine dehydrogenase (DPD) enzyme activity, which can be deficient in OI patients. This is the first report of gastric cancer mimicking achalasia in a patient with OI.

1537PNUTRITIONAL STATUS OF HOSPITALIZED CANCER PATIENTS

ABSTRACT Aim: In oncology practice, nutrition and also metabolic activity are essential .To support the nutritional status and prevent malignant cachexia, its important to evaluate the patients and plan the maneuvers at the start of the therapy. Here we evaluated the nutritional status of patients hospitalized in oncology clinic and factors affecting the nutrition. Methods: Patients hospitalized in oncology clinic for therapy were evaluated for food intake and nutritional status through structured interviews. The nutritional status was reported by direct observation of the total diet consumed. The clinical properties, medical therapies, elements of nutritional support were noted. Results: Four hundred twenty three patients, 16-82 year old (median:52),were evaluated. Female predominant group (60.9%) was mostly followed with a diagnosis of lung cancer (%31.4). Nearly half of the patients (43%) reported a better appetite at home than in hospital. One third of the patients were supporting their diet by their own effort. Most common reported reason for decreased oral intake was loss of appetite (80.4%). Total consumption of the diet provided by hospital was in only 60% of the patients. 10.6% of patients needed enteral nutrition, whereas 9.9% was followed with parenteral nutritional support. Food intake of patients with gastrointestinal malignancies were worse than others (p Conclusions: In oncology practice, all patients in all stages of clinical setting must be evaluated for nutritional status and the risk groups must be supported with specific maneuvers. Gastrointestinal malignancies, especially with symptoms of emesis and diarrhea must be evaluated cautiously. Because of the effect of hospitalization on nutritional status, all unnecessary inpatient follow-ups must be avoided. Megestrol acetat in selected patients may provide better nutritional support. Disclosure: All authors have declared no conflicts of interest.

Oligoklonal gammopati ile prezante olan bir ig a multipl miyelom olgusu

brahim Tek1, Dilsa M zrak2, Gungor Utkan1, Selami Kocak Toprak3, Huseyin Tutkak4, Abdullah Buyukcelik1, Bulent Yalc n1, Hakan Akbulut1, Fikri cli1 1Department of Medical Oncology, Ankara University School of Medicine, Ankara, Turkey 2Department of Internal Medicine, Ankara University School of Medicine, Ankara, Turkey 3Department of Hematology, Ankara University School of Medicine, Ankara, Turkey 4Department of Clinical Immunology and Rheumatology, Ankara University School of Medicine, Ankara, Turkey