Prognostic role of APC and RASSF1A promoter methylation status in cell free circulating DNA of operable gastric cancer patients.

Gastric carcinogenesis is a multistep process including not only genetic mutations but also epigenetic alterations. The best known and more frequent epigenetic alteration is DNA methylation affecting tumor suppressor genes that may be involved in various carcinogenetic pathways. The aim of the present study was to investigate the methylation status of APC promoter 1A and RASSF1A promoter in cell free DNA of operable gastric cancer patients. Using methylation specific PCR, we examined the methylation status of APC promoter 1A and RASSF1A promoter in 73 blood samples obtained from patients with gastric cancer. APC and RASSF1A promoters were found to be methylated in 61 (83.6%) and 50 (68.5%) of the 73 gastric cancer samples examined, but in none of the healthy control samples (p < 0.001). A significant association between methylated RASSF1A promoter status and lymph node positivity was observed (p = 0.005). Additionally, a significant correlation between a methylated APC promoter and elevated CEA (p = 0.033) as well as CA-19.9 (p = 0.032) levels, was noticed. The Kaplan-Meier estimates of survival, significantly favored patients with a non-methylated APC promoter status (p = 0.008). No other significant correlations between APC and RASSF1A methylation status and different tumor variables examined was observed. Serum RASSF1A and APC promoter hypermethylation is a frequent epigenetic event in patients with early operable gastric cancer. The observed correlations between APC promoter methylation status and survival as well as between a hypermethylated RASSF1A promoter and nodal positivity may be indicative of a prognostic role for those genes in early operable gastric cancer. Additional studies, in a larger cohort of patients are required to further explore whether these findings could serve as potential molecular biomarkers of survival and/or response to specific treatments.

γ -H2AX: A Novel Prognostic Marker in a Prognosis Prediction Model of Patients with Early Operable Non-Small Cell Lung Cancer.

Cancer is a leading cause of death worldwide and the prognostic evaluation of cancer patients is of great importance in medical care. The use of artificial neural networks in prediction problems is well established in human medical literature. The aim of the current study was to assess the prognostic value of a series of clinical and molecular variables with the addition of γ -H2AX-a new DNA damage response marker-for the prediction of prognosis in patients with early operable non-small cell lung cancer by comparing the γ -H2AX-based artificial network prediction model with the corresponding LR one. Two prognostic models of 96 patients with 27 input variables were constructed by using the parameter-increasing method in order to compare the predictive accuracy of neural network and logistic regression models. The quality of the models was evaluated by an independent validation data set of 11 patients. Neural networks outperformed logistic regression in predicting the patient's outcome according to the experimental results. To assess the importance of the two factors p53 and γ -H2AX, models without these two variables were also constructed. JR and accuracy of these models were lower than those of the models using all input variables, suggesting that these biological markers are very important for optimal performance of the models. This study indicates that neural networks may represent a potentially more useful decision support tool than conventional statistical methods for predicting the outcome of patients with non-small cell lung cancer and that some molecular markers, such as γ -H2AX, enhance their predictive ability.

H2AX a promising biomarker for lung cancer: a review.

Histone's H2A variant (H2AX) phosphorylation is an early indicator of DNA double-strand breaks formation and DNA damage response. Thus, it may act as a novel biomarker to monitor genotoxic events that can drive cancer development and tumor progression. This review will focus on the possible applications of H2AX as a key regulator of DNA damage response in lung cancer and as a biomarker of: sensitivity of lung tumors to chemotherapy and radiotherapy, treatment with PARP inhibitors, bystander effect, multistep lung carcinogenesis, environmental smoking, and chemical genotoxicity, chemoprevention, prognosis, and also as therapeutic targets in lung cancers.

Molecular pathogenesis of pancreatic cancer and clinical perspectives.

Pancreatic cancer remains stubbornly resistant to many key cytotoxic chemotherapeutic agents and novel targeted therapies. The molecular heterogeneity of this cancer may account for therapy failures to date, although our growing arsenal of novel targeted agents could translate into patient survival. The main objectives of this review are to elucidate histological subtypes of pancreatic neoplasms that exhibit the characteristic of a gradual process of differentiation from benign entities to malignant ones. In addition, important genes, molecular abnormalities, and significant pathways of pancreatic cancer are analyzed and a potential clinical interpretation is presented (p16/cdkn2a, k-ras mutations, smad-4/tgf-/stat3, stk-11, braf, brca-2, neurotensin, mucs proteins, palb2, mitochondrial mutations, DNA mismatch repair genes, methylation, microrna expression, epithelial-to-mesenchymal transition, egfr mutations, the pi3k-akt-mtor pathway, the vegf pathway, heat shock proteins, cxcr4, the cox pathway, the src pathway, the hedgehog pathway, pancreatic stellate cells, a progression model, and molecular events in uncommon pancreatic tumors). Finally, future therapeutic directions are elucidated.

Acute respiratory distress due to thymoma in a patient treated with TK inhibitor: a case report and review of the current treatment options.

Thymic malignancies are rare intrathoracic tumors that may be aggressive and difficult to treat in advanced stage. Surgery is the cornerstone of the management of thymomas: it is significant for the definite histopathological diagnosis and staging, and in most cases, it constitutes the first step of the treatment strategy. For patients with primary unresectable thymomas, the multimodal treatment schedule nowadays includes neoadjuvant chemotherapy, extensive surgery, adjuvant radiotherapy, and in some cases, adjuvant chemotherapy. A patient with a history of stage III COPD and an undiagnosed thoracic mass was admitted to the intensive care unit with acute respiratory distress. A radiologic evaluation by CT scan revealed a mass of 13 cm in diameter at the mediastinum. Fine needle aspiration was performed and revealed a thymoma. Due to poor performance status, the patient was not able to undergo surgery. He refused to be treated with neither chemotherapy nor radiotherapy, but due to EGFR overexpression, treatment with TK inhibitor was suggested. Fine needle aspiration biopsy is commonly used to identify metastasis to the mediastinum. However, it is less often employed as a primary diagnostic tool for tumors, particularly thymic neoplasms. The use of targeted therapies for the treatment of thymic malignancies has been described in the literature. Over the past years, significant efforts have been made to dissect the molecular pathways involved in the carcinogenesis of these tumors. Insights have been obtained following anecdotal clinical responses to targeted therapies, and large-scale genomic analyses have been conducted.

Exophthalmos as a first manifestation of small cell lung cancer: a long-term follow-up.

Small cell lung cancer is characterized by rapid growth and early metastasis. Despite its sensitivity to cytotoxic therapy, until now treatments have failed to control or cure this disease in most patients. Orbital metastases are a rare manifestation of systemic malignancies. Breast and lung cancers represent more than two thirds of the primary cancer sites. Metastases to the eye and orbit develop in approximately 0.7-12% of patients with lung cancer. Here, we report a rare case of exophthalmos as the first manifestation of a metastatic carcinoma due to small cell lung cancer, and a 6-months follow-up with complete exophthalmic response to chemotherapy.

Type I collagen biomarkers in the diagnosis of bone metastases in breast cancer, lung cancer, urinary bladder cancer and prostate cancer. Comparison to CEA, CA 15-3, PSA and bone scintigraphy.

PURPOSE: In this study we evaluated the clinical usefulness of serum pro-I collagen peptide (PICP) and I collagen telopeptide (ICTP) as indicators of early bone metastases in patients with breast (BC), lung (LC), urinary bladder (UBC) and prostate cancer (PC). PATIENTS AND METHODS: 305 patients were examined. 145 had histologically confirmed BC (92 with bone metastases), 20 UBC (6 with bone metastases), 11 LC (3 with bone metastases) and 129 PC (68 with bone metastases). In BC patients we compared the PICP and ICTP levels with those of CA 15-3, CEA and bone scintigraphy. Patients with LC and UBC had PICP and ICTP measurements, PC patients had serum PICP, prostate specific antigen (PSA) measurements and bone scans. 104 healthy individuals served as controls. RESULTS: ICTP and CA 15-3 levels were significantly higher in patients with BC and bone metastases in comparison to patients without metastases (p <0.05), while PICP and CEA were only marginally higher. Significant correlation was observed between existence of bone metastases and ICTP levels (p <0.05). The sensitivity of PICP, ICTP, CEA and CA 15-3 was 28.1, 48.6, 42, and 78%, respectively and specificity was 83.9, 94, 65 and 86%, respectively. ICTP and CA 15-3 were the most reliable markers for early diagnosis of bone metastases in BC. PICP alone or with ICTP were not sensitive enough. Only CA 15-3 showed sensitivity 78% and specificity 86%. When combined CA 15-3, ICTP and CEA the sensitivity and specificity increased to 82% and 96%, respectively. Furthermore, PICP and PSA levels were significantly higher in patients with PC and bone metastases in comparison to patients with benign prostate hyperplasia (BPH) (p <0.0001) or in patients with PC without bone metastases (p <0.0005 for PICP and p <0.0001 for PSA). The co-evaluation of PICP and PSA improved the sensitivity (78%), specificity (96%), accuracy (97%) and positive predictive value (97%). In LC patients, ICTP levels differed significantly between patients with and without bone metastases (p=0.025). In UBC patients, PICP levels differed significantly between patients with and without bone metastases (p=0.017). CONCLUSION: ICTP and CA 15-3 are the most reliable markers for early diagnosis of bone metastases in BC patients. PICP could be useful for diagnosing early bone metastases of PC and combined with PSA and bone scan can be an additional tool in the follow-up of PC patients. For LC patients, ICTP showed a significant difference in the discrimination of patients with and without bone metastases. In UBC patients, PICP showed a significant difference in the discrimination of patients with and without bone metastases.

Association between bone scintigraphy and serum levels of procollagen (I) and PSA in the detection of bone disease in prostate cancer patients.

PURPOSE: To evaluate the clinical usefulness of serum procollagen I carboxyterminal propeptide (PICP) and prostate specific antigen (PSA) in relation to bone scan results in Greek patients with prostate cancer (PC). PATIENTS AND METHODS: 108 patients (mean age 58+/-4.3 years; range 42-81) with PC and 52 healthy blood donors as control group were examined for serum PICP and PSA levels. The diagnosis of PC was confirmed histologically. Bone metastases were diagnosed in 68 of the patients with the use of (99m)Tc-MDP bone scan, while 40 patients had no bone metastases. During the one year follow-up new PICP and PSA measurements were obtained along with a new bone scan for all groups studied. RESULTS: The levels of serum PICP and PSA were significantly higher in patients with PC and bone metastases in comparison to patients with no bone metastases. The sensitivity and specificity of the combination of PICP and PSA were 78% and 96%, respectively. CONCLUSION: PICP could be useful for diagnosing early bone metastases of prostate adenocarcinoma and in combination with PSA and bone scan can be an additional tool in the follow-up of patients with PC.

Association between bone scintigraphy and serum levels of tumor markers in the detection of bone disease in breast cancer patients.

PURPOSE: To evaluate the diagnostic value of bone scan in association with measurements of serum CEA, CA 15-3 and TPA levels in breast cancer (BC) patients. PATIENTS AND METHODS: From September 1999 to January 2005, 89 women with BC who had undergone bone scintigraphy as part of their follow-up were retrospectively evaluated. Serum tumor markers levels were compared with the results of bone scintigraphy. Patients with positive bone scans were divided into 3 groups: group 1: 1-3, group 2: 4-5, group 3: >5 bone lesions. Serum CEA, CA 15-3 and TPA levels of 7 ng/ml, 35 U/ml and 90 U/I, respectively, were adopted as the upper limit of normal. RESULTS: Serum CA 15-3 was significantly higher in patients with a positive bone scan (p=0.017). For CEA and TPA, no significant difference was found between patients with and without bone metastases. Twenty-five of 70 patients (36%) with normal CEA had bone metastases. Four of 50 (8%) patients with normal CA 15-3 and 15 of 51 (29%) patients with normal TPA had a positive bone scan. The combination of CA 15-3 with TPA showed 100% sensitivity in detecting bone metastases in all patient subgroups. In all 42 patients without bone metastases, CA 15-3 and/or TPA levels were normal. CONCLUSION: CA 15-3 but not CEA or TPA is sensitive and specific for the correct determination of bone scintigraphy. CA 15-3 plus TPA represent the best combination in association with bone scanning. However, due to frequent false negative results of all tumor markers, it is not recommended to reject a bone scan on the basis of tumor markers levels.

A dose escalation study of docetaxel plus capecitabine in combination with gemcitabine in patients with advanced solid tumors.

Capecitabine (CAP), gemcitabine (GEM), and docetaxel (DOC) have shown interesting activity in a wide range of solid tumors. A phase I study was conducted in order to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of their combination in patients with refractory solid tumors. Eighteen patients were enrolled. The patients' median age was 60 years, 15 were male, and 11 were chemo-naive. DOC was administered on day 1 as an 1-h (IV) infusion at escalating doses ranging from 40 to 50 mg/m2. GEM was administered on day 1 as a 30-min (IV) infusion at a standard dose of 1500 mg/m2. CAP was administered orally on days 1 to 7 at escalating doses ranging from 1750 to 2500 mg/m2 given as two daily divided doses. Treatment was repeated every 2 weeks. Five different dose levels were examined. At dose level V two out of three enrolled patients presented DLTs (one patient grade 4 neutropenia and grade 3 stomatitis and another grade 3 diarrhea), and thus the recommended MTD for future phase II studies are CAP 2250 mg/m2, DOC 50 mg/m2, and GEM 1500 mg/m2. A total of 124 treatment cycles were administered. Toxicity was generally mild. Grade 3/4 neutropenia was observed in eight (7%) treatment cycles and grade 3 thrombocytopenia in one (1%). There was no febrile episode. Grade 2/3 asthenia was observed in six (33%) patients, grade 2/3 diarrhea in four (22%), and grade 2/3 hand-foot syndrome in three (17%). Other toxicities were uncommon. There was no treatment-related death. One (6%) CR, four (25%) PRs, and six (38%) SD were observed among 16 evaluable patients. Responses were seen in patients with breast (one CR), gastric (three PRs), and pancreatic (one PR) cancer. These results demonstrate that CAP, DOC, and GEM can be safely combined at clinically relevant doses and this regimen merits further evaluation.