Extended prophylaxis with bemiparin for the prevention of venous thromboembolism after abdominal or pelvic surgery for cancer: the CANBESURE randomized study.

BACKGROUND: There is not enough clinical evidence to make a strong recommendation on the optimal duration of thromboprophylaxis using low-molecular weight heparins (LMWH) in patients undergoing major cancer surgery. PATIENTS AND METHODS: CANBESURE is a randomized, double-blind study which enrolled patients admitted for abdominal or pelvic surgery for cancer. They received 3500 IU of bemiparin subcutaneously once daily for 8 days and were then randomized to receive either bemiparin or placebo for 20 additional days. Bilateral venography was performed after 20 days and evaluated blinded. The primary efficacy outcome was the composite of deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE) and all-cause mortality at the end of double-blind period. Major venous thromboembolism (proximal deep-vein thrombosis, non-fatal pulmonary embolism and venous thromboembolism-related deaths) was also evaluated. The primary safety outcome was major bleeding. RESULTS: Six hundred and twenty-five and 488 patients were included in the safety and main efficacy analyzes, respectively. The primary efficacy outcome occurred in 25 out of 248 patients (10.1%) in the bemiparin group and 32 out of 240 (13.3%) in the placebo group (relative risk reduction 24.4%; 95% CI: -23.7-53.8%; P = 0.26). At the end of double-blind period, major venous thromboembolism occurred in 2 (0.8%) and 11 (4.6%) patients, respectively (relative risk reduction 82.4%; 95% CI: 21.5-96.1%; P = 0.010). No significant difference was found in major bleedings. CONCLUSIONS: Four weeks compared with 1 week of prophylaxis with bemiparin after abdominal or pelvic cancer surgery did not significantly reduce the primary efficacy outcome, but decreased major venous thromboembolism (VTE) without increasing hemorrhagic complications.

[Late ischemic stricture following anterior rectal resection]. / Estenosis isquémica tardía tras resección anterior de recto.

A considerable incidence of colonic strictures after oncologic low anterior resections has been reported. The present paper describes a colonic stricture 5 years after the surgery, and not related to radiotherapy, that required a challenging differential diagnosis with local recurrence of rectal cancer. The role of endoscopy in the management of this condition is discussed.

Perianal metastases from lobular breast carcinoma.

Breast cancer gastrointestinal and soft tissue metastases are extremely rare. We present the case of a woman with perianal metastases from a primary lobular breast carcinoma 11 years after mastectomy and local radiotherapy.

Optimal dosing of bemiparin as prophylaxis against venous thromboembolism in surgery for cancer: an audit of practice.

AIMS: Low-molecular-weight heparins are drugs of first choice for thromboprophylaxis in cancer surgery. We sought to determine the optimal use of bemiparin in cancer surgery in standard clinical practice. PATIENTS AND METHODS: A retrospective, multicentre audit on the use of bemiparin in patients undergoing cancer surgery and given prophylaxis with bemiparin was undertaken. Surgeons' assessment of venous thromboembolic (VTE) risk (moderate or high) was compared to the criteria of current Consensus Guidelines for VTE management. We assessed the incidence of documented symptomatic VTE, bleeding events, thrombocytopenia, deaths and total events related to VTE or bemiparin prophylaxis (i.e. bleeding, thrombocytopenia). The potential economic impact of postoperative vs. preoperative bemiparin was also analysed. RESULTS: Clinical records from 197 patients from 5 Spanish centres were checked. Prophylaxis was started postoperatively in 45 patients (22.8%). According to the surgeons' criteria, 73 (37.1%) patients were at high VTE risk and received bemiparin 3500 IU/d. However, according to the criteria of current Guidelines, 189 (95.9%) patients were at high risk of VTE (heterogeneity P-value<0.0001). Three (1.5%) patients, all of them receiving bemiparin 2500 IU/d, developed a symptomatic confirmed VTE. There were 4 major and 5 minor bleeding events during bemiparin prophylaxis. A lower incidence of bleeding (2.2% vs. 5.3%; P=0.48) and total events (2.2% vs. 9.9%; P=0.11) was seen with bemiparin started postoperatively as compared to preoperative bemiparin. Bleeding rates did not significantly differ between patients given low or high bemiparin prophylactic doses (4.0% vs. 5.5%; P=0.72). Two patients died due to cardio-respiratory failure and sepsis, respectively. Postoperative bemiparin provided net cost savings of 909 euro per patient compared to preoperative start of prophylaxis due to shorter hospital stays (9 vs. 11 days) and lower incidence of complications in the postoperative bemiparin group. CONCLUSIONS: Many cancer patients are still poorly assessed for risk of VTE. Bemiparin 3500 IU/d is associated with a lower incidence of VTE without significant increase in complications as compared with bemiparin 2500 IU/d. Postoperative bemiparin prophylaxis seems to be as effective and safer than preoperative start of prophylaxis. Further prospective clinical studies are needed to fully address this issue.

Efficacy of albendazole against Anisakis simplex larvae in vitro.

BACKGROUND: The growing popularity in western countries of eating uncooked seafood has resulted in an increased incidence of anisakidosis. AIM: To study the in vitro activity of different concentrations of albendazole against Anisakis simplex larvae under different media pH. METHODS: A. simplex larvae were obtained from fresh hakes acquired from the fish market of Madrid. They were divided into groups and placed in culture dishes (15 larvae each) containing RPMI-1640, in the presence or absence of different concentrations of albendazole (300, 400 and 500 microg/mL). RESULTS: Albendazole dose-dependently reduced the survival of the larvae, its maximum activity being at 500 microg/mL when it killed almost all larvae at 48 h. Acidic medium pH significantly reduced the efficacy of albendazole. CONCLUSION: Albendazole is effective in killing A. simplex larvae at different pH in vitro, suggesting that this molecule could be useful in treating clinical manifestations of human anisakidosis.

Overexpression of c-myc and loss of heterozygosity on 2p, 3p, 5q, 17p and 18q in sporadic colorectal carcinoma.

AIM: The aim of the present study is to evaluate the prognostic influence of loss of heterozygosity on 2p, 3p, 5q, 17p and 18q, and c-myc overexpression on surgically treated sporadic colorectal carcinoma. METHODS: Tumor and non-tumor tissue samples from 153 patients were analyzed. Fifty-one percent of patients were male, and mean age in the series was 67 years. Tumors were located in the proximal colon in 37 cases, in the distal bowel in 37, and in the rectum in 79 patients. c-myc overexpression was studied by means of Northern blot analysis, and loss of heterozygosity through microsatellite analysis. RESULTS: c-myc overexpression was detected in 25% of cases, and loss of heterozygosity in at least one of the studied regions in 48%. There was no association between clinical and pathologic features, and genetic alterations. The disease-free interval was significantly shorter for patients with both genetic alterations; the presence of both events was an independent prognostic factor for poor outcome in the multivariate analysis (RR: 4.34, p < 0.0001). CONCLUSIONS: The presence of both loss of heterozygosity and overexpression of the c-myc oncogene separates a subset of colorectal carcinoma patients who have a shorter disease-free interval after curative-intent surgery.

Clinical relevance of MMP-9, MMP-2, TIMP-1 and TIMP-2 in colorectal cancer.

The main aim of this study was to evaluate the clinical relevance of Gelatinases in colorectal cancer (CRC). Ninety-five CRCs and their paired normal tissues were investigated to detect total levels of MMP-9, MMP-2, and the tissue inhibitors TIMP-1 and TIMP-2. Also, pro-MMP and MMP activity, and potential associations with clinical parameters were estimated. MMP-9, MMP-2 and TIMP-1 levels were greater in CRCs than in normal tissues, differences being significant for MMP-9 and TIMP-1. However, TIMP-2 showed significantly lower levels in tumour samples. Moreover, significant differences in the state of activation between gelatinases were found. TIMP-1 low levels were significantly associated with poor clinical outcome of patients. According to these data, different roles have to be attributed to MMP-2 and MMP-9 in CRC progression. Moreover, TIMP-1 level evaluation emerges as the main prognostic factor in relation to Gelatinases A and B activity in CRC.

Non-heart-beating donation: current state of the art.

The use of non-heart-beating donors (NHBD) helps us to deal with the problem of the organ shortage. In addition to difficulties with legal and ethical acceptability, there are concerns regarding medical safety, which prevent the widespread use of these donors. To make optimum use of this potential organ supply, the ischemic injury that occurs after a period of warm ischemia needs to be reversed. To minimize the warm ischemia time, once the subject is declared dead, most centers commence in situ cold perfusion via a femoral access or a rapid aortic cannulation. This usually occurs within minutes of arriving at the emergency department, before the next of kin have been notified of the patient's death. The European experience of kidney transplantation from NHBD shows promising results. The long-term outcomes are similar to HBD kidneys notwithstanding a higher rate of delayed graft function, which seems not to affect the long-term survival of these kidneys. In summary, NHBD may have an important impact on the large discrepancy that exists between the organ supply and the demand. Current data suggest that the results may be further improved by better patient selection and retrieval team organization.

Prognostic significance of the p185 protein in colorectal cancer.

The amplification and/or overexpression of the c-erbB-2/neu oncogene may play a role in tumor development and progression. The aim of this prospective study was to evaluate the prognostic value of p185 protein in colorectal cancer using immunohistochemical techniques. We analyzed 106 colorectal tumor tissue specimens from patients who had been operated on by the same surgeon and subjected to a median follow-up of 3 years. Thirty-three per cent of patients showed p185 overexpression related to an advanced stage of the disease. In patients with adenocarcinoma tumors of the colon without distant metastases, p185 detection was found to be of clinical prognostic relevance (p = 0.06).

Relationship between 3p deletions and telomerase activity in non-small-cell lung cancer: prognostic implications.

3p deletions and telomerase reactivation are two of the most frequent events described in relation to non-small-cell lung cancer (NSCLC) pathogenesis. Moreover, a number of genes that map on 3p have been proposed as candidates to tumour-suppressor genes of importance in the lung cancer process. In this work, we analysed deletions at different 3p loci in relationship to telomerase activity in 66 NSCLCs obtained from patients who had suffered potentially curative surgery. Also, we evaluated prognostic implications. DNA samples were analysed for 3p deletions using five different polymorphic human dinucleotide repeat DNA markers (D3S1619 at 3p22.2, D3S3623 at 3p22.1, D3S1260 at 3p21.33, D3S3697 at 3p14.3, and D3S3722 at 3p21.2). Telomerase activity was investigated by a TRAP-based method. Possible correlations between the different molecular markers and distributions of disease-free survival were estimated. Our data revealed a significant correlation between telomerase activity and losses of heterozygosity (LOH) on D3S3697 (P=0.040), since all of the tumours showing deletion at this locus were positives for telomerase. Moreover, our results revealed clear associations with poor prognosis of patients, in the case of LOH at D3S1260 and D3S3697 (P=0.005 and 0.005, respectively). According to our data, potential repressors for telomerase may be located in chromosome 3p.

3p21, 5q21, and 9p21 allelic deletions are frequently found in normal bronchial cells adjacent to non-small-cell lung cancer, while they are unusual in patients with no evidence of malignancy.

Molecular cytogenetic and loss of heterozygosity (LOH) analyses of non-small-cell lung cancer (NSCLC) have shown frequent allelic deletions in a variety of chromosomes, such as 1p, 3p, 5q, 8p, 9p, 11p, 11q, and 17p. Allelic loss at 3p21, 9p21, and 5q21 has also been reported in premalignant epithelial lesions of the bronchus and in normal bronchial cells. These findings suggest that a tissue field of somatic genetic alterations precedes the histopathological phenotypic changes of carcinoma. LOH at chromosomal regions 3p21, 5q21, 9p21, and 17p (TP53) was looked for in the peritumoural normal bronchial cells from 30 archival surgically resected tumours. Microdissected normal bronchial cells from 20 benign cytological smears were also added to the study. Matched populations of lymphocytes, tumour cells, and normal bronchial cells adjacent to the tumour were microdissected from paraffin-embedded tissues, while matched populations of normal bronchial cells and inflammatory cells were microdissected from benign cytological smears (bronchial brushings). Polymerase chain reaction (PCR) amplification was performed utilizing the specific markers D5S346, D3S1300, D9S157, D9S171, and TP53. Within the NSCLC tumour cells, LOH was more frequently found at the 5q21 locus (72% of the informative cases), the 3p21 locus (47%), 9p21 (48%), and 17p (33%). Within the peritumoural normal bronchial cells, LOH at 5q21 was found in 37.5% of the cases, 22% showed LOH at 3p21, 27% at 9p21, and 13% at 17p (TP53). LOH was also detected in one case, in normal bronchial cells obtained from cytological smears at one locus (5q21). In conclusion, normal bronchial mucosa adjacent to NSCLC has frequent allelic losses at 3p21, 5q21, and 9p21, while LOH at these loci is unusual in normal bronchial cells obtained from cytological smears from patients with no evidence of malignancy. LOH at these loci may be present before the onset of the malignant growth. LOH studies may supplement the histopathological evaluation of bronchial cells to detect genotypic alterations in both cytological and biopsy specimens.

Glucagon-like peptide-1(7-36) amide stimulates surfactant secretion in human type II pneumocytes.

To determine the influence of glucagon-like peptides on the secretion of human pulmonary surfactant, we used human type II pneumocytes. In these cells, GLP-1(7-36) amide and exendin-4 stimulated phosphatidylcholine secretion (PC) and cAMP formation in a concentration-dependent manner; these effects were reversed by exendin(9-39). No changes were observed with other related peptides. The mechanism by which GLP-1(7-36) amide exerts its stimulatory effect was investigated with various agents that are well known to be stimulators or inhibitors of PC secretion. Thus, 8-bromo-cAMP increased and both Rp-cAMPS and H-89, the latter an inhibitor of protein kinase A (PKA), reduced pulmonary surfactant secretion in type II pneumocytes. Also, GLP-1(7-36) amide and TPA exerted additive effects in stimulating PC secretion, and Calph C, a potent inhibitor of protein kinase C (PKC), blocked most of the effect of GLP-1(7-36) amide. By contrast, both the calcium ionophore A23187 and GLP-1(7-36) amide had additive effects in increasing PC secretion, and the specific inhibitor of Ca(2+)-calmodulin-dependent protein kinase (Ca-CM-PK), KN-62, inhibited the effect of A23187 but did not alter the stimulatory action of GLP-1(7-36) amide. Our findings suggest that both PKA and PKC are involved in the stimulatory effects of GLP-1(7-36) amide on PC secretion, whereas this peptide has no effect on PC secretion through a Ca-CM-PK mechanism.

Cefminox versus metronidazole plus gentamicin intra-abdominal infections: a prospective randomized controlled clinical trial.

BACKGROUND: The aim of this prospective study was to compare the safety and efficacy of a new cephamycin, cefminox 2 g/12 h, to those of the usual regimen combining metronidazole 500 mg/8 h and gentamicin 80 mg/8 h (M+G). PATIENTS AND METHODS: 160 patients with clinically proven intra-abdominal infection were prospectively included in an open parallel randomized comparative multicenter trial. Antibiotics were started preoperatively and discontinued after clinical and laboratory evidence of resolution of the infection. Serum and peritoneal fluid levels and serum bactericidal activities were also studied. RESULTS: 150 patients were clinically evaluable. There was one failure in the cefminox group and three in the M+G group (not significant, RR: 1.07, 95% CI: 1-1.15). No differences were found in the number of wound infections, length of stay or duration of antibiotic therapy. Adverse effects were reported in 11 cases, all of them mild to moderate. Escherichia coli and Bacteroides fragilis were the most frequently found microorganisms. CONCLUSION: Cefminox is as effective and as safe as M+G in the treatment of intra-abdominal infections.

Effect of surfactant protein A (SP-A) on the production of cytokines by human pulmonary macrophages.

Surfactant protein A (SP-A) is thought to play a role in the modulation of lung inflammation during acute respiratory distress syndrome (ARDS). However, SP-A has been reported both to stimulate and to inhibit the proinflammatory activity of pulmonary macrophages (Mphi). Because of the interspecies differences and heterogeneity of Mphi subpopulations used may have influenced previous controversial results, in this study, we investigated the effect of human SP-A on the production of cytokines and other inflammatory mediators by two well-defined subpopulations of human pulmonary Mphi. Surfactant and both alveolar (aMphi) and interstitial (iMphi) macrophages were obtained from multiple organ donor lungs by bronchoalveolar lavage and enzymatic digestion. Donors with either recent history of tobacco smoking, more than 72 h on mechanical ventilation, or any radiological pulmonary infiltrate were discarded. SP-A was purified from isolated surfactant using sequential butanol and octyl glucoside extractions. After 24-h preculture, purified Mphi were cultured for 24 h in the presence or absence of LPS (10 microg/mL), SP-A (50 microg/mL), and combinations. Nitric oxide and carbon monoxide (CO) generation (pmol/microg protein), cell cGMP content (pmol/microg protein), and tumor necrosis factor alpha (TNFalpha), interleukin (IL)-1, and IL-6 release to the medium (pg/microg protein) were determined. SP-A inhibited the lipopolysaccharide (LPS)-induced TNFalpha response of both interstitial and alveolar human Mphi, as well as the IL-1 response in iMphi. The SP-A effect on TNFalpha production could be mediated by a suppression in the LPS-induced increase in intracellular cGMP. In iMphi but not in aMphi, SP-A also inhibited the LPS-induced IL-1 secretion and CO generation. These data lend further credit to a physiological function of SP-A in regulating alveolar host defense and inflammation by suggesting a fundamental role of this apoprotein in limiting excessive proinflammatory cytokine release in pulmonary Mphi during ARDS.

Loss of heterozygosity at 3p23 is correlated with poor survival in patients with colorectal carcinoma.

BACKGROUND: Loss of heterozygosity (LOH) of chromosome 3p has been observed commonly in carcinomas of various tumor tissues, including colorectal carcinoma (CRC). Because there is no report analyzing 3p deletions in relation to patient prognosis in CRC, the authors investigated the prognostic value of LOH on 3p in 87 patients with sporadic CRC. METHODS: DNA samples from tumor and nontumor tissues were amplified by using polymerase chain reaction (PCR) and were analyzed for LOH on 3p using four different polymorphic human dinucleotide repeat DNA markers that map on this chromosome arm. The correlations with prognosis were established by the Kaplan-Meier method, and the Cox proportional hazards model was used to identify which independent factors jointly had a significant influence on patient survival. RESULTS: Overall, allelic losses were detected in 19.5% of the patients evaluated. Only considering informative tumors, the data indicated that LOH was observed in 17 of 71 (29.4%) informative cases. Results from survival analysis showed a significant correlation between this molecular abnormality and both overall survival and disease free survival (P = 0.02 and P = 0.0005, respectively). The worst prognosis was found for the group of patients with LOH at 3p23: This alteration was an independent prognostic factor according to Cox multivariate analysis. CONCLUSIONS: This study is the first to demonstrate the prognostic significance of LOH at chromosome arm 3p for patients CRC and may help to identify patients who need an intensive postoperative follow-up protocol.

Prognostic value of the quantified expression of p185 in non-small cell lung cancer.

BACKGROUND: We sought to assess the relationship between tissue concentration of erb -b-2 or neu oncogene-encoded protein (p185(neu)) with overall survival in patients with non-small cell lung cancer. METHODS: Levels of protein p185(neu) were determined in 102 patients with the diagnosis of non-small cell lung cancer. Concentration of p185(neu) protein was determined by using enzyme immunoassay and evaluated by using several variables. The relative prognostic importance of this marker and its influence on other prognostic factors was evaluated by using the Cox regression model. RESULTS: The mean p185(neu) value in these samples was 250 +/- 200 U/mg (95% confidence interval, 210-290). This distinguished two groups within the tumoral population: those with less than 350 U/mg and those with 350 U/mg or greater (80th percentile). Multivariable analysis established an independent prognostic value for protein p185(neu). Patients with p185(neu) values of the 80th percentile or greater had a risk of death that was 2.11-fold (95% confidence interval, 1.10-4.05) that of patients with values of less than 350 U/mg (P =.03), and increases in the neu oncogene of 100 U/mg increased the probability of death by 17% (P =.02; 95% confidence interval, 1.04-1.31). CONCLUSION: This study shows that the p185(neu) expression is an objective and comparable variable for the assessment of phenotypic aggressivity in non-small cell lung cancer, and in the future, it could be included in daily clinical practice.

Detection of telomerase activity in human carcinomas using a trap-ELISA method: correlation with hTR and hTERT expression.

We have evaluated telomerase activity in a tumour population of 65 human cancers by using a TRAP-based method, in which detection is performed by an enzyme immunoassay (ELISA). We have corroborated that sensitivity and specificity of this new procedure can be considered similar to that of classical TRAP method, having the advantage of a rapid and reproducible analysis of large pools of samples. Thus, telomerase activity was detected in 83% of the tumours included in our population. Moreover, we found a significant association between enzyme activity and both hTR and hTERT expression (P=0.004 and P=0.04, respectively).

LOH at the APC/MCC gene (5Q21) is frequent in early stages of non-small cell lung cancer.

Lung cancer is the leading cause of death in both women and men in the United States and many European countries. Molecular cytogenetic and LOH analyses of non-small cell lung cancer have shown somatic genetic alterations in a variety of chromosomes, such as 1p, 3p, 5q, 8p, 9p, 11p, 11q and 17p. Allelic deletions of the known tumor suppressor gene APC at 5q21 are frequently observed in advanced stages of lung cancer and have been correlated with poor prognosis in previous reports. We investigated 33 cases of NSCL for LOH at 5q21: 22 squamous cell and 11 adenocarcinomas. Normal and tumor cells were microdissected from paraffin embedded tissues and PCR amplification was performed utilising the specific markers D5S299 and D5S346 at 5q21 and PYGM at 11q13, respectively. Clinicopathological data, survival and recurrence rates were obtained in all cases. We detected LOH at 5q21 in 4/9 (44%) informative adenocarcinomas and in 13/16 (81%) informative SCC. LOH was frequent in early stages (12/15 stage I cases) and did not correlate with recurrence or poor survival. Our results show that LOH at 5q21 is more frequent in squamous cell carcinomas than in adenocarcinomas, is frequent in early stages of the disease, and does not have prognostic significance.