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Tumor‐associated macrophages (TAMs) have a unique favorable effect on the prognosis of colorectal cancer (CRC), although their association with stage‐specific outcomes remains unclear. We assessed the densities of CD68+ and CD163+ TAMs at the invasive front of resected CRC stage III CRC from 236 patients, 165 of whom received post‐surgical FOLFOX treatment, and their relationship with disease‐free survival (DFS). Associations between macrophage mRNAs and clinical outcome were investigated in silico in 59 stage III CRC and FOLFOX‐treated patients from The Cancer Genome Atlas (TCGA). Biological interactions of SW480 and HT29 cells and macrophages with FOLFOX were tested in co‐culture models. Low TAM densities were associated with shorter DFS among patients receiving FOLFOX (CD68+, p = 0.0001; CD163+, p = 0.0008) but not among those who were untreated. By multivariate Cox analysis, only low TAM (CD68+, p = 0.001; CD163+, p = 0.002) and nodal status (CD68+, p = 0.009; CD163+, p = 0.007) maintained an independent predictive value. In the TCGA cohort, high CD68 mRNA levels were associated with better outcome (p = 0.02). Macrophages enhanced FOLFOX cytotoxicity on CRC cells (p < 0.01), and drugs oriented macrophage polarization from M2‐ to M1‐phenotype. Low TAM densities identify stage III CRC patients at higher risk of recurrence after adjuvant therapy, and macrophages can augment the chemo‐sensitivity of micro‐metastases. [ABSTRACT FROM AUTHOR]

Background: People with cluster headache (CH) are frequently burdened by misdiagnosis or diagnostic delay. The peculiar somatic and behavioral changes characterizing patients with CH are not useful to improve diagnostic accuracy. In our clinical experience, we noticed a typical voice quality with low and croaking tone in patients with CH. In this cross‐sectional study, we evaluated, by digital voice analysis, whether it is possible to identify typical voice quality characterizing patients with CH compared with healthy controls (HCs). Furthermore, to investigate whether putative differences in voice characteristics could be underpinned by constitutional aspects or pathological processes of vocal cords, subjects underwent a videolaryngostroboscopy. Smoking habits and alcohol consumption were specifically investigated. Methods: After conducting digital recording of the voices from both patients with CH and HCs in a soundproof insulated cabin in the laboratory of the Audiology Department, a set of voice parameters was analyzed. We included the measures of fundamental frequency, calculations of jitter and shimmer, and noise‐to‐harmonics ratios as well as quantities related to the spectral tilt (i.e., H1–H2, H1–A1, H1–A2, and H1–A3) in 20 patients with CH and in 13 HCs. A videolaryngostroboscopy was performed in all subjects. Results: Patients with CH, explored during the cluster bout period, showed significantly lower second harmonic (H1–H2) values compared with HCs (−6.9 ± 7.6 vs. 2.1 ± 6.7, p = 0.002), usually characterizing the so‐called creaky voice. By using a laryngoscopy investigation, a significantly higher prevalence of mild to moderate vocal cord edema and laryngopharyngeal reflux signs were found in patients with CH (100% of patients with CH vs. 15% of HC, p < 0.001). Conclusion: Creaky phonation is a "physiological mode of laryngeal operation" usually underpinned by shortened and thickened vocal folds. Creaky voice phonation can be due to a vocal fold's reduced capability to become slack or flaccid secondary to vocal cord edema underpinned by laryngopharyngeal reflux affecting the phonatory mechanisms in patients with CH. The laryngopharyngeal reflux may represent a dysautonomic sign related to the increased parasympathetic tone during in‐bout period, reinforcing the hypothesis of an extracranial autonomic dysfunction as part of CH clinical picture. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most malignant tumors worldwide. Stromal cells residing in the tumor microenvironment strongly contribute to cancer progression through their crosstalk with cancer cells and extracellular matrix. Here we provide the first evidence that CRC‐associated lymphatic endothelium displays a distinct matrisome‐associated transcriptomic signature, which distinguishes them from healthy intestinal lymphatics. We also demonstrate that CRC‐associated human intestinal lymphatic endothelial cells regulate tumor cell growth via growth differentiation factor 11, a soluble matrisome component which in CRC patients was found to be associated with tumor progression. Our data provide new insights into lymphatic contribution to CRC growth, aside from their conventional role as conduits of metastasis. What's new? Stromal cells residing in the tumor microenvironment strongly contribute to tumor progression through their crosstalk with cancer cells and extracellular matrix (ECM). In this study, the authors demonstrate that colorectal cancer (CRC)‐associated human intestinal lymphatic endothelial cells (HILEC) regulate tumor cell growth via the soluble matrisome component Growth Differentiation Factor 11 (GDF11), pointing to an unconventional role of lymphatics in controlling CRC growth and progression aside from their classical role as conduit of metastasis. The findings pave the way for new studies ultimately aiming at the identification of GDF11 inhibitors for the treatment of CRC in its early phases. [ABSTRACT FROM AUTHOR]

Inflammatory cells are an essential component of the tumor microenvironment. Neutrophils have emerged as important players in the orchestration and effector phase of innate and adaptive immunity. The significance of tumor-associated neutrophils (TAN) in colorectal cancer (CRC) has been the subject of conflicting reports and the present study was designed to set up a reliable methodology to assess TAN infiltration in CRC and to evaluate their clinical significance. CD66b and myeloperoxidase (MPO) were assessed as candidate neutrophil markers in CRC using immunohistochemistry. CD66b was found to be a reliable marker to identify TAN in CRC tissues, whereas MPO also identified a subset of CD68+ macrophages. CRC patients ( n = 271) (Stages I-IV) were investigated retrospectively by computer-assisted imaging on whole tumor sections. TAN density dramatically decreases in Stage IV patients as compared to Stage I-III. At Cox analysis, higher TAN density was associated with better prognosis. Importantly, multivariate analysis showed that prognostic significance of TAN can be influenced by clinical stage and 5-fluorouracil(5-FU)-based chemotherapy. On separate analysis of Stage III patients ( n = 178), TAN density had a dual clinical significance depending on the use of 5-FU-based chemotherapy. Unexpectedly, higher TAN density was associated with better response to 5-FU-based chemotherapy. Thus, TAN are an important component of the immune cell infiltrate in CRC and assessment of TAN infiltration may help identify patients likely to benefit from 5-FU-based chemotherapy. These results call for a reassessment of the role of neutrophils in cancer using rigorous quantitative methodology. [ABSTRACT FROM AUTHOR]

KRAS mutant colorectal cancer ( CRC) patients develop lung and brain metastases more frequently than KRAS wild-type ( WT) counterpart. We retrospectively investigated the prognostic role of KRAS, BRAF, and PIK3 CA (exon 20) mutations and loss of phosphatase and tensin homolog ( PTEN) in surgically resected lung metastases. Lung specimens from 75 metastatic CRC ( mCRC) patients treated with one or more metastasectomies with curative intent were analyzed. Sixty-four percent of patients had KRAS WT lung metastases. PTEN loss-of-function was found in 75%. BRAF and PIK3 CA exon 20 mutations were not found. Seven patients subsequently developed brain metastases and 43% of them had KRAS mutation. In univariate analysis, median overall survival ( OS) for KRAS WT patients was longer, compared to KRAS mutant patients (median 60.9 vs. 36.6 months, P = 0.035). In addition, both progression-free survival ( PFS) and lung disease-free survival ( LDFS) between lung surgery and relapse were not associated with KRAS and PTEN status. In multivariate analysis, the risk of death was significantly increased by KRAS mutational status ( OS Hazard ratio ( HR) 2.17, 95% IC 1.19-3.96, P = 0.012) and lack of adjuvant chemotherapy ( OS HR 0.10, 95% IC 0.01-0.74, P = 0.024). The proportion of KRAS mutations in lung metastases was similar to the expected proportion in primary tumors. Patients harboring KRAS mutation had a poorer survival rate compared to WT group both in univariate and multivariate analysis. Moreover, administration of adjuvant chemotherapy after lung metastasectomy ( LM) significantly improved both PFS and OS. KRAS mutation is a negative prognostic factor in mCRC patients undergoing LM. Further larger and prospective studies are necessary to confirm these findings. [ABSTRACT FROM AUTHOR]

Background Autonomic nervous system ( ANS) regulation may be altered in functional diseases, including irritable bowel syndrome ( IBS), but published data are not clear to date. The aim of the study was to analyze ANS function in IBS subjects classified by Rome III criteria and healthy controls using standardized technique. Methods ANS activity was evaluated by autoregressive spectral analysis of RR interval and systolic arterial pressure variabilities, to obtain indices of sympatho-vagal modulation of the heart and of spontaneous cardiac baroreflex ( α index). A symptom list was used to score 18 somatic complaints (score 0-180) (4 SQ). Fatigue and stress were assessed through the use of a global scoring index (0-10). Key Results We enrolled 41 IBS subjects (29 F, age 40 ± 2 years) and 42 healthy matched controls. Heart rate was higher in IBS than control subjects (69 ± 2 vs 61 ± 1; p < 0.001). The total variance of RR interval variability, and α index, were significantly lower in IBS compared to controls (1983.12 ± 384.64 ms2 vs 4184.55 ± 649.59 ms2; 18.1 ± 2 ms/mmHg vs 29 ± 3 ms/mmHg; p < 0.01). The α index results showed an inverse correlation with stress scores and somatic symptoms. Conclusions & Inferences IBS subjects display a significant reduction in α index, an established marker of cardiac baroreflex. ANS dysfunction appears to be involved in the pathophysiology of IBS and its assessment may open new perspectives for clinical management of patients suffering from IBS. [ABSTRACT FROM AUTHOR]

BACKGROUND: Colorectal cancer (CRC) prognosis and survival are strictly related to the development of distant metastases. New targeted therapies have increased patient survival, but the objective response rate is still very limited, partially because of a traditional focus on designing treatment according to the molecular profile of the primary tumor regardless the diversity between the primary tumor and metastases. The objective of this study was to evaluate the presence of molecular heterogeneity during metastatic progression and its potential impact on clinical treatment. METHODS: The authors analyzed v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS) codon 12 mutations, the v-Raf murine sarcoma viral oncogene homolog B1 ( BRAF) thymine to adenine substitution at codon 1788, and tumor protein 53 ( p53) mutations and investigated promoter methylation of Ras association (RalGDS/AF-6) domain family member 1 protein ( RASSF1a), E-cadherin, and cyclin-dependent kinase inhibitor 2A ( p16INK4a) in 101 primary CRCs (67 stage III and 34 stage IV) and related lymph node and liver metastases. RESULTS: Lymph node metastases were characterized by fewer alterations compared with primary tumors and liver metastases, especially KRAS ( P = .03) and p16INK4a ( P = .05). Genetic changes, when detectable in metastases, mostly were retained from the primary tumor, whereas epigenetic changes more frequently were acquired de novo. Overall, 31 distinct CRC molecular profiles were detected, none of which characterized a particular tumor stage. When the metastatic lesions also were included in the profiles, there were 53 distinct molecular profiles in 67 patients with stage III disease and 34 distinct molecular profiles in 34 patients with stage IV disease. CONCLUSIONS: Lymph node and liver metastases appear to originate in clonally different processes, with more molecular alterations occurring in distant metastases than in lymph node metastases and with elevated heterogeneity of the primary tumor. Thus, potential prognostic targets should be carefully evaluated for their heterogeneity in both primary tumors and distant metastases to avoid erroneous misclassification. Cancer 2013. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: The introduction of contrast-enhanced ultrasound has been a major innovation in liver and pancreatic imaging. Previous studies have validated its intraoperative use during liver surgery, while there is a lack of data regarding its use during pancreatic surgery. The purpose of the present study was to prospectively evaluate the possible role of contrast-enhanced intraoperative ultrasound (CEIOUS) during resective pancreatic surgery for primary lesion characterization and intraoperative staging. Materials and Methods: Thirty-four patients (70% males, mean age 67.9 years) were selected for pancreatic surgery between October 2006 and July 2009. All patients underwent intraoperative ultrasound with intravenous injection of 4.8 mL sulfur-hexafluoride microbubbles. Location of the primary tumor, relation to the main vessels, contrast medium uptake modalities, presence of liver metastases, and multifocal pancreatic involvement were evaluated. The majority of operations were pancreatoduodenectomies (70.6%) performed for pancreatic ductal adenocarcinoma (64.7%). Results: Additional lesions were detected by ultrasound in six patients (17.6%: liver metastases in four patients, a hemangioma in one patient, and a further pancreatic lesion in one patient). In five of these patients (5/34, 14.7%) surgical management was modified by these findings. All these new findings were diagnosed before injection of contrast medium, except for a metastasis from a neuroendocrine tumor; the characterization of the hemangioma was possible only after contrast injection. Intraoperative findings regarding location of primary tumor, relation to the main vessels, and lesion characterization did not differ from those obtained with preoperative imaging. Conclusions: In our experience intraoperative ultrasound is a valid technique for intraoperative staging prior to pancreatic resection; it is unclear whether, in pancreatic surgery, the addition of contrast enhancement adds any benefit to traditional intraoperative ultrasound. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 2011; 34: 476-486 Summary Background Limited data are available regarding the frequency of oesophageal motility and bolus transit abnormalities in subgroups of patients with gastro-oesophageal reflux disease (GERD). Aim To assess oesophageal motility and bolus transit in endoscopically defined GERD subgroups. Methods Patients ( N = 755) with typical reflux symptoms underwent upper endoscopy, conventional or impedance oesophageal manometry and/or impedance-pH testing. They were divided into: erosive oesophagitis (EO; N = 340), Barrett Oesophagus (BO; N = 106), non-erosive reflux disease (NERD; endoscopy−, abnormal pH and/or SAP/SI+; N = 239) and functional heartburn (FH; endoscopy−, normal pH and SAP/SI−; N = 70). Manometric patterns and bolus transit were defined according to previously published criteria. Results Increasing GERD severity was associated with decreased lower oesophageal sphincter resting pressure ( P < 0.05) and distal oesophageal amplitude ( P < 0.01), higher prevalence of hiatal hernia ( P < 0.01) and increased prevalence of ineffective oesophageal motility ( P < 0.01). Patients with EO and BO had a significantly lower percentage of complete bolus transit compared with NERD and FH ( P < 0.01). Overall, abnormal bolus transit (ABT) for liquid swallows was found in 12% of FH, 20% of NERD, 54% of EO and 56% of BO ( P < 0.01). Combined impedance-manometry showed abnormal oesophageal function in 4% of FH, 4% of NERD, 22% of EO and 21% of BO patients with normal oesophageal manometry. Conclusions Oesophageal motility abnormalities increase in parallel with the severity of GERD from NERD to EO and BO. Bolus transit abnormalities in severe reflux disease underscore the importance of impaired oesophageal function in the development of mucosal injury. [ABSTRACT FROM AUTHOR]

Although angiogenesis is viewed as a fundamental component of inflammatory bowel disease (IBD) pathogenesis, we presently lack a thorough knowledge of the cell type(s) involved in its induction and maintenance in the inflamed intestinal mucosa. This study aimed to determine whether platelet (PLT) adhesion to inflamed intestinal endothelial cells of human origin may favour angiogenesis. Unstimulated or thrombin-activated human PLT were overlaid on resting or tumour necrosis factor (TNF)-α-treated human intestinal microvascular endothelial cells (HIMEC), in the presence or absence of blocking antibodies to either vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, integrin αβ, tissue factor (TF) or fractalkine (FKN). PLT adhesion to HIMEC was evaluated by fluorescence microscopy, and release of angiogenic factors (VEGF and soluble CD40L) was measured by ELISA. A matrigel tubule formation assay was used to estimate PLT capacity to induce angiogenesis after co-culturing with HIMEC. TNF-α up-regulated ICAM-1, αβ and FKN expression on HIMEC. When thrombin-activated PLT were co-cultured with unstimulated HIMEC, PLT adhesion increased significantly, and this response was further enhanced by HIMEC activation with TNF-α. PLT adhesion to HIMEC was VCAM-1 and TF independent but ICAM-1, FKN and integrin αβ dependent. VEGF and sCD40L were undetectable in HIMEC cultures either before or after TNF-α stimulation. By contrast, VEGF and sCD40L release significantly increased when resting or activated PLT were co-cultured with TNF-α-pre-treated HIMEC. These effects were much more pronounced when PLT were derived from IBD patients. Importantly, thrombin-activated PLT promoted tubule formation in HIMEC, a functional estimate of their angiogenic potential. In conclusion, PLT adhesion to TNF-α-pre-treated HIMEC is mediated by ICAM-1, FKN and αβ, and is associated with VEGF and sCD40L release. These findings suggest that inflamed HIMEC may recruit PLT which, upon release of pro-angiogenic factors, actively contribute to inflammation-induced angiogenesis. [ABSTRACT FROM AUTHOR]

Introduction and aims. Balanced propofol sedation (BPS) administered by gastroenterologists has gained popularity in endoscopic procedures. Few studies exist about the safety of this approach during endosonography with fine needle aspiration (EUS-FNA). We assessed the safety of BPS in EUS-FNA. Materials and methods. 112 consecutive patients, referred to our unit to perform EUSFNA, from February 2008 to December 2009, were sedated with BPS. A second gastroenterologist administered the drugs and monitorized the patient. Results. All the 112 patients (62 males, mean age 58.35) completed the examination. The mean dose of midazolam and propofol was, respectively, of 2.1 mg (range 1-4mg) and 350 mg (range 180-400). All patients received oxygen with amean flux of 4 liter/minute (range 2-6 liters/minute). Themean recovery time after procedure was 25minutes (range 18-45 minutes). No major complications related to sedation were registered during all procedures. The oxygen saturation of all patients never reduced to less than 85%. Blood systolic pressure during and after the procedure never reduced to less than 100mmHg. Conclusions. In our experience BPS administered by non-anaesthesiologists provided safe and successful sedation in patients undergoing EUS-FNA. [ABSTRACT FROM AUTHOR]

Background The current therapies for Crohn’s disease (CD) are mainly focused on blockade of inflammation. Fibrosis remains one of the major complications of CD often leading to surgery, affecting patients’ quality-of-life. Aim To summarize the published data regarding the potential anti-fibrotic role of drugs commonly used in CD and the most effective anti-fibrotic drugs used in other diseases evaluating their potential use to treat intestinal fibrosis in CD. Methods A literature search was performed in the PubMed, Medline, Cochrane and EMBASE databases, considering in vitro, animal and human studies on fibrosis in inflammatory bowel disease and other similar chronic pathologies. Results Treatment of fibrosis in CD is limited to surgery or endoscopic dilatation, although some of the drugs currently used may have anti-fibrotic activity. In other diseases, anti-fibrotic agents are already used or are in preclinical or clinical trials. ACE inhibitors, Angiotensin Receptor Blockers, and HMG-CoA inhibitors merit further investigation in CD because of their role in preventing fibrosis in cardiovascular and renal diseases. Conclusions Anti-fibrotic drugs are under evaluation or already used in clinical practice in other chronic inflammatory diseases. In CD, there is a great need for investigation into agents that may prevent, reduce or reverse intestinal fibrosis. Aliment Pharmacol Ther 31, 189–201 [ABSTRACT FROM AUTHOR]

Background Anti TNF-α agents are used successfully for several autoimmune diseases, including IBD and psoriasis. An emerging challenge is the increasing incidence of anti TNF-α induced psoriasis. A total of 120 cases have been currently reported, of whom 18 patients were treated with biological agents for IBD. Objectives To analyse all cases of anti TNF-α induced psoriasis in patients with IBD in the literature and to investigate potential mechanisms of action. Methods A literature review was performed in the PubMed, Medline, Cochrane and EMBASE databases, with simple analysis of demographic data, drug administration and psoriasis onset. Risk and incidence patient/year/duration (pyd) was calculated. Results A total of 18 patients with IBD treated by anti TNF-α agents developed drug-induced psoriasis of which, 17 patients developed with infliximab, one with adalimumab. The most frequent time of onset is between 3rd and 4th infusion of infliximab. Withdrawal of infliximab led to regression of lesions in 16 patients. In six patients, infliximab was reintroduced with no further recurrence of psoriasis. Conclusions Although anti TNF-α induced psoriasis is extremely rare, understanding the mechanism will be a key step towards better realizing the role played by TNF-α and its pharmacological inhibitors in immune-mediated diseases. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colonic mucosa. Over the last decade, the increasing knowledge on the pathogenic mechanisms underlying intestinal inflammation has led to the development of a number of biological agents, mainly addressed to molecules and/or pathways demonstrated to have a pathogenic role in UC. In UC, clinical course and therapeutic decisions mainly depend on disease activity and extent. While therapeutic approach to mild-to-moderate UC by using aminosalicylates and corticosteroids has been well established, treatment of severe UC is far from being satisfactory. A severe attack of UC remains a challenge to be managed jointly by gastroenterology, surgery, and intensive care units. However, the recent introduction of biological therapies has led to promising changes in the management of UC patients. Aim of this paper is to review the recent advances and future perspectives for the use of biological agents in UC. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 2, 201-218, 2008 [ABSTRACT FROM AUTHOR]

Background: It is controversial whether CARD15 variants are truly associated with a more severe form of Crohn's disease. The relative role of CARD15 genotype and smoking in Crohn's disease progression is also debated. Aim: To investigate the association between CARD15 variants and history of resective surgery in patients with Crohn's ileal disease, taking into account smoking as a possible confounding factor. Methods: We originally assessed CARD15 genotype in 239 north Italian Crohn's disease patients (mean follow-up: 10.1 ± 8.1 years). We then focused on 193 patients with proven ileal involvement, 70 of whom (36.3%) carried CARD15-mutated alleles (G908R, R702W, L1007fs). Results: Carriage of CARD15 variants was positively associated with family history and ileal-only disease and negatively associated with uncomplicated behaviour at maximal follow-up ( P < 0.05). Ileal resection was the only variable independently associated with CARD15 variants at multivariate analysis (OR 3.8; 95% CI 1.6–9.2; P = 0.003). Kaplan–Meier analysis showed that ileal resection was favoured both by CARD15 variant-carriage ( P = 0.01) and by smoking ( P = 0.05), but smoking did not affect progression to surgery in variant carriers ( P = 0.31). Thirteen of 14 (93%) patients being resection-free at 15-year follow-up, had CARD15 wild-type genotype ( P = 0.01), whereas only seven (50%) had never smoked ( P = 1.0). Conclusions: In summary, CARD15 variant-associated Crohn's ileitis is virtually committed to stricturing and/or penetrating disease and, eventually, to resective surgery. Smoking accelerates progression to surgery in patients with wild-type CARD15 genotype, but it seems to exert no additional effect in CARD15-variant carriers. [ABSTRACT FROM AUTHOR]

Summary Background: Loxiglumide is a potent and selective cholecystokinin-1 (CCK-1) receptor antagonist able to inhibit gall-bladder contraction. Aim: To assess the effect of CCK-1 receptor blockade on the pain of patients with biliary colic. Patients and methods: Fourteen patients with biliary colic but no suspicion for acute cholecystitis, were randomly and blindly assigned to loxiglumide (50 mg i.v.) or hyoscine-N-butyl bromide (20 mg i.v.) treatment. Pain intensity was monitored by a Visual Analogue Scale. Patients with less than 80% response at 30 min, were retreated with a second injection of the same compound. Results: Reduction in pain score (mean ± S.E.M.) was faster and significantly greater in patients treated with loxiglumide (n = 7) than in controls (n = 7): 88 ± 7% vs. 47 ± 12% after 20 min, P < 0.05; 92 ± 6% vs. 49 ± 13%, after 30 min, P < 0.05. Only one of seven patients treated with loxiglumide needed a second injection at 30 min (vs. six of seven controls, P < 0.05). No adverse effect was observed after either treatment. Conclusions: Loxiglumide is highly effective in obtaining pain relief in patients with biliary colic. The analgesic effect of CCK-1 receptor blockade is superior to that of a conventional anticholinergic treatment. [ABSTRACT FROM AUTHOR]

Background It is now clear that the extent to which gastric acid secretion must be suppressed varies with the clinical condition being treated. Aim To assess the 24-h control of gastric acidity and the individual response variability of three different doses of pantoprazole. Methods Sixty-four duodenal ulcer patients were recruited for this prospective, randomized, multicentre, double-blind, parallel-group study. They were subdivided into three well-matched groups treated with 20 mg o.m., 40 mg o.m. and 40 mg b.d. of pantoprazole, respectively. Endoscopy and intragastric pH monitoring were performed in each patient before and after 14 days of treatment. Results Fifty-five patients were eligible for final analysis (17 treated with 20 mg o.m., 18 with 40 mg o.m. and 20 with 40 mg b.d. pantoprazole). The ulcer crater healed in 94, 88 and 95% of cases, respectively. The three dosages of pantoprazole produced significant increases in gastric pH compared to basal levels (P < 0.0001). There was also a clear dose-dependent pharmacodynamic effect, which augmented on moving from the lowest dosage of 20 mg o.m. pantoprazole to the highest dosage of 40 mg b.d. (P < 0.01–0.001). The inter-individual response variability within the three treatment groups was more marked with the dose of 20 mg than with the two higher doses of pantoprazole. Conclusions All three doses of pantoprazole we tested are highly effective in decreasing gastric acidity and there is a clear dose-dependent pharmacodynamic effect on moving from the lowest to the highest dosage. The greatest inter individual variation in the degree of acid inhibition was seen with pantoprazole 20 mg o.m., while the majority of patients responded adequately to the two higher doses of the drug. [ABSTRACT FROM AUTHOR]