Showing papers by "Alexandra Giatromanolaki published in 2008"
TL;DR: It is found that lactate and pyruvate excretion after 16–48 h of hypoxia was suppressed to normoxic levels, indicating that PDK-1 plays an important role in maintaining glycolysis and that the investigation of PDk-1 inhibitors should be investigated for antitumour effects.
Abstract: Here we describe the expression and function of a HIF-1-regulated protein pyruvate dehydrogenase kinase-1 (PDK-1) in head and neck squamous cancer (HNSCC). Using RNAi to downregulate hypoxia-inducible PDK-1, we found that lactate and pyruvate excretion after 16–48 h of hypoxia was suppressed to normoxic levels. This indicates that PDK-1 plays an important role in maintaining glycolysis. Knockdown had no effect on proliferation or survival under hypoxia. The immunohistochemical expression of PDK-1 was assessed in 140 cases of HNSCC. PDK-1 expression was not expressed in normal tissues but was upregulated in HNSCC and found to be predominantly cytoplasmic with occasional strong focal nuclear expression. It was strongly related to poor outcome (P=0.005 split by median). These results indicate that HIF regulation of PDK-1 has a key role in maintaining lactate production in human cancer and that the investigation of PDK-1 inhibitors should be investigated for antitumour effects.
172 citations
TL;DR: The correlation between the presence of FOXP3(+) Tregs and high vessel density in endometrial adenocarcinomas suggests a link between immunity, intratumoral angiogenesis and poor prognosis.
88 citations
TL;DR: An unusual case of a large (50 x 43 x 30 mm) carotid paraganglioma of Shamblin type III in a 13-year-old female, living at high altitude until the age of 9 years is reported.
51 citations
TL;DR: High levels of the hypoxia regulated proteins HIF1α and CA9 in HNC predict resistance to platinum based radio-chemotherapy, in accord with previously reported studies.
Abstract: Purpose: Tumor hypoxia and low intrinsic radiosensitivity may counteract the efficacy of standard radiotherapy for locally advanced head and neck cancer (HNC). We investigated the involvement of hypoxia-regulated proteins (Hypoxia inducible factors HIF1α, HIF2α and carbonic anhydrase CA9) in HNC resistance to accelerated and hypofractionated radiotherapy.Materials and methods: Thirty-nine patients with locally advanced HNC received 15 daily fractions of 3.4 Gy amounting to a total tumor dose of 51 Gy (equivalent to 63 Gy in four weeks – one week split); this was combined with platinum chemotherapy and amifostine cytoprotection administered subcutaneously. Immunohistochemical analysis of hypoxia-regulated proteins, namely HIF1α, HIF2α and CA9, was performed in formalin-fixed paraffin-embedded tissues obtained prior to radio-chemotherapy.Results: HIF1α and HIF2α were expressed in the nuclei and cytoplasm of cancer cells, while CA9 had a membrane reactivity. A high expression of HIF1α, HIF2α and CA9 was note...
42 citations
TL;DR: It is concluded that the VEGF/receptor pathway is active in more than half of NHLs and particularly in DLBCL, and the intimate correlation of VEGf production with the presence of phosphorylated V EGF‐receptors strongly supports the concept of an autocrine pathway.
Abstract: The expression of hypoxia inducible factors (HIF) 1alpha and 2alpha, of vascular endothelial growth factor (VEGF) and of the phosphorylated form of its receptor VEGFR2 (pVEGFR2/KDR) were investigated immunohistochemically in a series of 146 B-cell non-Hodgkin's lymphomas and 48 normal lymph nodes. These proteins were significantly up-regulated in neoplastic lymphocytes and a significantly higher expression of HIF1alpha (p = 0.05), VEGF (p = 0.02) and pVEGFR2/KDR (p = 0.007) was recorded in diffuse large B-cell lymphomas(DLBCL) compared to follicular lymphomas (FL). A strong statistical association of pVEGFR2/KDR expression with high HIF1alpha, HIF2alpha and VEGF was noted in both DLBCL and FL. HIF1alpha andHIF2alpha were linked with VEGF expression but no association between HIF1alpha and HIF2alpha was noted. Vascular density was significantly higher in the lymphoma compared to normal tissue, but there was no association with any of the examined parameters. It is concluded that the VEGF/receptor pathway is active in more than half of NHLs and particularly in DLBCL. The intimate correlation of VEGF production with the presence of phosphorylated VEGF-receptors strongly supports the concept of an autocrine pathway. The strong association of HIFalphas with the expression of VEGF and pVEGFR2/KDR found in the study provide strong evidence on the role of HIFalphas inthe activation of angiogenic and VEGF-autocrine pathways that may be critical therapeutic targets for HIF-inhibitors or other anti-angiogenic agents.
35 citations
TL;DR: The oxygen sensitive prolyl-hydroxylase domain enzymes (PHDs) and the asparagines hydroxylases (FIH, factor inhibiting HIF) regulate the transcriptional activity of HIFs.
23 citations
TL;DR: It is concluded that LDH5 is highly upregulated in B-cell non-Hodgkin lymphomas and is in direct relation to HIFs expression.
Abstract: The expression of lactate dehydrogenase 5 (LDH5), the major LDH isoenzyme sustaining the anaerobic transformation glycolysis was examined in B-cell non-Hodgkin lymphomas. Multi-tissue slides obtained from patients with diffuse large B-cell lymphomas (DLBCL; 95 cases), follicular lymphomas (FL; 49 cases) and from non-neoplastic lymph nodes (48 cases) were used for immuhistochemical analysis. High LDH5 expression (cytoplasmic and nuclear) was noted in 79/95 and 29/49 cases of DLBCL and FL, respectively (p = 0.002). No expression was noted in non-neoplastic lymphocytes. In DLBCL, LDH5 expression was significantly related to hypoxia inducible factor HIF1alpha, HIF2alpha, vascular endothelial growth factor (VEGF) and phosphorylated vascular endothelial growth factor receptor 2 (VEGFR2/KDR) expression. In FL, however, a significant relation was confirmed with pVEGFR2/KDR and HIF2alpha. FL cases with the highest microvessel density were those, which lacked both LDH5 and VEGF expression. It is concluded that LDH5 is highly upregulated in B-cell non-Hodgkin lymphomas and is in direct relation to HIFs expression. LDH5 expression is linked with activated VEGFR2/KDR expression in both lymphoid lesions.
22 citations
TL;DR: A new classification was recently proposed which combines simple and complex endometrial hyperplasia within one diagnostic category known asendometrialhyperplasia and defines new criteria for recognising the precancerous lesions.
Abstract: The proliferating lesions in the endometrium form a morphological continuum extending from benign to malignant, through a transitional pre-invasive stage. Within this spectrum, several classifications of endometrial hyperplasia have been developed over the years in which the precancerous lesions gained a substantial distinction, although not without inconsistencies in definitions and terminology. The revised WHO 1994 classification explicitly recognizes cytological atypia as the defining feature for distinguishing genuine hyperplastic lesions (simple and complex endometrial hyperplasia) from those that are potentially precancerous (simple and complex atypical endometrial hyperplasia) and puts an end to the verbal anarchy by adopting a common language of communication. This taxonomy, however, was criticized for complexity and low level of reproducibility. Thus, in the name of improved reproducibility a new classification was recently proposed which (a) combines simple and complex endometrial hyperplasia within one diagnostic category known as endometrial hyperplasia and (b) defines new criteria for recognising the precancerous lesions: a monoclonal growth, known as endometrial intraepithelial neoplasia (EIN), comprising clusters of crowded glands, greater than 1 mm in diameter, having a cytologically altered epithelium. The EIN concept was challenged of not being independently tested and received with great enthusiasm by some scholars and relative skepticism by others.
21 citations
TL;DR: CK18 is expressed in the gallbladder epithelial cells and the levels of total CK18, as well as caspase-cleaved CK 18, do not seem to differ between active and inactive chronic cholecystitis.
Abstract: Background
Cell death mode has been studied in cancer, autoimmune, and neurodegenerative diseases. In this study, apoptosis and necrosis are investigated for the first time in patients with chronic calculous cholecystitis.
12 citations
TL;DR: An unusual case of a mature cystic teratoma, or dermoid cyst, in the hepatoduodenal ligament of a young woman is reported, which is required for a definitive diagnosis.
Abstract: We report an unusual case of a mature cystic teratoma, or dermoid cyst, in the hepatoduodenal ligament of a young woman. Mature cystic teratomas are rarely found in extragonadal sites, especially the hepatoduodenal ligament. Surgical resection remains the mainstay of therapy and is required for a definitive diagnosis. Patients who undergo complete resection of a mature cystic teratoma normally have an excellent prognosis.
9 citations
TL;DR: A 75-year-old man suffering from symptomatic cholelithiasis underwent laparoscopic cholecystectomy using the four-port technique and died from metastatic disease of the abdomen four months later.
Abstract: A 75-year-old man suffering from symptomatic cholelithiasis underwent laparoscopic cholecystectomy using the four-port technique. No malignancy was observed in the resected gall-bladder and the patient exhibited a good postoperative course. Eleven months postoperatively he presented with two subcutaneous tumours: one at the port-site on the right anterior axillary line (at the position of the vacuum drain) and the other at the subumbilical port-site. The patient underwent an incisional biopsy, which revealed metastatic adenocarcinomas of the primary extrahepatic duct, with no evidence of a primary tumour or other distant metastasis. The patient underwent wide excision of the subcutaneous tumours. Six months later he again presented with subcutaneous tumours at the same positions. Magnetic resonance imaging of the abdomen revealed only the subcutaneous tumours. The patient again underwent wide excision of the subcutaneous tumours, followed by radiotherapy. At a 21-month follow-up the patient was symptom-free. Magnetic resonance imaging of the abdomen and magnetic resonance cholangiopancreatography results were normal, and there was no evidence of other metastasis. Four months later the patient died from metastatic disease of the abdomen.
TL;DR: It is considered that different surgical instruments, such as automatic anastomotic devices and automatic suturing devices, must be used in each phase of the surgical procedure for gastric cancer.
Abstract: Local recurrence at a gastrojejunal anastomosis is common in patients after gastrectomy for gastric carcinoma, but recurrence at a jejunojejunal anastomosis without recurrence at a gastrojejunal anastomosis is extremely rare. We report a case of suture-line recurrence at a jejunojejunal anastomosis without recurrence at the gastrojejunal anastomosis or in the remnant stomach in a patient 23 months after receiving a Billroth II gastrectomy for gastric cancer. We attributed the implantation of cancer cells at the jejunojejunal anastomosis to contamination of the stapler with cancer cells exfoliated in the gastric mucus during the construction of the gastrojejunal anastomosis. We therefore consider that different surgical instruments, such as automatic anastomotic devices and automatic suturing devices, must be used in each phase of the surgical procedure for gastric cancer.
Journal Article•
TL;DR: Capecitabine-based hypoARC is feasible with only minimal early and late toxicity and encouraging efficacy and the 2-year local relapse-free survival was 85-90% in patients treated with pre- or postoperative radiotherapy and 35% in Patients with inoperable tumors.
Abstract: Background: This is a report on the feasibility and efficacy of hypofractionated accelerated radiotherapy combined with amifostine cytoprotection ( hypoARC) and capecitabine in the treatment of rectal adenocarcinoma. Patients and Methods:Twenty-seven patients (pts) received pre- (14 pts) or postoperative (13 pts) conformal radiotherapy with 10 consecutive fractions of 3.4 Gy in 12 days,supportedwithsubcutaneouslyadministeredhigh-dose amifostine(upto1000mg)andcapecitabine(dailydoseof 600 mg/m 2 twice a day, 5 days per week for 4 weeks).Ten additionalpatientswithinoperabletumorsreceivedahigher dose(15fractionsof3.4Gy)asaradicalinterventionand5 receivedalowerdoseforpalliation.Results:Chemotherapy- relatedtoxicitywasminimalandradiationgrade2diarrhoea andproctitiswasnotedin3/42and4/42cases,respectively. No peri- or postoperative complications were noted in patients receiving pre-operative radiochemotherapy. Significanttumorregressionwasconfirmedinpost-RTCT- imaging and major histological responses were noted in 85% of cases treated before surgery. Late toxicity (median follow-up 26 months) was negligible. The 2-year local relapse-free survival was 85-90% in patients treated with