Autologous Haematopoietic Stem Cell Transplantation for Refractory Crohn's Disease: Efficacy in a Single-Centre Cohort.

BACKGROUND: Haematopoietic stem cell transplantation [HSCT] is considered a therapeutic option for patients with severe Crohn's disease [CD] unresponsive to currently available therapies. METHODS: Autologous HSCT was considered for CD patients with active disease, unresponsive or intolerant to approved medications and unsuitable for surgery. After HSCT, patients were closely followed up every 6 weeks during the first 2 years and every 6 months thereafter up to 5 years. Colonoscopy and/or magnetic resonance imaging were performed at Months 6, 12, 24, and 48 after HSCT. RESULTS: From December 1, 2007 to December 31, 2015, 37 CD patients were assessed for HSCT. Of these, 35 patients [13 within the ASTIC trial] underwent mobilisation. Six patients did not complete the transplant for various reasons and 29 patients were finally transplanted. Patients were followed up during a median of 12 months [6-60]. At 6 months, 70% of patients achieved drug-free clinical remission (Crohn's Disease Index of Severity [CDAI] < 150). The proportion of patients in drug-free remission (CDAI < 150, Simple Endoscopic activity Score [SES]-CD < 7] was 61% at 1 year, 52% at 2 years, 47% at 3 years, 39% at 4 years, and 15% at 5 years. Patients who relapsed were re-treated and 80% regained clinical remission. Six out of the 29 [21%] required surgery. One patient died due to systemic cytomegalovirus infection 2 months after transplant. CONCLUSIONS: HSCT is a salvage therapy for patients with extensive and refractory CD. Although relapse occurs in a majority of patients within 5 years after transplant, drug responsiveness is regained and clinical remission achieved in 80% of cases.

IV Conferencia Española de Consenso sobre el tratamiento de la infección por Helicobacter pylor / IV Spanish Consensus Conference on Helicobacter pyloriinfection treatment

La infección por Helicobacter pylori afecta aproximadamente al 50% de la población española y es causante de la gastritis crónica, la úlcera péptica y el cáncer gástrico. Se han llevado a cabo hasta el momento, en nuestro país, 3 reuniones de Consenso sobre el manejo de la infección por H. pylori (la última de ellas en 2012). Los cambios en los esquemas de tratamiento y la creciente evidencia disponible al respecto han justificado la organización de esta IV Conferencia Española de Consenso en marzo de 2016, centrada en el tratamiento de esta infección. Participaron 19 expertos sobre el tema, que realizaron una búsqueda sistemática de la evidencia científica y elaboraron una serie de recomendaciones que fueron sometidas a un proceso de interacción de votaciones anónimas seriadas mediante metodología Delphi. Para clasificar la evidencia científica y la fuerza de las recomendaciones se utilizó el sistema GRADE. Este consenso establece, como punto de partida, un aumento de la exigencia en la eficacia de los tratamientos recomendados, que deben alcanzar, o preferiblemente superar, el 90% de curación al ser administrados de forma empírica. De este modo, tanto en primera como en segunda línea se recomiendan tratamientos cuádruples con o sin bismuto, generalmente prescritos durante 14días. El tratamiento cuádruple sin bismuto concomitante, que incluye un inhibidor de la bomba de protones, claritromicina, amoxicilina y metronidazol, se recomienda como primera línea. En el presente consenso se revisan también con detalle otras alternativas de tratamiento tanto de primera línea como de rescate

Helicobacter pylori approximately infect 50% of Spanish population and causes chronic gastritis, peptic ulcer and gastric cancer. Until now, three consensus meetings on H. pyloriinfection had been performed in Spain (the last in 2012). The changes in the treatment schemes, and the increasing available evidence, have justified organizing the IV Spanish Consensus Conference (March 2016), focused on the treatment of this infection. Nineteen experts participated, who performed a systematic review of the scientific evidence and developed a series of recommendation that were subjected to an anonymous Delphi process of iterative voting. Scientific evidence and the strength of the recommendation were classified using GRADE guidelines. As starting point, this consensus increased the minimum acceptable efficacy of recommended treatments that should reach, or preferably surpass, the 90% cure rate when prescribed empirically. Therefore, only quadruple therapies (with or without bismuth), and generally lasting 14 days, are recommended both for first and second line treatments. Non-bismuth quadruple concomitant regimen, including a proton pump inhibitor, clarithromycin, amoxicillin and metronidazole, is recommended as first line. In the present consensus, other first line alternatives and rescue treatments are also reviewed and recommended

IV Spanish Consensus Conference on Helicobacter pylori infection treatment. / IV Conferencia Española de Consenso sobre el tratamiento de la infección por Helicobacter pylori.

Helicobacter pylori approximately infect 50% of Spanish population and causes chronic gastritis, peptic ulcer and gastric cancer. Until now, three consensus meetings on H.pylori infection had been performed in Spain (the last in 2012). The changes in the treatment schemes, and the increasing available evidence, have justified organizing the IVSpanish Consensus Conference (March 2016), focused on the treatment of this infection. Nineteen experts participated, who performed a systematic review of the scientific evidence and developed a series of recommendation that were subjected to an anonymous Delphi process of iterative voting. Scientific evidence and the strength of the recommendation were classified using GRADE guidelines. As starting point, this consensus increased the minimum acceptable efficacy of recommended treatments that should reach, or preferably surpass, the 90% cure rate when prescribed empirically. Therefore, only quadruple therapies (with or without bismuth), and generally lasting 14 days, are recommended both for first and second line treatments. Non-bismuth quadruple concomitant regimen, including a proton pump inhibitor, clarithromycin, amoxicillin and metronidazole, is recommended as first line. In the present consensus, other first line alternatives and rescue treatments are also reviewed and recommended.

Improving safety of autologous haematopoietic stem cell transplantation in patients with Crohn's disease.

OBJECTIVE: To evaluate the feasibility and toxicity of autologous haematopoietic stem cell transplantation (HSCT) for the treatment of refractory Crohn's disease (CD). DESIGN: In this prospective study, patients with refractory CD suffering an aggressive disease course despite medical treatment, impaired quality of life and in whom surgery was not an acceptable option underwent HSCT. Toxicity and complications during the procedure and within the first year following transplantation were evaluated, along with the impact of the introduction of supportive measures on safety outcomes. RESULTS: 26 patients were enrolled. During mobilisation, 16 patients (62%) presented febrile neutropaenia, including one bacteraemia and two septic shocks. Neutropaenia median time after mobilisation was 5 days. 5 patients withdrew from the study after mobilisation and 21 patients entered the conditioning phase. Haematopoietic recovery median time for neutrophils (>0.5×10(9)/L) was 11 days and for platelets (>20×10(9)/L) 4 days. Twenty patients (95%) suffered febrile neutropaenia and three patients (27%) presented worsening of the perianal CD activity during conditioning. Among non-infectious complications, 6 patients (28.5%) presented antithymocyte globulin reaction, 12 patients (57%) developed mucositis and 2 patients (9.5%) had haemorrhagic complications. Changes in supportive measures over the study, particularly antibiotic prophylaxis regimes during mobilisation and conditioning, markedly diminished the incidence of severe complications. During the first 12-month follow-up, viral infections were the most commonly observed complications, and one patient died due to systemic cytomegalovirus infection. CONCLUSIONS: Autologous HSCT for patients with refractory CD is feasible, but extraordinary supportive measures need to be implemented. We suggest that this procedure should only be performed in highly experienced centres.

Outcomes of treatment for achalasia depend on manometric subtype.

BACKGROUND & AIMS: Patients with achalasia are treated with either pneumatic dilation (PD) or laparoscopic Heller myotomy (LHM), which have comparable rates of success. We evaluated whether manometric subtype was associated with response to treatment in a large population of patients treated with either PD or LHM (the European achalasia trial). METHODS: Esophageal pretreatment manometry data were collected from 176 patients who participated in the European achalasia trial. Symptoms (weight loss, dysphagia, retrosternal pain, and regurgitation) were assessed using the Eckardt score; treatment was considered successful if the Eckardt score was 3 or less. Manometric tracings were classified according to the 3 Chicago subtypes. RESULTS: Forty-four patients had achalasia type I (25%), 114 patients had achalasia type II (65%), and 18 patients had achalasia type III (10%). After a minimum follow-up period of 2 years, success rates were significantly higher among patients with type II achalasia (96%) than type I achalasia (81%; P < .01, log-rank test) or type III achalasia (66%; P < .001, log-rank test). The success rate of PD was significantly higher than that of LHM for patients with type II achalasia (100% vs 93%; P < .05), but LHM had a higher success rate than PD for patients with type III achalasia (86% vs 40%; P = .12, difference was not statistically significant because of the small number of patients). For type I achalasia, LHM and PD had similar rates of success (81% vs 85%; P = .84). CONCLUSIONS: A higher percentage of patients with type II achalasia (based on manometric tracings) are treated successfully with PD or LHM than patients with types I and III achalasia. Success rates in type II are high for both treatment groups but significantly higher in the PD group. Patients with type III can probably best be treated by LHM. Trialregister.nl number NTR37; ISRCTN56304564.

Utilidad de la biopsia endoscópica en el esófago de Barrett / Usefulness of endoscopic biopsy in Barrett's esophagus

Fundamento y objetivo: La endoscopia con obtención de biopsias múltiples es la técnica estándar para el diagnóstico y seguimiento del esófago de Barrett (EB). El objetivo de este trabajo fue estudiar la utilidad de las biopsias endoscópicas en el diagnóstico y seguimiento de los pacientes con EB. Pacientes y método: Estudio retrospectivo de todos los pacientes con EB controlados en el Hospital Clínic desde febrero de 2002 hasta marzo de 2010. Resultados: En el período de estudio se realizaron 493 endoscopias a 206 pacientes. Se excluyeron 86 pacientes a los que se les había realizado solo una endoscopia, siendo la muestra final de 117 pacientes (edad media [DE] de 61 [12] años y 73% de varones) con 407 endoscopias y un tiempo medio de seguimiento de 45 (38) meses. Un total de 57 pacientes tenían un EB corto (49%), 28 un EB largo (24%) y en 32 (27%) no se pudo deducir del informe. En 25 casos (21%) no se detectó metaplasia intestinal (MI) en la endoscopia inicial. Durante el seguimiento, las biopsias fueron negativas para MI en algún momento en 45 pacientes (38,4%) y se produjo un cambio en el grado histológico en 100 ocasiones (24,6%). La presencia de un EB corto (43% en EB corto frente a 7% en EB largo; p=0,001) y un menor número de biopsias (media de 3 [1,5] frente a 6,2 [4,5], p=0,005) se asociaron a una mayor frecuencia de biopsias negativas para MI. Conclusión: Las biopsias endoscópicas múltiples no son una buena herramienta para el diagnóstico y seguimiento de los pacientes con EB (AU)

Background and objetive: Endoscopy with random biopsies is the standard technique for the diagnosis of Barrett's esophagus (BE). We studied the usefulness of endoscopic biopsies in the diagnosis and surveillance of patients with BE.Patients: We reviewed all patients with BE controlled at the Hospital Clínic from February 2002 to March 2010. Results: During the study period, 493 endoscopies were performed in 206 patients. We excluded 86 patients who had undergone one endoscopy only, hence the final sample consisted of 117 patients (mean age 61 [12] years, 73% men) with 407 endoscopies and a mean follow-up of 45 (38) months. Fifty-seven patients had a short-BE (49%), 28 a long-BE (24%) and 32 (27%) could not be inferred from the report. In 25 cases (21%), intestinal metaplasia (IM) was not detected at the endoscopic index. During follow-up, biopsies were negative for IM at some point in 45 patients (38.4%) and there was a change in the histologic grade in 100 cases (24.6%). The presence of a short-BE (43% in short-BE vs 7% in long-BE, P=.001) and few biopsies (3 [1.5] vs 6.2 [4.5]; P=.005) were associated with a higher frequency of negative biopsies for IM. Conclusion: Random endoscopic biopsies are not a good tool for diagnosis and surveillance of patients with BE (AU)

[Usefulness of endoscopic biopsy in Barrett's esophagus]. / Utilidad de la biopsia endoscópica en el esófago de Barrett.

BACKGROUND AND OBJECTIVE: Endoscopy with random biopsies is the standard technique for the diagnosis of Barrett's esophagus (BE). We studied the usefulness of endoscopic biopsies in the diagnosis and surveillance of patients with BE. PATIENTS: We reviewed all patients with BE controlled at the Hospital Clínic from February 2002 to March 2010. RESULTS: During the study period, 493 endoscopies were performed in 206 patients. We excluded 86 patients who had undergone one endoscopy only, hence the final sample consisted of 117 patients (mean age 61 [12] years, 73% men) with 407 endoscopies and a mean follow-up of 45 (38) months. Fifty-seven patients had a short-BE (49%), 28 a long-BE (24%) and 32 (27%) could not be inferred from the report. In 25 cases (21%), intestinal metaplasia (IM) was not detected at the endoscopic index. During follow-up, biopsies were negative for IM at some point in 45 patients (38.4%) and there was a change in the histologic grade in 100 cases (24.6%). The presence of a short-BE (43% in short-BE vs 7% in long-BE, P=.001) and few biopsies (3 [1.5] vs 6.2 [4.5]; P=.005) were associated with a higher frequency of negative biopsies for IM. CONCLUSION: Random endoscopic biopsies are not a good tool for diagnosis and surveillance of patients with BE.

Pneumatic dilation versus laparoscopic Heller's myotomy for idiopathic achalasia.

BACKGROUND: Many experts consider laparoscopic Heller's myotomy (LHM) to be superior to pneumatic dilation for the treatment of achalasia, and LHM is increasingly considered to be the treatment of choice for this disorder. METHODS: We randomly assigned patients with newly diagnosed achalasia to pneumatic dilation or LHM with Dor's fundoplication. Symptoms, including weight loss, dysphagia, retrosternal pain, and regurgitation, were assessed with the use of the Eckardt score (which ranges from 0 to 12, with higher scores indicating more pronounced symptoms). The primary outcome was therapeutic success (a drop in the Eckardt score to ≤3) at the yearly follow-up assessment. The secondary outcomes included the need for retreatment, pressure at the lower esophageal sphincter, esophageal emptying on a timed barium esophagogram, quality of life, and the rate of complications. RESULTS: A total of 201 patients were randomly assigned to pneumatic dilation (95 patients) or LHM (106). The mean follow-up time was 43 months (95% confidence interval [CI], 40 to 47). In an intention-to-treat analysis, there was no significant difference between the two groups in the primary outcome; the rate of therapeutic success with pneumatic dilation was 90% after 1 year of follow-up and 86% after 2 years, as compared with a rate with LHM of 93% after 1 year and 90% after 2 years (P=0.46). After 2 years of follow-up, there was no significant between-group difference in the pressure at the lower esophageal sphincter (LHM, 10 mm Hg [95% CI, 8.7 to 12]; pneumatic dilation, 12 mm Hg [95% CI, 9.7 to 14]; P=0.27); esophageal emptying, as assessed by the height of barium-contrast column (LHM, 1.9 cm [95% CI, 0 to 6.8]; pneumatic dilation, 3.7 cm [95% CI, 0 to 8.8]; P=0.21); or quality of life. Similar results were obtained in the per-protocol analysis. Perforation of the esophagus occurred in 4% of the patients during pneumatic dilation, whereas mucosal tears occurred in 12% during LHM. Abnormal exposure to esophageal acid was observed in 15% and 23% of the patients in the pneumatic-dilation and LHM groups, respectively (P=0.28). CONCLUSIONS: After 2 years of follow-up, LHM, as compared with pneumatic dilation, was not associated with superior rates of therapeutic success. (European Achalasia Trial Netherlands Trial Register number, NTR37, and Current Controlled Trials number, ISRCTN56304564.).

Cyclooxygenase 2 expression in colorectal cancer with DNA mismatch repair deficiency.

BACKGROUND: Cyclooxygenase 2 (COX-2) overexpression is a frequent but not universal event in colorectal cancer. It has been suggested that COX-2 protein expression is reduced in colorectal cancer with a defective mismatch repair (MMR) system, a phenomenon commonly associated with hereditary nonpolyposis colorectal cancer (HNPCC) but also present in up to 15% of sporadic tumors. AIM: To assess COX-2 expression in a large series of fully characterized colorectal cancer patients with respect to the MMR system and to dissect the mechanisms responsible for altered COX-2 expression in this setting. PATIENTS AND METHODS: MMR-deficient colorectal cancer were identified in a nationwide, prospective, multicenter study (EPICOLON project). Control MMR-proficient colorectal cancer patients were randomly selected. COX-2 expression was evaluated by immunohistochemistry. Personal and familial characteristics, as well as MSH2/MLH1 expression and germ line mutations, were evaluated. RESULTS: One hundred fifty-three patients, 46 with MMR deficiency and 107 with MMR proficiency, were included in the analysis. Overall, tumor COX-2 overexpression was observed in 107 patients (70%). COX-2 overexpression was observed in 85 patients (79%) with a MMR-proficient system, but only in 22 patients (48%) with a MMR-deficient colorectal cancer (P < 0.001). The lack of COX-2 overexpression was independently associated with a MMR-deficient system (odds ratio, 3.89; 95% confidence interval, 1.78-8.51; P = 0.001) and a poor degree of differentiation (OR, 3.83; 95% CI, 1.30-11.31; P = 0.015). In the subset of patients with a MMR-deficient colorectal cancer, lack of COX-2 overexpression correlated with a poor degree of differentiation, no fulfillment of Amsterdam II criteria, absence of MSH2/MLH1 germ line mutations, presence of tumor MSH2 expression, and lack of tumor MLH1 expression. CpG island promoter hypermethylation of COX2 was observed in 6 of 18 (33%) tumors lacking COX-2 expression in comparison with 2 of 28 (7%) tumors expressing this protein (P = 0.04). CONCLUSIONS: Up to half of MMR-deficient colorectal cancer do not show COX-2 overexpression, a fact observed almost exclusively in patients with sporadic forms. COX2 hypermethylation seems to be responsible for gene silencing in one third of them. These results suggest the potential utility of nonsteroidal anti-inflammatory drugs in HNPCC chemoprevention and may explain the lack of response of this approach in some sporadic tumors.

Effects of Helicobacter pylori eradication on platelet activation and disease recurrence in patients with acute coronary syndromes.

BACKGROUND: Platelet activation is consistently observed in animal models of Helicobacter pylori infection and could help to explain the alleged epidemiological association between H. pylori and coronary heart disease. MATERIALS AND METHODS: Ninety-two patients with recent acute coronary syndromes were enrolled. Helicobacter pylori-positive patients were randomized to receive a 7-day course of omeprazole, amoxycillin and metronidazole or placebos. Two months later, H. pylori status was reassessed and baseline parameters, including soluble P-selectin and platelet surface expression of CD62P, CD63 and CD41, were measured again. Patients were followed-up for 1 year or until death or readmission. RESULTS: No baseline differences were observed between H. pylori-positive and -negative cases. Among H. pylori-positive patients, 18 received placebo and 31 received active medication resulting in eradication in 21 cases. No differences were observed in inflammatory parameters or platelet activation markers between patients with persistent or resolved H. pylori infection. However, coronary events recurred at 6 and 12 months, respectively, in 35% and 55% of patients with persisting H. pylori infection compared with 10% and 25% of patients in whom H. pylori was either absent or eradicated (p = .01). Only final H. pylori status [RR 3.07 (95% CI 1.35-98)] and number of coronary risk factors [RR 2.58 (95% CI 1.51-4.41)] were independent predictors of recurrence. CONCLUSIONS: Infection with H. pylori does not induce significant platelet activation in patients treated for coronary disease. Helicobacter pylori-infected patients, however, may have an increased risk of recurrence of coronary events.

A tumor-associated glycoprotein that blocks MHC class II-dependent antigen presentation by dendritic cells.

Tumors evade immune surveillance despite the frequent expression of tumor-associated Ags (TAA). Tumor cells escape recognition by CD8(+) T cells through several mechanisms, including down-regulation of MHC class I molecules and associated Ag-processing machinery. However, although it is well accepted that optimal anti-tumor immune responses require tumor-reactive CD4(+) T cells, few studies have addressed how tumor cells evade CD4(+) T cell recognition. In this study, we show that a common TAA, GA733-2, and its murine orthologue, mouse epithelial glycoprotein (mEGP), function in blocking MHC class II-restricted Ag presentation by dendritic cells. GA733-2 is a common TAA that is expressed normally at low levels by some epithelial tissues and a subset of dendritic cells, but at high levels on colon, breast, lung, and some nonepithelial tumors. We show that ectopic expression of mEGP or GA733-2, respectively, in dendritic cells derived from murine bone marrow or human monocytes results in a dose-dependent inability to stimulate proliferation of Ag-specific or alloreactive CD4(+) T cells. Dendritic cells exposed to cell debris from tumors expressing mEGP are similarly compromised. Furthermore, mice immunized with dendritic cells expressing mEGP from a recombinant adenovirus vector exhibited a muted anti-adenovirus immune response. The inhibitory effect of mEGP was not due to down-regulation of functional MHC class II molecules or active suppression of T cells, and did not extend to T cell responses to superantigen. These results demonstrate a novel mechanism by which tumors may evade CD4(+) T cell-dependent immune responses through expression of a TAA.

Prognostic value of postoperative detection of blood circulating tumor cells in patients with colorectal cancer operated on for cure.

OBJECTIVE: To assess whether postoperative detection of circulating tumor cells in peripheral blood influenced the prognosis of patients with colorectal cancer after radical surgery. SUMMARY BACKGROUND DATA: In a previous study, the authors demonstrated that baseline detection of blood circulating tumor cells does not have prognostic significance in patients with colorectal cancer. However, surgical procedures may increase tumor cell detachment and mobilization. METHODS: Sixty-six patients with histologically confirmed colorectal cancer operated on for cure were included in this study. Circulating tumor cells were detected by means of reverse transcriptase-polymerase chain reaction targeting to carcinoembryonic antigen messenger RNA in peripheral blood samples obtained 24 hours after surgery. Endpoints of the study were tumor recurrence, overall survival, and cancer-related survival. Univariate (Kaplan-Meier method) and multivariate (Cox regression model) analyses were performed. RESULTS: After a median follow-up of 36 months, 15 patients (23%) had tumor relapse and 14 had died (21%), 8 of them from a cancer-related cause. Cox regression analysis identified lymph node metastases and gender as independent predictors of tumor recurrence and cancer-related survival, whereas overall survival was dependent on the degree of differentiation of the primary tumor. More importantly, the presence of circulating tumor cells after surgery had no prognostic influence on tumor recurrence, overall survival, or cancer-related survival. CONCLUSIONS: Postoperative detection of blood circulating tumor cells had no prognostic significance in patients with colorectal cancer operated on for cure.

Gastric mucosal blood flow changes in Helicobacter pylori infection and NSAID-induced gastric injury.

BACKGROUND: The impact of H. pylori infection on gastric mucosal blood flow and NSAID-induced gastric damage is unclear. AIM: To study the effects of H. pylori infection on gastric mucosal blood flow, both at basal conditions and after NSAID exposure, and its relation with mucosal damage and nitric oxide production. METHODS: Gastric mucosal blood flow, nitric oxide production and gastric damage were assessed in time after H. pylori SS1 or E. coli inoculation in mice. Experiments were conducted in basal conditions or after oral exposure to indomethacin (20 mg/kg). RESULTS: H. pylori infected mice exhibited a significant increase in gastric blood flow and gastric nitric oxide production 1 week after infection, but those parameters returned to basal levels by 4 weeks. NSAID challenge elicited a similar reduction in gastric blood flow [25-35%] in H. pylori-infected and control animals. However, only 1 week H. pylori-infected mice, which exhibited a significant baseline hyperemia, were able to maintain gastric blood flow values within the normal range after NSAID exposure. NSAID-induced gastric damage was increased in H. pylori-infected mice by 4 weeks, but not 1 week after infection. CONCLUSIONS: Underlying H. pylori infection aggravates acute NSAID-induced gastric damage. However, at early phases, gastric hyperemia associated with increased nitric oxide production may exert some protective role.

Leukocyte recruitment in colon cancer: role of cell adhesion molecules, nitric oxide, and transforming growth factor beta1.

BACKGROUND & AIMS: A deficient leukocyte recruitment has been suggested in tumor vasculature, but little is known about the underlying molecular mechanism. To characterize leukocyte-endothelium interaction in experimental colon cancer, quantify the main endothelial cell adhesion molecules (CAMs), and evaluate the effect of tumor-derived products. METHODS: Leukocyte recruitment was assessed by intravital videomicroscopy in mice bearing HT29-derived tumors. Endothelial CAMs were measured using the dual-radiolabeled antibody technique. The role of molecules mediating leukocyte rolling (P-, E-, and L-selectin) or adhesion (intercellular adhesion molecule 1 [ICAM-1] and vascular cell adhesion molecule 1 [VCAM-1]) carcinoembryonic antigen (CEA), and transforming growth factor (TGF) beta1 was assessed through immunoblockade, whereas participation of nitric oxide (NO) and cyclooxygenase (COX) metabolites were evaluated by means of nonselective and selective inhibition. RESULTS: Basal and lipopolysaccharide-stimulated leukocyte rolling and adhesion were markedly reduced in tumor vasculature. ICAM-1 immunoblockade prevented leukocyte adhesion in both tumor and nontumor microvessels. Neither baseline nor LPS-induced endothelial ICAM-1, P-, and E-selectin expression in tumors were reduced with respect to nontumor vasculature. Although VCAM-1 expression was reduced in tumor endothelium, immunoneutralization of VCAM-1 failed to reverse LPS-induced leukocyte recruitment in this setting. CEA immunoblockade and COX inhibition did not modify the deficient leukocyte rolling. Nonselective NO inhibition partially reversed the defective adhesion response in tumor microvessels. Finally, TGF-beta1 immunoblockade partially and selectively restored impaired leukocyte rolling and adhesion in tumor microvessels. CONCLUSIONS: Impaired leukocyte recruitment in tumor vasculature cannot be attributed to a depressed expression of the main CAMs. Selective restoration after NO inhibition and TGF-beta1 immunoblockade suggests involvement of both molecules in this phenomenon.