Mismatch repair protein MSH2, cytokeratin 18 and cytokeratin 20 expression: clinicopathological correlation and prognostic value in colorectal cancer patients.

BACKGROUND/AIMS: The survival of patients with colorectal cancer has not varied appreciably in recent years. The knowledge that genetic factors and disruption in apoptosis could play a role in the etiology and prognosis of patients with sporadic colorectal cancer has opened up new lines of research. We have studied a group of patients with colorectal cancer and the possible influence on the prognosis of immunohistochemical MSH2, M30 cytodeath and cytokeratin 20 expression. METHODOLOGY: Forty-nine consecutive patients with unselected colorectal cancer treated by resection and with a minimum follow-up period of 5 years. Tumor specimens were evaluated by an inmunohistochemical method for MSH2, cytokeratin 18 (M30 cytodeath) and cytokeratin 20 expression and correlated with epidemiological, clinicopathological and survival data. RESULTS: Thirty-four patients were resected with curative intention. At the end of the follow-up period, 25 (51%) had died, the majority (21) in relation to tumor progression, the overall median survival period being 47.9 months (95% CI = 27-86.6). Only vascular invasion, (lower median values), (p = 0.04) was related to MSH2 expression and tumor stage (p = 0.02) with cytokeratin 20. Patients' survival was related to tumoral stage (p = 0.04) and vascular invasion (p = 0.002). MSH2 expression, apoptosis (M30 cytodeath) and cytokeratin 20 staining did not influence the prognosis of patients. CONCLUSIONS: A change in the percentage of tumoral staining cells for MSH2, M30 cytodeath and cytokeratin 20 is frequent in patients with colorectal cancer. Only vascular invasion was correlated with MSH2 expression and stage of disease with cytokeratyn 20. Survival was related to TNM stage and vascular invasion, but not to MSH2, M30 cytodeath or cytokeratin 20 expressions.

Altered intragenic DNA methylation of HOOK2 gene in adipose tissue from individuals with obesity and type 2 diabetes.

AIMS/HYPOTHESIS: Failure in glucose response to insulin is a common pathology associated with obesity. In this study, we analyzed the genome wide DNA methylation profile of visceral adipose tissue (VAT) samples in a population of individuals with obesity and assessed whether differential methylation profiles are associated with the presence of type 2 diabetes (T2D). METHODS: More than 485,000 CpG genome sites from VAT samples from women with obesity undergoing gastric bypass (n = 18), and classified as suffering from type 2 diabetes (T2D) or not (no type 2 diabetes, NT2D), were analyzed using DNA methylation arrays. RESULTS: We found significant differential methylation between T2D and NT2D samples in 24 CpGs that map with sixteen genes, one of which, HOOK2, demonstrated a significant correlation between differentially hypermethylated regions on the gene body and the presence of type 2 diabetes. This was validated by pyrosequencing in a population of 91 samples from both males and females with obesity. Furthermore, when these results were analyzed by gender, female T2D samples were found hypermethylated at the cg04657146-region and the cg 11738485-region of HOOK2 gene, whilst, interestingly, male samples were found hypomethylated in this latter region. CONCLUSION: The differential methylation profile of the HOOK2 gene in individuals with T2D and obesity might be related to the attendant T2D, but further studies are required to identify the potential role of HOOK2 gene in T2D disease. The finding of gender differences in T2D methylation of HOOK2 also warrants further investigation.

Mortality risk scales in esophagectomy for cancer: their usefulness in preoperative patient selection.

BACKGROUND/AIMS: To improve esophagectomy outcome, preoperative identification of high-risk patients should allow the surgical approach to be modified or alternative treatment methods to be employed. METHODOLOGY: Preoperative risk assessment of 114 patients with resected esophageal cancer. One half of the cases affected the middle third of the esophagus. The tumor stage was III (33.3%) or IV (29.8%). The combined thoracoabdominal approach was the preferred route for resection (88.6%). We analyzed the influence of different variables (epidemiological, clinicopathological and surgical) affecting postoperative mortality. RESULTS: Sixty-six (57.9%) patients developed postoperative complications, mainly pulmonary. The mortality rate was 12.3% (14 patients). Multivariate analysis of preoperative variables found significant association between postoperative death and previous neoplasm (p=0.01), liver cirrhosis (p=0.001), abnormal functional respiratory test (p=0.01) and low serum cholesterol (p=0.005) and albumin (p=0.01). Using those variables, we created a composite scoring system that provides a separation of patients into three postoperative death risk groups. If this knowledge was used, we could avoid 50% of postoperative mortality via improved patient selection. CONCLUSIONS: The development of risk scales based on preoperative mortality risk factors may be useful in the selection and preparation of patients suitable for esophageal resection in order to diminish postoperative mortality.

Comparison of methods for circulating cell-free DNA isolation using blood from cancer patients: impact on biomarker testing.

BACKGROUND: The implementation of liquid biopsy for biomarker testing and response to treatment monitoring in cancer patients would presumable increase laboratory throughput, requiring the development of automated methods for circulating free DNA (cfDNA) isolation. METHODS: The present study compares the MagNA Pure Compact (MPC) Nucleic Acid Isolation Kit I and Maxwell® RSC (MR) ccfDNA Plasma Kit and the later with QIAamp Circulating Nucleid Acid (QCNA) Kit using 57 plasma samples from cancer patients. cfDNA concentration was measured using the Qubit fluorometer. DNA fragments lengt were assessed using the Agilent 2100 Bioanalyzer. Circulating tumor DNA (ctDNA) was quantified by digital PCR (dPCR). RESULTS: Firstly, we observed that MPC method significantly extracted less cfDNA than MR (P<0.0001). However, there were no significant differences in extraction yields of QCNA and MR kits. cfDNA isolation yield was also associated with tumor stage but not with tumor location. Secondly, an oligonucleosomal DNA ladder pattern was observed in 88% of the samples and significant differences in the recovery of mono-, di- and tri-nucleosomes DNA fragments were observed between MPC and MR methodologies. Finally, tumor mutation quantification on cfDNA was performed on 38 paired samples using digital PCR. Mutant allele fractions (MAFs) between paired samples were not significantly different. CONCLUSIONS: Methods for isolation of cfDNA can affect DNA yield and molecular weight fractions recovery. These observations should be taken into account for cfDNA analysis in routine clinical practice.

Prognostic value of micrometastases in esophageal and colorectal carcinoma (a clinical experience).

BACKGROUND/AIMS: The term "micrometastases" has been confused in many aspects. While the influence of lymph node metastases in esophageal and colorectal cancer is well known, the presence and importance of micrometastases is under debate. We investigated micro lymph node invasion in two different kinds of digestive tumors with very high mortality, and identified its possible repercussion on patient survival. METHODOLOGY: Lymph nodes of two groups of patients N0 on routine histopathology after radical resection (R0): 21 with esophageal carcinoma (Group I), and 21 with colorectal carcinoma (Group II), were studied by immunohistochemistry using monoclonal antibodies directed against cytokeratins of wide spectrum. The results were classified as positive or negative and compared with patient survival. RESULTS: Five of twenty-one (5/21) patients in group I and eight of twenty-one (8/21) in group II were positive for micrometastases. Median survival time in the positive esophageal group was 9.5 months vs. 68 in the negative one (p=0.16). Median survival time in the positive subset colorectal group was 54.5 months vs. 76.8 in the negative subgroup (p=0.5). Our results did not show statistical differences in survival time between patients positive or negative for micrometastases; however it is evident, especially in the esophageal cancer group, that there is a negative tendency of positive micrometastases on survival time. CONCLUSIONS: The presence of micrometastases in lymph nodes of patients N0 after conventional histopathology is frequent. Our preliminary results did not allow definitive conclusions but we may suppose its negative influence on patient survival.

SIADH secundario a adenocarcinoma seroso de ovario tratado con tolvaptán / SIADH secondary to serous ovarian adenocarcinoma treated with tolvaptan

La hiponatremia es la alteración electrolítica más frecuente en el medio hospitalario, y en un 30% de los casos se debe a un síndrome de secreción inapropiada de vasopresina (SIADH). El SIADH está descrito como cuadro paraneoplásico endocrinológico en múltiples tumores, entre los que excepcionalmente se encuentra el de ovario y las neoplasias ginecológicas en general. Presentamos un caso de SIADH paraneoplásico por un citoadenocarcinoma seroso de ovario de alto grado, estadio IV. Se trata del primer caso de SIADH crónico por cáncer de ovario tratado con Tolvaptán. En el presente caso el objetivo de eunatremia se alcanzó con una dosis baja de acuarético, lo que apoya la elevada sensibilidad, ya previamente documentada, de los SIADH tumorales al tratamiento con Tolvaptán.

Hyponatremia is the most common electrolyte disturbance in hospitals, and 30% of cases are due to syndrome of inappropriate secretion of antidiuretic hormone (SIADH). SIADH is described as an endocrine paraneoplastic syndrome in multiple tumors including, ovary and gynecological malignancies in general, although these are exceptional. We report a case of paraneoplastic SIADH for high-grade serous ovarian cystoadenocarcinoma stage IV. This is the first case of chronic SIADH for ovarian cancer treated with Tolvaptan. In this case the target of eunatremia was reached with a low dose of aquaretic, which supports the high sensitivity, as previously documented, of paraneoplasic SIADH to Tolvaptan.

Cetuximab in metastatic or recurrent head and neck cancer: the EXTREME trial.

Expression of EGF receptor (EGFR) is frequently elevated in squamous cell carcinoma of the head and neck (SCCHN). Cetuximab is an anti-EGFR monoclonal antibody that has been shown to improve overall survival in patients with locally advanced SCCHN when combined with radiotherapy. Data from Phase II trials suggest an interesting activity of cetuximab in patients with recurrent or metastatic SCCHN who are refractory to cisplatin. The Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer (EXTREME) Phase III trial compared platin-5-fluorouracil alone versus combined with cetuximab as first-line treatment in recurrent or metastatic SCCHN. In the cetuximab arm of this study, a significant improvement in the overall survival (the main objective), progression-free survival and response rate were observed. The quality of life analyses (QLQ-C30 and QLQ-H&N35) showed no significant differences in most of the studied scores between the two treatment arms. Nevertheless, patients in the cetuximab arm displayed significant improvements in pain, swallowing problems and scores for speech and social eating problems. The results of the EXTREME study (and other studies evaluating cetuximab for the treatment of SCCHN) suggest a lack of a predictive value for the expression of EGFR (determined by immunohistochemistry) by the tumor and other biomarkers need to be investigated. The role of other targeted drugs and of possible combinations of these new drugs with cetuximab should be investigated in properly designed preclinical studies and clinical trials.

Prognostic value of cytosolyc cathepsin D content in resectable gastric cancer.

BACKGROUND AND AIMS: Cathepsin D (Cath-D) is an aspartyl protease involved in protein catabolism and tissue remodelling. In the present article, we evaluate the tumor content of Cath-D in resectable gastric carcinomas and its relation with clinical and pathological parameters, as well as its prognostic significance. METHOD: This prospective study included a series of 60 patients with primary gastric adenocarcinoma, who first underwent a complete surgical resection of their tumors and then were evaluated for disease recurrence and survival status during a mean follow-up period of 41.5 months. Cath D was measured in cytosolic samples using an immune-radiometric assay which determined the total amount of Cath-D (52K, 48K, and 34K). RESULTS: The tumor content of Cath-D ranged from 4 to 247 pmol/mg protein and from 6.4 to 97.7 pmol/mg protein in adjacent non-neoplastic mucosa samples. Cytosolic Cath-D levels were significantly higher in neoplastic tissues (P < 0.001). Statistical analysis also demonstrated that younger patients showed lower Cath-D tumor levels than older ones. Likewise, patients with lower tumor levels of Cath-D had better survival than those with intermediate or high Cath-D tumor content (P = 0.002). This finding showed an independent prognostic value on survival (P = 0.02). CONCLUSIONS: The present study demonstrates the presence of higher Cath-D content in gastric carcinomas than in adjacent non-neoplastic mucosa, and that high intratumor Cath-D levels identify a subgroup of resectable gastric cancer patients with a high probability of relapse as well as worse survival.