Use of analgesics and nonsteroidal anti-inflammatory drugs, genetic predisposition, and bladder cancer risk in Spain.

BACKGROUND: We assessed use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAID), aspirin, paracetamol (acetaminophen), phenacetin, and metamizol (dipyrone) and risk of bladder cancer and their interaction with polymorphisms in drug-metabolizing genes. METHODS: We analyzed personal interview data from 958 incident bladder cancer cases and 1,029 hospital controls from a multicenter case-control study in Spain. A drug matrix was developed to estimate cumulative lifetime dose of active ingredients. Polymorphisms in GSTP1, SULT1A1, CYP2E1, CYP2C9, and NAT2 were examined. RESULTS: A significant reduction in bladder cancer risk [adjusted odds ratio (OR), 0.4; 95% confidence interval (95% CI), 0.2-0.9] was observed for regular users of nonaspirin NSAIDs compared with never users. Regular users of aspirin experienced no reduction in risk (OR, 1.0; 95% CI, 0.7-1.5). Regular users of paracetamol had no overall increased risk of bladder cancer (OR, 0.8; 95% CI, 0.4-1.3), but our data suggested a qualitative interaction with the GSTP1 I105V genotype. Subjects with at least one copy of the 359L or 144C variant alleles in the NSAID-metabolizing gene CYP2C9 had a slightly decreased risk of bladder cancer (OR, 0.8; 95% CI, 0.7-1.0; P = 0.037); however, having at least one copy of the 359L or 144C variant alleles did not significantly modify the protective effect of nonaspirin NSAID use. CONCLUSION: Regular use of nonaspirin NSAIDs was associated with a reduced risk of bladder cancer, which was not modified by polymorphisms in the NSAID-metabolizing gene CYP2C9. We found no evidence of an overall effect for paracetamol or aspirin use.     

Cofactors associated with liver disease mortality in an HBsAg-positive Mediterranean cohort: 20 years of follow-up

The risk of developing liver cancer in hepatitis B virus (HBV) carriers differs across geographical areas, suggesting that exposure to other risk factors may contribute to HBV-linked cancer risk. Our study estimates the mortality due to liver disease and the role of other risk factors in a Spanish HBV cohort. 2,352 hepatitis B surface antigen (HBsAg)-positive and 15,504 HBsAg-negative subjects were identified among blood donors during 1972-1985 and were followed until December 2000 through the Mortality Registry. Clinical examination and an epidemiological questionnaire were performed on 1,000 HBsAg-positive survivors during 1994-1996. In subjects deceased from liver disease, medical records were revised and relatives were interviewed. A nested case-control analysis was conducted comparing both groups. In HBsAg-positive men, an excess mortality from liver cancer [standardized mortality ratio (SMR): 14.1; 7.7-23.6], cirrhosis (SMR: 10.5; 7.0-15.1), haematological neoplasms (SMR: 3.2; 1.2-6.9) and AIDS was detected (SMR: 5.5; 2.2-11.4). In women, an excess was found for cirrhosis (SMR: 7.2; 1.4-21.1). Progression factors to liver disease were alcohol intake [odds ratio (OR): 6.3; 3.1-12.8], diabetes (OR: 3.6; 1.3-9.6), HBV replication (OR: 50.0; 14.9-167.3) and hepatitis C virus (HCV) infection (OR: 27.4; 7.1-107.7). In conclusion, in Spain after 20 years of follow-up, chronic HBV exposure appears as a major risk factor for liver cancer among men and for cirrhosis in both sexes. The risk of death from liver disease among HBV carriers with the presence of HBV replication, HCV, alcohol consumption and diabetes was significantly increased and suggests synergism among these exposures and HBV. Mortality from haematological neoplasms was detected and could be associated to HIV coinfection. These results support screening and adequate follow-up among HBsAg-positive subjects at high risk to develop liver disease, particularly when these risk cofactors are present.     

m7FLIPI and targeted sequencing in high‐risk follicular lymphoma

Patients with follicular lymphoma (FL) refractory to front‐line immunochemotherapy (ICT) have a poor overall survival (OS). Gene mutation analysis may be more accurate than classical risk factors to pick out these patients before treatment. This study aimed to describe the prevalence of selected genetic mutations in a cohort of patients with high‐risk FL. Twenty‐five patients with FL refractory to front‐line ICT and 10 non‐refractory patients matched for age, sex, and FLIPI score were included. We sequenced 18 genes (custom targeted sequencing panel) previously reported to potentially have prognostic impact, including the seven genes necessary to determine m7FLIPI risk. The 35 patients had a median age of 62. The FLIPI and FLIPI2 were high in 27 (84%) and 14 (48%), respectively. Three‐year progression‐free survival (PFS) and OS probabilities were 25% (95% CI, 13%‐41%) and 53% (34%‐69%), respectively. There were 73 variants in the 18 genes among the 35 patients. The median number of mutations per patient was 1 (interquartile range, 0‐3). The most commonly mutated genes were CREBBP (11 of 35, 31%) and EP300 (10 of 35, 29%). EP300 mutations were associated with refractoriness to treatment (10 of 25 among refractory and 0 of 10 among non‐refractory). In conclusion, in this study, patients with high‐risk follicular lymphoma were genetically heterogeneous.     

Muscle wasting associated with cancer cachexia is linked to an important activation of the atp-dependent ubiquitin-mediated proteolysis

Rats bearing the Yoshida AH-130 ascites hepatoma for 7 days showed an important decrease in muscle mass—over 30% in gastrocnemius and extensor digitorum longus (EDL)—in relation to non-tumour-bearing controls, which is associated with an increased proteolytic rate-in in vitro incubation. In order to identify the precise biochemical process which was involved, we measured different proteolytic systems in incubated EDL muscles. The capacity for intralysosomal proteolysis, as measured by sensitivity to methylamine, was not increased in tumour-bearing rats, suggesting that the mechanism involved in the increased proteolytic rate was extralysosomal. Incubations using the Ca²⁺ ionophore A23187 revealed no change in the activity of calcium-dependent proteases as a consequence of tumour growth. Finally, muscle incubation in an ATP-depleted medium allowed us to conclude that energy-dependent proteases were involved in the activation of muscle proteolysis in tumour-bearing rats. In particular, the ubiquitin-dependent proteolytic system is involved, since there is an important increase in ubiquitin conjugates in the skeletal muscle of tumour-bearing rats. It may thus be suggested that extralysosomal ATP-and ubiquitin-dependent proteases underlie the biochemical mechanism of muscle wastage associated with cancer cachexia. © 1995 Wiley-Liss, Inc.     

Targeted therapies in thyroid cancer

Differentiated thyroid carcinoma is the most frequent neoplasm of the endocrine system. Although thyroid cancer usually has an excellent prognosis, no therapeutic options are available for patients that develop metastases and are or became resistant to radioiodine therapy. The deeper knowledge of molecular aberrations that characterize tumor growth has provided novel targets in cancer therapy. Several proteins have been implicated as having a crucial role in the carcinogenesis of differentiated thyroid cancer, such as those involved in RET/PTC-RAS-RAF-MAPK pathway. Moreover, vascular aberrations and angiogenesis equilibrium have also been related to tumor growth. The development of new, targeted therapies and their encouraging initial results have opened a hopeful opportunity of treatment for these orphan therapy tumor patients.     

Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition

Journal of Neuro-Oncology - Patients diagnosed with primary central nervous system lymphoma (PCNSL) often face dismal outcomes due to the limited availability of therapeutic options. PCNSL cells...     

Utility of serum tumor markers as an aid in the differential diagnosis of patients with clinical suspicion of cancer and in patients with cancer of unknown primary site

Cancer may be diagnosed in advanced stages, when the patient has already developed metastasis, with symptoms that can be also observed in benign diseases. The objective of this study was to evaluate tumor marker sensitivity and specificity in the differential diagnosis of patients with suspected signs of cancer. We studied 2.711 consecutive patients admitted to the Internal Medicine Department of our hospital with suspected cancer; 1.240 patients had non-malignant processes and 1.471 had malignant disease. Determinations were considered positive for suspected malignancy when serum levels were carcinoembryonic antigen >15 ng/ml (>20 in patients with renal failure or liver disease), alpha fetoprotein >40 ng/ml (>80 ng/ml in patients with liver diseases), carbohydrate antigen (CA) 19.9 > 200 U/ml (>500 U/ml in patients with liver diseases or gamma glutamyl transpeptidase (GGT) <150 UI/L or effusions; >1.000 U/ml in patients with jaundice or GGT > 150 UI/L), neuron-specific enolase >45 ng/ml (renal failure >50 ng/ml; samples with hemolysis were excluded), prostate-specific antigen > 30 ng/ml (excluding acute prostatitis), tumor-associated glycoprotein-72 >80 U/ml, cytokeratin 19 fragment 21-1 > 7.5 ng/ml (>19 ng/ml in patients with renal failure; >11 ng/ml in patients with liver cirrhosis or jaundice), >3.5 ng/ml for squamous cell carcinoma (excluding patients with renal failure or skin disorders), CA 15.3 >100 U/ml, and CA 125 >350 U/ml (>600 U/ml in patients with pleural effusion and >900 U/ml in those with ascites). There was a specificity of 97.6% in patients without malignancy, 67.4% of sensitivity in patients with malignancy, and 75.4% of sensitivity in the 1,280 patients with epithelial tumors (53.7% in patients with locally advanced tumors and 79.4% in patients with metastases). Sensitivity was 81.4% in patients with cancer of unknown primary site. Tumor markers were useful in the differential diagnosis between epithelial and non-epithelial tumors, brain masses (metastases vs. primary tumors), and between benign or malignant origin of different clinical situations such as wasting syndrome, effusions, liver or bone lesions, and effusions with a positive predictive value higher than 95%. Tumor markers are useful as an aid in the evaluation of the risk of cancer of these patients with suspected cancer and may be useful to reduce the hospitalization time, morbidity, and the number of diagnostic tests required for diagnosis.     

Susceptibility genetic variants associated with early-onset colorectal cancer

Colorectal cancer (CRC) is the second most common cancer in Western countries. Hereditary forms only correspond to 5% of CRC burden. Recently, genome-wide association studies have identified common low-penetrant CRC genetic susceptibility loci. Early-onset CRC (CRC<50 years old) is especially suggestive of hereditary predisposition although 85-90% of heritability still remains unidentified. CRC<50 patients (n = 191) were compared with a late-onset CRC group (CRC>65 years old) (n = 1264). CRC susceptibility variants at 8q23.3 (rs16892766), 8q24.21 (rs6983267), 10p14 (rs10795668), 11q23.1 (rs3802842), 15q13.3 (rs4779584), 18q21 (rs4939827), 14q22.2 (rs4444235), 16q22.1 (rs9929218), 19q13.1 (rs10411210) and 20p12.3 (rs961253) were genotyped in all DNA samples. A genotype-phenotype correlation with clinical and pathological characteristics in both groups was performed. Risk allele carriers for rs3802842 [Odds ratio (OR) = 1.5, 95% confidence interval (CI) 1.1-2.05, P = 0.0096, dominant model) and rs4779584 (OR = 1.39, 95% CI 1.02-1.9, P = 0.0396, dominant model) were more frequent in the CRC<50 group, whereas homozygotes for rs10795668 risk allele were also more frequent in the early-onset CRC (P = 0.02, codominant model). Regarding early-onset cases, 14q22 (rs4444235), 11q23 (rs3802842) and 20p12 (rs961253) variants were more associated with family history of CRC or tumors of the Lynch syndrome spectrum excluding CRC. In our entire cohort, sum of risk alleles was significantly higher in patients with a CRC family history (OR = 1.40, 95% CI 1.06-1.85, P = 0.01). In conclusion, variants at 10p14 (rs10795668), 11q23.1 (rs3802842) and 15q13.3 (rs4779584) may have a predominant role in predisposition to early-onset CRC. Association of CRC susceptibility variants with some patient's familiar and personal features could be relevant for screening and surveillance strategies in this high-risk group and it should be explored in further studies.     

Differences between public and private hospital care in Spain: the realities of health care or a numerical fallacy?

OBJECTIVE: To give an example of the misleading interpretations of the concepts "public and private" when dealing with simple data from hospital resources and activities in Spain. MATERIAL AND METHODS: Data comes from the survey of hospitals (EESCRI) for the year 2002 in Catalonia. Using the figures corresponding to resources (number of centers and beds) and activities (discharges, stays, mean stay, occupancy, and rotation) comparisons are made among different variables (managing authority and funding source) reclassified, according to the concepts of public and private. RESULTS: The figures on resources and activities offer a very different portrait about the public or private nature of the care provided, according to the variables being used for classification. CONCLUSIONS: It is necessary to specify the concepts and variables to be used when analyzing the performance of health services and to improve the information sources in order to adapt them to the new management forms of the health services.