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Koji Tanaka

Publications and source records attributed to Koji Tanaka.

At least 19 recordsLinked to original sources
PubMed2026

Prevalence and chronology of colibactin-associated mutational processes and their microbiome spectra in Japanese colorectal cancer.

The incidence of colorectal cancer (CRC) has risen in recent decades, with a disproportionate increase observed among younger individuals in Japan and other countries. The etiological contribution of the gut microbiota to CRC pathogenesis is recognized, yet the mechanisms involved remain to be fully clarified. Here we integrated whole-genome sequencing (WGS) and transcriptome profiling of CRC with whole-genome metagenomic sequencing of fecal samples to interrogate host-microbiome interactions at high resolution. Application of interpretable artificial intelligence enabled the stratification of CRC into four distinct microbiome-informed subtypes. WGS analysis identified mutational signatures SBS88 and ID18, linked to colibactin exposure, as early clonal events detected in 44.8% of non-hypermutated patients. Notably, these signatures were significantly more frequent among patients born after the 1960s. Microbiome-based subclassification revealed subtype-specific clinical and molecular features. Collectively, our findings indicate that colibactin exposure constitutes a prevalent and potentially modifiable risk factor for CRC in the Japanese population.

Humans↗
PubMed2026

ALID score for treatment-effect heterogeneity of adjunctive low-voltage area ablation in persistent atrial fibrillation: A post hoc analysis of SUPPRESS-AF.

BACKGROUND: In persistent atrial fibrillation (AF), the incremental benefit of adjunctive low-voltage area (LVA) ablation beyond pulmonary vein isolation (PVI) remains inconsistent. OBJECTIVE: To examine whether a simple clinical score characterizes treatment-effect heterogeneity of adjunctive LVA ablation among patients with mapped LVA&#xa0;>&#xa0;5&#xa0;cm2 and to perform an exploratory supportive analysis in an independent randomized cohort. METHODS: In this post-hoc analysis of SUPPRESS-AF, which included patients with persistent AF and mapped LVA&#xa0;>&#xa0;5&#xa0;cm2 after PVI, four variables-age&#xa0;&#x2265;&#xa0;75&#xa0;years, left atrial diameter&#xa0;>&#xa0;44&#xa0;mm, estimated glomerular filtration rate&#xa0;<&#xa0;60&#xa0;mL/min/1.73&#xa0;m2, and absence of diabetes-were combined into the ALID score (0-4). Patients were stratified into low (0-1), intermediate (2), and high (3-4) score groups. Because EARNEST-PVI did not use LVA-guided ablation or select patients based on mapped LVA, it was analyzed as an exploratory supportive cohort rather than as an external validation cohort. RESULTS: In SUPPRESS-AF (n&#xa0;=&#xa0;336), a significant treatment-by-score interaction was observed (P&#xa0;<&#xa0;0.001). Adjunctive LVA ablation was associated with increased recurrence in the low-score stratum (HR 3.92; 95% CI 1.50-10.20) and reduced recurrence in the high-score stratum (HR 0.48; 95% CI 0.26-0.86). In EARNEST-PVI (n&#xa0;=&#xa0;494), a qualitatively similar interaction pattern was observed for additional ablation beyond PVI (interaction P&#xa0;=&#xa0;0.029), although the ablation strategy differed from LVA-guided ablation. CONCLUSIONS: Among patients with persistent AF and mapped LVA >5&#xa0;cm2, the ALID score identified heterogeneity in response to adjunctive LVA ablation. These hypothesis-generating findings require prospective validation before clinical implementation.

Humans↗
PubMed2026

Real-world outcomes of ipilimumab plus nivolumab in esophageal squamous cell carcinoma: a multi-institutional large cohort study.

BACKGROUND: Combination immune checkpoint inhibition with ipilimumab plus nivolumab (NIVO&#x2009;+&#x2009;IPI) has shown promising efficacy in advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate648 trial. However, real-world evidence regarding its safety, efficacy as first-line therapy, and host-related biomarkers relevant to immunotherapy remains limited. METHODS: This multicenter retrospective study evaluated a large cohort of 111 patients with unresectable advanced or recurrent ESCC who received first-line NIVO&#x2009;+&#x2009;IPI therapy. Treatment response, treatment-related adverse events, and prognostic factors were analyzed. RESULTS: The objective response and disease control rates in cases with target lesions were 44.0% and 70.7%, respectively. Treatment-related adverse events&#x2009;&#x2265;&#x2009;Grade 2 occurred in 58 (52.3%) patients, including one Grade 4 event (type 1 diabetes) and two Grade 5 events (biliary infection and myocarditis). The median overall survival (OS) and progression-free survival were 22&#xa0;months (95% confidence interval [CI]: 13-not reached) and 5&#xa0;months (95% CI 3-8), respectively. OS was significantly affected by lymph node metastasis in unresectable advanced disease and by liver metastasis in recurrent disease. Multivariate analysis of OS identified the C-reactive protein-to-albumin ratio (CAR), a marker of host immune-inflammatory status, as the only independent prognostic parameter (hazard ratio&#x2009;=&#x2009;2.99, 95% CI 1.35-6.63, P&#x2009;=&#x2009;0.0071). CONCLUSIONS: In this large real-world cohort, first-line NIVO&#x2009;+&#x2009;IPI therapy demonstrated meaningful clinical activity and an acceptable safety profile in advanced ESCC. Treatment outcomes varied according to metastatic patterns, suggesting an influence of organ-specific immune microenvironments, and CAR emerged as a simple and robust prognostic biomarker. These findings support the real-world applicability of dual immune checkpoint blockade and highlight the importance of host immune context in patient selection.

Humans↗
PubMed2006

Diagnostic and prognostic value of a type 1 Brugada electrocardiogram at higher (third or second) V1 to V2 recording in men with Brugada syndrome.

To evaluate the diagnostic and prognostic value of an electrocardiogram (ECG) recorded at a higher (third or second) intercostal space, 98 men (17 to 76 years of age, mean +/- SD 47 +/- 13; with documented ventricular fibrillation [VF] in 22 and syncope in 32) were categorized into 3 groups; 68 men had a spontaneous type 1 ECG in standard leads V(1) and V(2) (S group), 19 had a spontaneous type 1 ECG only in the higher V(1) and V(2) leads (H group), and 11 had a type 1 ECG only after receiving class Ic sodium channel blockers (Ic group). There were no significant differences in baseline clinical characteristics, including VF episodes, syncope, atrial fibrillation, family history, late potentials, and inducibility of VF during electrophysiologic study across the 3 groups. During prospective follow-up periods (779 +/- 525, 442 +/- 282, and 573 +/- 382 days, respectively), subsequent cardiac events occurred in 11 men (16%) within the S group, in 2 men (11%) in the H group, and in 0 men (0%) in the Ic group (p = NS, S vs H group). In men with previous episodes of VF, subsequent cardiac events occurred in 7 (44%) within the S group and in 2 (50%) in the H group (p = NS). In conclusion, men with a spontaneous type 1 Brugada ECG recorded only at higher leads V(1) and V(2) showed a prognosis similar to that of men with a type 1 ECG in using standard leads V(1) and V(2).

Adolescent↗
PubMed2006

Experimental and theoretical evaluation of the charge distribution over the ruthenium and dioxolene framework of [Ru(OAc)(dioxolene)(terpy)] (terpy = 2,2':6',2' '-terpyridine) depending on the substituents.

A series of ruthenium complexes [Ru(OAc)(dioxolene)(terpy)] having various substituents on the dioxolene ligand (dioxolene = 3,5-t-Bu2C6H2O2 (1), 4-t-BuC6H3O2 (2), 4-ClC6H3O2 (3), 3,5-Cl2C6H2O2 (4), Cl4C6O2 (5); terpy = 2,2':6'2' '-terpyridine) were prepared. EPR spectra of these complexes in glassy frozen solutions (CH2Cl2:MeOH = 95:5, v/v) at 20 K showed anisotropic signals with g tensor components 2.242 > g1 > 2.104, 2.097 > g2 > 2.042, and 1.951 > g3 > 1.846. An anisotropic value, Deltag = g1 - g3, and an isotropic g value, g = [(g1(2) + g2(2) + g3(2))/3]1/2, increase in the order 1 < 2 < 3 < 4 < 5. The resonance between the Ru(II)(sq) (sq = semiquinone) and Ru(III)(cat) (cat = catecholato) frameworks shifts to the latter with an increase of the number of electron-withdrawing substituents on the dioxolene ligand. DFT calculations of 1, 2, 3, and 5 also support the increase of the Ru spin density (Ru(III) character) with an increase of the number of Cl atoms on the dioxolene ligand. The singly occupied molecular orbitals (SOMOs) of 1 and 5 are very similar to each other and stretch out the Ru-dioxolene frameworks, whereas the lowest unoccupied molecular orbital (LUMO) of 5 is localized on Ru and two oxygen atoms of dioxolene in comparison with that of 1. Electron-withdrawing groups decrease the energy levels of both the SOMO and LUMO. In other words, an increase in the number of Cl atoms in the dioxolene ligand results in an increase of the positive charge on Ru. Successive shifts in the electronic structure between the Ru(II)(sq) and Ru(III)(cat) frameworks caused by the variation of the substituents are compatible with the experimental data.

Journal Article↗
PubMed2006

All-solid-state Z-scheme in CdS-Au-TiO2 three-component nanojunction system.

Natural photosynthesis, which achieves efficient solar energy conversion through the combined actions of many types of molecules ingeniously arranged in a nanospace, highlights the importance of a technique for site-selective coupling of different materials to realize artificial high-efficiency devices. In view of increasingly serious energy and environmental problems, semiconductor-based artificial photosynthetic systems consisting of isolated photochemical system 1 (PS1), PS2 and the electron-transfer system have recently been developed. However, the direct coupling of the components is crucial for retarding back reactions to increase the reaction efficiency. Here, we report a simple technique for forming an anisotropic CdS-Au-TiO2 nanojunction, in which PS1(CdS), PS2(TiO2) and the electron-transfer system (Au) are spatially fixed. This three-component system exhibits a high photocatalytic activity, far exceeding those of the single- and two-component systems, as a result of vectorial electron transfer driven by the two-step excitation of TiO2 and CdS.

Journal Article↗
PubMed2006

An in vivo platform for translational drug development in pancreatic cancer.

Effective development of targeted anticancer agents includes the definition of the optimal biological dose and biomarkers of drug activity. Currently available preclinical models are not optimal to this end. We aimed at generating a model for translational drug development using pancreatic cancer as a prototype. Resected pancreatic cancers from 14 patients were xenografted and expanded in successive groups of nude mice to develop cohorts of tumor-bearing mice suitable for drug therapy in simulated early clinical trials. The xenografted tumors maintain their fundamental genotypic features despite serial passages and recapitulate the genetic heterogeneity of pancreatic cancer. The in vivo platform is useful for integrating drug screening with biomarker discovery. Passages of tumors in successive cohorts of mice do not change their susceptibility to anticancer agents and represent a perpetual live bank, facilitating the application of new technologies that will result in the creation of an integrated stable database of tumor-drug response data and biomarkers.

Animals↗
PubMed2006

Vascular remodelling after cardiac transplantation: a 3-year serial intravascular ultrasound study.

AIMS: To assess the time-course of intimal hyperplasia and vascular remodelling, and their relative contributions on luminal narrowing in transplant coronary artery disease (TCAD) by a 3-year serial intravascular ultrasound (IVUS) study. METHODS AND RESULTS: Serial IVUS examinations were performed in 90 cardiac transplant recipients at 1.4+/-0.6 months after transplantation and again annually thereafter for 3 years. From 90 arteries, 304 sites were matched from baseline to the third year post-transplant. Based on the change in external elastic membrane (EEM) area +/-10% at 1 year, 304 sites were divided into three groups: sites with no remodelling (52%); early constrictive remodelling (26%); and early compensatory enlargement (22%). Greater intimal growth was seen at 1 year in sites with early compensatory enlargement, whereas there was no change in intimal area in sites with early constrictive remodelling. Over 3 years, the cumulative lumen loss was greater in sites with early constrictive remodelling than in sites with early compensatory enlargement or no remodelling (P<0.001). When luminal narrowing occurred for each annual interval, the contribution from the decrease in EEM area was greater than that due to intimal thickening (P<0.001). CONCLUSION: During the first 3 years post-transplant, the largest intimal growth occurs in the first year, mostly in sites with early compensatory enlargement. The contribution to luminal loss in TCAD is greater from constrictive remodelling than from intimal hyperplasia. The type of remodelling pattern that occurs in transplanted coronary arteries within the first year post-transplant may be a predictor of the progression of luminal narrowing during subsequent years.

Analysis of Variance↗
PubMed2006

Influence of pre-existing donor atherosclerosis on the development of cardiac allograft vasculopathy and outcomes in heart transplant recipients.

OBJECTIVES: This study sought to evaluate the influence of donor lesions on the development of cardiac allograft vasculopathy and outcomes in heart transplant recipients. BACKGROUND: After orthotopic heart transplantation (OHT), coronary artery narrowing occurs as a combination of pre-existing donor lesions and new lesions that develop as a result of cardiac allograft vasculopathy. METHODS: Intravascular ultrasound (IVUS) studies were performed in 301 recipients at 1.3 +/- 0.6 months and again at 12.2 +/- 0.8 months after OHT. Additional IVUS studies were performed in 90 patients at two and three years of follow-up. Sites at baseline with maximum intimal thickness > or =0.5 mm were defined as pre-existing donor lesions. The angiographic diagnosis of transplant coronary artery disease (TCAD) was defined as a new > or =50% diameter narrowing of a major epicardial vessel. RESULTS: Donor lesions were present in 30% of the hearts. By IVUS, sites with donor lesions did not have a greater increase in intimal area compared with sites without donor lesions. Angiographically, the incidence of TCAD up to three years after transplantation was higher in recipients with donor lesions than in recipients without donor lesions (25% vs. 4%, p < 0.001). However, the three-year mortality rate was similar between recipients with or without donor lesions (4.5% vs. 5.2%, p = 1.0). CONCLUSIONS: Pre-existing donor lesions do not act as a nidus for accelerating the progression of intimal hyperplasia. However, patients with donor lesions have a higher incidence of angiographic TCAD. Donor lesions do not affect the long-term survival of patients with OHT up to three years.

Adult↗
PubMed2006

Epidermal growth factor receptor messenger RNA expression, gene dosage, and gefitinib sensitivity in non-small cell lung cancer.

PURPOSE: Epidermal growth factor receptor (EGFR) mRNA expression and EGFR gene dosage by quantitative PCR in tumor samples obtained from patients with gefitinib-treated non-small cell lung cancer were analyzed in order to determine the association with treatment outcome, clinical, and biological features [EGFR copy number by fluorescent in situ hybridization (FISH), EGFR tyrosine kinase mutations, and EGFR protein expression]. EXPERIMENTAL DESIGN: EGFR mRNA expression was measured by real-time quantitative reverse transcription-PCR in 64 patients, and EGFR gene dosage was analyzed by real-time quantitative PCR in 82 patients from paraffin-embedded specimens. RESULTS: EGFR mRNA expression was higher in responders to gefitinib as compared with nonresponders (P = 0.012). Patients with high EGFR mRNA expression (>5.01) had 43% response probability, whereas patients with low EGFR mRNA expression had 8% response probability (P = 0.006). Patients with high EGFR mRNA expression had longer median progression-free (5.3 versus 2.8 months, P = 0.028) but not overall survival (13.8 versus 10.9 months, P = 0.87). EGFR mRNA expression was higher in FISH-positive patients (P = 0.001) and in patients with positive EGFR immunostaining (P < 0.001) but not in patients with EGFR mutations (P = 0.19). EGFR gene dosage did not predict response (P = 0.54), progression-free (P = 0.73), or overall survival (P = 0.89). EGFR gene dosage was not associated with FISH positivity (P = 0.15), relative mRNA expression (P = 0.27), EGFR mutation status (P = 0.39), and EGFR protein expression (P = 0.35). CONCLUSION: EGFR mRNA expression is a predictive biomarker for response to gefitinib and to progression-free survival after gefitinib treatment. EGFR gene dosage is neither predictive for response nor progression-free nor overall survival.

Adult↗
PubMed2006

Compensatory enlargement in transplant coronary artery disease: an intravascular ultrasound study.

BACKGROUND: It is unclear to what extent the "Glagov phenomenon" occurs in transplant coronary artery disease (TCAD). The objective of this study was to evaluate the relationship between intimal hyperplasia and compensatory enlargement in TCAD. METHODS: Intravascular ultrasound imaging was performed on 190 cardiac transplant recipients at (1.4 +/- 0.6) months and again (12.1 +/- 0.7) months after cardiac transplantation. Studies 1 year apart were matched at 625 sites. There were 345 coronary artery sites that had an increase in intimal area > 10% from baseline to one year, and this comprised the data set of the present study. RESULTS: At the first year, 91% of coronary artery sites with intimal growth had a total cross-sectional area stenosis < or = 40%, but 38% of the sites showed a decrease of > 10% in lumen area. Receiver operating characteristic curve demonstrated that the change in cross-sectional area stenosis cut-off level at year 1 was 8% with a sensitivity of 75% and a specificity of 82% in predicting lumen loss. At a total cross-sectional area stenosis of 20%, sensitivity was 65% with a specificity of 81% in predicting lumen loss. CONCLUSIONS: In TCAD, vessel enlargement as a compensatory mechanism for plaque growth is generally inadequate. Instead of continued vessel expansion, luminal narrowing develops when there is more than 8% cross-sectional area filled with intimal hyperplasia. In distinction to native coronary artery atherosclerotic disease, the transition point in transplant vasculopathy where the lumen is diminished by increasing intimal growth, occurs at a lower threshold, 20% vs 40% of vessel cross-sectional area.

Adult↗
PubMed2006

Sequential reaction intermediates in aliphatic C-H bond functionalization initiated by a bis(mu-oxo)dinickel(III) complex.

The reaction of [Ni2(OH)2(Me2-tpa)2]2+ (1) (Me2-tpa = bis(6-methyl-2-pyridylmethyl)(2-pyridylmethyl)amine) with H2O2 causes oxidation of a methylene group on the Me2-tpa ligand to give an N-dealkylated ligand and oxidation of a methyl group to afford a ligand-based carboxylate and an alkoxide as the final oxidation products. A series of sequential reaction intermediates produced in the oxidation pathways, a bis(mu-oxo)dinickel(III) ([Ni2(O)2(Me2-tpa)2]2+ (2)), a bis(mu-superoxo)dinickel(II) ([Ni2(O2)2(Me2-tpa)2]2+ (3)), a (mu-hydroxo)(mu-alkylperoxo)dinickel(II) ([Ni2(OH)(Me2-tpa)(Me-tpa-CH2OO)]2+ (4)), and a bis(mu-alkylperoxo)dinickel(II) ([Ni2(Me-tpa-CH2OO)2]2+ (5)), was isolated and characterized by various physicochemical measurements including X-ray crystallography, and their oxidation pathways were investigated. Reaction of 1 with H2O2 in methanol at -40 degrees C generates 2, which is extremely reactive with H2O2, producing 3. Complex 2 was isolated only from disproportionation of the superoxo ligands in 3 in the absence of H2O2 at -40 degrees C. Thermal decomposition of 2 under N2 generated an N-dealkylated ligand Me-dpa ((6-methyl-2-pyridylmethyl)(2-pyridylmethyl)amine) and a ligand-coupling dimer (Me-tpa-CH2)2. The formation of (Me-tpa-CH2)2 suggests that a ligand-based radical Me-tpa-CH2* is generated as a reaction intermediate, probably produced by H-atom abstraction by the oxo group. An isotope-labeling experiment revealed that intramolecular coupling occurs for the formation of the coupling dimer. The results indicate that the rebound of oxygen to Me-tpa-CH2* is slower than that observed for various high-valence bis(mu-oxo)dimetal complexes. In contrast, the decomposition of 2 and 3 in the presence of O2 gave carboxylate and alkoxide ligands, respectively (Me-tpa-COO- and Me-tpa-CH2O-), instead of (Me-tpa-CH2)2, indicating that the reaction of Me-tpa-CH2* with O2 is faster than the coupling of Me-tpa-CH2* to generate ligand-based peroxyl radical Me-tpa-CH2OO*. Although there is a possibility that the Me-tpa-CH2OO* species could undergo various reactions, one of the possible reactive intermediates, 4, was isolated from the decomposition of 3 under O2 at -20 degrees C. The alkylperoxo ligands in 4 and 5 can be converted to a ligand-based aldehyde by either homolysis or heterolysis of the O-O bond, and disproportionation of the aldehyde gives a carboxylate and an alkoxide via the Cannizzaro reaction.

Catalysis↗
PubMed2006

Usefulness and safety of percutaneous coronary interventions for cardiac transplant vasculopathy.

Late morbidity and death as a result of progressive coronary vascular obliteration remains a major unsolved problem after orthotopic heart transplantation. Various percutaneous catheter intervention (PCI) methods have been used to treat transplant coronary artery disease (CAD), but few reports have assessed the longitudinal results of these procedures. Of 1,440 cardiac transplant patients at University of California, Los Angeles, Medical Center, treated between 1984 and 2004, 65 patients who had undergone orthotopic heart transplantation underwent PCI on a total of 156 coronary artery lesions because of transplant CAD between July 1993 and August 2004. The procedural success rate was 93%. Angiographic follow-up was available for 42 patients and 101 lesions 9.5 +/- 5.8 months after PCI. The global restenosis rate was 36%. Multivariate analysis was used to assess 49 clinical, angiographic, and immunologic variables per lesion. The use of a cutting balloon increased the risk of restenosis (odds ratio 11.5, p <0.01) and the use of stents decreased the risk of restenosis (odds ratio 0.34, p <0.05) compared with other PCI methods. The restenosis rate with drug-eluting stents was 19%, lower than that with bare metal stents (31%). Of the 65 patients, 20 (31%) died within 1.9 +/- 1.8 years after PCI. The actuarial survival rate was 56% at 5 years after the first PCI. In conclusion, although the restenosis rate after PCI was higher than that in nontransplant patients with CAD, the immediate and long-term results were acceptable in this high-risk population. Despite the intense inflammation associated with transplant CAD, drug-eluting stents appeared to reduce the occurrence of restenosis. Compared with historical controls, PCI may also improve the actuarial survival rate of patients undergoing orthotopic heart transplantation.

Adult↗
PubMed2006

An anatomic study of the intermuscular septum of the lower leg; branches from the posterior tibial artery and potential for reconstruction of the lower leg and the heel.

The anatomy of the intermuscular septum (IMS) of the lower leg has been studied in 10 legs of 10 cadavers. The IMS was well developed in the distal half of the lower leg and its vascular supply from the posterior tibial artery was frequently seen at 60mm proximal from the tip of the medial malleolus. We advocate that these anatomical features contribute to clinical applications of the IMS flap. It may be useful for reconstruction of the lower leg and heel as safer options with less morbidity.

Cadaver↗
PubMed2006

Mycophenolate mofetil reduces intimal thickness by intravascular ultrasound after heart transplant: reanalysis of the multicenter trial.

UNLABELLED: The mycophenolate mofetil (MMF) trial involved 650 heart transplant patients from 28 centers who received MMF or azathioprine (AZA), both in combination with cyclosporine and corticosteroids. Baseline and 1-year intravascular ultrasound (IVUS) were performed in 196 patients (102 MMF and 94 AZA) with no differences between groups in IVUS results analyzed by morphometric analysis (average of 10 evenly spaced sites, without matching sites between studies). Baseline to first-year IVUS data can also be analyzed by site-to-site analysis (matching sites between studies), which has been reported to be more clinically relevant. Therefore, we used site-to-site analysis to reanalyze the multicenter MMF IVUS data. RESULTS: IVUS images were reviewed and interpretable in 190 patients (99 MMF and 91 AZA) from the multicenter randomized trial. The AZA group compared to the MMF group had a larger number of patients with first-year maximal intimal thickness (MIT)>or=0.3 mm (43% vs. 23%, p=0.005), a greater decrease in the mean lumen area (p=0.02) and a decrease in the mean vessel area (the area actually increased in the MMF group, p=0.03). CONCLUSION: MMF-treated heart transplant patients compared to AZA-treated patients, both concurrently on cyclosporine and corticosteroids, in this study have significantly less progression of first-year intimal thickening.

Adrenal Cortex Hormones↗
PubMed2006

Assessment of celecoxib pharmacodynamics in pancreatic cancer.

Cyclooxygenase-2 (COX-2) inhibitors are being developed as chemopreventive and anticancer agents. This study aimed to determine the biological effect of the COX-2 inhibitor celecoxib in pancreatic cancer as an early step to the further development of the agent in this disease. Eight patients scheduled for resection of an infiltrating adenocarcinoma of the pancreas were randomized to receive celecoxib at a dose of 400 mg twice daily or placebo for 5 to 15 days before the surgery. In addition, carcinomas from nine additional patients were xenografted in nude mice, expanded, and treated with vehicle or celecoxib for 28 days. Celecoxib markedly decreased the intra-tumor levels of prostaglandin E2 in patient carcinomas and in the heterotransplanted xenografts. However, this effect did not result in inhibition of cell proliferation or microvessel density (as assessed by Ki67 and CD31 staining). In addition, a panel of markers, including bcl-2, COX-1, COX-2, and VEGF, did not change with treatment in a significant manner. Furthermore, there was no evidence of antitumor effects in the xenografted carcinomas. In summary, celecoxib efficiently inhibited the synthesis of prostaglandin E2 both in pancreatic cancer surgical specimens and in xenografted carcinomas but did not exert evident antitumor, antiproliferative, or antiangiogenic effect as a single agent. The direct pancreatic cancer xenograft model proved to be a valuable tool for drug evaluation and biological studies and showed similar results to those observed in resected pancreatic cancer specimens.

Animals↗