Azpiroz F.,Hospital General Vall dHebron |
Azpiroz F.,Autonomous University of Barcelona |
Feinle-Bisset C.,University of Adelaide |
Grundy D.,University of Sheffield |
Tack J.,Catholic University of Leuven
Journal of Gastroenterology | Year: 2014
Both reflex and sensory mechanisms control the function of the stomach, and disturbances in these mechanisms may explain the pathophysiology of disorders of gastric function. The objective of this report is to perform a literature-based critical analysis of new, relevant or conflicting information on gastric sensitivity and reflexes, with particular emphasis on the comprehensive integration of basic and clinical research data. The stomach exerts both phasic and tonic muscular (contractile and relaxatory) activity. Gastric tone determines the capacity of the stomach and mediates both gastric accommodation to a meal as well as gastric emptying, by partial relaxation or progressive recontraction, respectively. Perception and reflex afferent pathways from the stomach are activated independently by specific stimuli, suggesting that the terminal nerve endings operate as specialized receptors. Particularly, perception appears to be related to stimulation of tension receptors, while the existence of volume receptors in the stomach is uncertain. Reliable techniques have been developed to measure gastric perception and reflexes both in experimental and clinical conditions, and have facilitated the identification of abnormal responses in patients with gastric disorders. Gastroparesis is characterised by impaired gastric tone and contractility, whereas patients with functional dyspepsia have impaired accommodation, associated with antral distention and increased gastric sensitivity. An integrated view of fragmented knowledge allows the design of pathophysiological models in an attempt to explain disorders of gastric function, and may facilitate the development of mechanistically orientated treatments. © 2013 Springer Japan.
Alvarez-Larran A.,Hospital del Mar |
Arellano-Rodrigo E.,Hospital General Vall dHebron |
Perez-Andreu V.,Hospital Morales Messeguer |
Hernandez-Boluda J.-C.,Hospital Clinico |
And 9 more authors.
Blood | Year: 2010
The effectiveness of antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia (ET) is not proven. In this study, the incidence rates of arterial and venous thrombosis were retrospectively analyzed in 300 lowrisk patients with ET treated with antiplatelet drugs as monotherapy (n = 198) or followed with careful observation (n = 102). Follow-up was 802 and 848 person-years for antiplatelet therapy and observation, respectively. Rates of thrombotic events were 21.2 and 17.7 per 1000 person-years for antiplatelet therapy and observation, respectively (P = .6). JAK2 V617F-positive patients not receiving antiplatelet medication showed an increased risk of venous thrombosis (incidence rate ratio [IRR]: 4.0; 95% CI: 1.2-12.9; P = .02). Patients with cardiovascular risk factors had increased rates of arterial thrombosis while on observation (IRR: 2.5; 95% CI: 1.02-6.1; P = .047). An increased risk of major bleeding was observed in patients with platelet count greater than 1000 × 109/L under antiplatelet therapy (IRR: 5.4; 95% CI: 1.7-17.2; P = .004). In conclusion, antiplatelet therapy reduces the incidence of venous thrombosis in patients with JAK2-positive ET and the rate of arterial thrombosis in patients with associated cardiovascular risk factors. In the remaining low-risk patients, this therapy is not effective as primary prophylaxis of thrombosis, and observation may be an adequate option. © 2010 by The American Society of Hematology.
A Comparison of Proposed Biosimilar LA-EP2006 and Reference Pegfilgrastim for the Prevention of Neutropenia in Patients With Early-Stage Breast Cancer Receiving Myelosuppressive Adjuvant or Neoadjuvant Chemotherapy: Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2), a Phase III, Randomized, Double-Blind Trial
PubMed | Hexal AG a Sandoz company, Ludwig Maximilians University of Munich, Jones Clinic, Duke University and 4 more.
Type: Journal Article | Journal: The oncologist | Year: 2016
Pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. In highly regulated markets, there are currently no approved biosimilars of pegfilgrastim. Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2) was a confirmatory efficacy and safety study designed to compare proposed biosimilar LA-EP2006 with reference pegfilgrastim (Neulasta, Amgen) in early-stage breast cancer patients receiving adjuvant or neoadjuvant myelosuppressive chemotherapy.A total of 308 patients were randomized to LA-EP2006 or reference pegfilgrastim. Each patient received TAC (intravenous docetaxel 75 mg/m(2), doxorubicin 50 mg/m(2), and cyclophosphamide 500 mg/m(2)) on day 1 of each cycle, for six or more cycles. Pegfilgrastim (LA-EP2006 or reference) was given subcutaneously (6 mg in 0.6 mL) on day 2 of each cycle. The primary endpoint was duration of severe neutropenia (DSN) during cycle 1 (number of consecutive days with an absolute neutrophil count <0.5 10(9)/L), with equivalence confirmed if 90% and 95% confidence intervals (CIs) were within a 1-day margin.Baseline characteristics were well balanced. DSN was equivalent between groups at mean SD 1.36 1.13 (LA-EP2006, n = 155) and 1.19 0.98 (reference, n = 153) in cycle 1. With a treatment difference (reference minus LA-EP2006) of -0.16 days (90% CI -0.36 to 0.04; 95% CI -0.40 to 0.08), LA-EP2006 was equivalent to reference pegfilgrastim. Secondary efficacy parameters were similar between groups during cycle 1 and across cycles. Safety profiles were also similar between groups. No neutralizing antibodies against pegfilgrastim, filgrastim, or polyethylene glycol were detected.LA-EP2006 and reference pegfilgrastim were therapeutically equivalent and comparable regarding efficacy and safety in the prevention of neutropenia in patients with early-stage breast cancer receiving TAC.The granulocyte colony-stimulating factor pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. Biosimilars are biologics with similar quality, safety, and efficacy to a reference product that may increase the affordability of treatment compared with their reference compounds. There are currently no approved biosimilars of pegfilgrastim in highly regulated markets. No previous phase III studies have been performed with LA-EP2006. PROTECT-2 was conducted to confirm the similarity of the proposed biosimilar LA-EP2006 to pegfilgrastim. Biosimilar pegfilgrastim (LA-EP2006) may benefit oncology patients by offering increased access to biological treatments that may improve clinical outcomes. This means that patients could potentially be treated prophylactically with biologics rather than only after complications have occurred.
Carles J.,Institute Oncologia Of La Vall Dhebron |
Carles J.,Hospital General Vall dHebron |
Castellano D.,Hospital Universitario 12 Of Octubre |
Climent M.A.,Instituto Valenciano Of Oncologia |
And 3 more authors.
Clinical and Translational Oncology | Year: 2012
Prostate cancer (PCa) is the most common cancer in the male population in Western countries, second to skin cancer. Hormonal therapy allows long-lasting and effective control of cancer-related symptoms in advanced stages; however, in almost all patients with metastatic PCa the disease will progress when it becomes castration-resistant (CRPC). Chemotherapy with docetaxel was a turning point in CRPC, as, for the first time, it resulted in an increased survival time in comparison with mitoxantrone and prednisone. Combination therapy with docetaxel and prednisone is the first-line treatment of choice. Once the cancer has progressed, there is no clear alternative, although some new agents have shown promise in the treatment of this type of cancer. This review will provide an overview of the current status of CRPC, including clinical status, prognosis, firs-tline treatment and new second-line treatment options.
Gonzalez S.V.,Imoma Instituto Medicina Oncologica Y Molecular Of Asturias |
Pijuan X.M.,Hospital General Vall dHebron
BJU International | Year: 2011
OBJECTIVE • To study whether luteinizing hormone-releasing hormone (LHRH) analogues are agents of the same pharmacological class, i.e. whether they have the same clinical effect, using an evidence-based medicine approach. MATERIAL AND METHODS • We reviewed the evidence on the alleged 'drug class effect' among analogues and the existing bibliographic support for their use in various medical indications. We used PubMed as the main search source. Evidence level and degree of recommendation were assigned to each conclusion based on the 'Scottish Intercollegiate Guidelines Network'. RESULTS • There are no studies designed to answer the question of class effect between LHRH analogues or agonists. Reviews and meta-analyses have been performed on many other issues related to therapeutic management either with analogues alone, or in combination with radiation therapy and surgery. • Direct comparisons do not allow definitive conclusions to be reached. Indirect evidence is obtained from randomized studies comparing the different LHRH analogues with other treatments used to obtain androgen deprivation. Other issues related to pharmacokinetics and pharmacodynamics that can support either the existence or non-existence of class effect were evaluated. CONCLUSION • The current available evidence is not enough to support a presumed class effect of the drug among the different analogues in the treatment of prostate carcinoma in its various clinical situations. © 2010 the authors. bju international.
Martinez C.,Hospital General Vall Dhebron |
Churchman M.,St James's Hospital |
Freeman T.,University of Edinburgh |
Ilyas M.,University of Nottingham
Experimental and Molecular Pathology | Year: 2010
Osteopontin is thought to play an important role in tumour metastasis. In a previous expression profiling study of murine intestinal adenomas, we found that Opn was up-regulated. We also found β-catenin binding motifs in the Opn promoter implying that, contrary to current beliefs, induction of Opn may occur during early tumourigenesis.We studied 59 murine intestinal adenomas for Opn expression and every tumour showed up-regulation compared to normal mucosa confirming early deregulation in these tumours. To determine whether Opn makes a functional contribution to tumourigenesis, Opn was knocked down in the murine colorectal cancer cell line CMT93. Inhibition of Opn expression resulted in decreased cell numbers.To determine the mechanism of Opn induction in these tumours, the Opn promoter was cloned and each of the putative β-catenin binding motifs was mutated. No major change in Opn promoter activity was observed thereby excluding Opn as a direct β-catenin target gene. However, mutation of one of two putative c-myc binding sites in the Opn promoter led to near complete loss of promoter activity whilst mutation of one of four PEA3 binding sites led to a 50% reduction in promoter activity.We conclude that Opn deregulation is an early event in intestinal tumourigenesis which may promote tumour development by altering either proliferation or apoptosis to increase tumour cell numbers. Opn expression in the intestine is dependent on c-myc binding sites in the promoter. Since c-myc is a known β-catenin target gene, deregulation of Opn may be a secondary effect of aberrant Wnt signalling. © 2010 Elsevier Inc.
Serra J.,Hospital Universitari Germans Trias i Pujol |
Azpiroz F.,Hospital General Vall dHebron
Neurogastroenterology and Motility | Year: 2010
Background Intestinal manometry is the current gold standard for diagnosing small bowel dysmotility; however, the functional significance of abnormal manometry is unknown. Our aim was to determine whether, and to what extent, intestinal gas propulsion is impaired in patients with manometrically proven dysmotility compared with healthy controls and patients with IBS. Methods Clearance and tolerance of a jejunal gas load (12 mL min-1 for 2 h) were measured in 15 patients with severe abdominal symptoms and intestinal dysmotility evidenced by manometry, 15 patients with IBS and 15 healthy subjects. Thereafter, the effect of neostigmine (0.5 mg i.v. bolus) vs placebo (i.v. saline) was tested in six dysmotility patients. Key Results After 2-h gas infusion, patients with dysmotility developed significantly more gas retention (717 ± 91 mL) than IBS patients (372 ± 82 mL; P = 0.0037) and healthy subjects (17 ± 67 mL; P < 0.0001 vs dysmotility; P = 0.0060 vs IBS). Despite the greater retention in dysmotility patients, abdominal perception (2.5 ± 0.6 score) and distension (7 ± 2 mm girth increment) were similar to IBS (3.9 ± 0.6 score and 7 ± 2 mm, respectively). In dysmotility patients, neostigmine produced immediate clearance of gas, and by 30 min had reduced gas retention (by -552 ± 182 vs 72 ± 58 mL after saline; P = 0.008), abdominal symptoms (by -0.8 ± 0.3 score vs 0.3 ± 0.2 after saline; P = 0.019) and distension (girth change -5 ± 1 mm; P = 0.003 vs-2 ± 2 mm after saline). Conclusion & Inferences Patients with manometric dysmotility have markedly impaired intestinal gas propulsion. In IBS patients, impaired gas propulsion is less pronounced but associated with concomitant sensory dysfunction and poor tolerance of gas retention. © 2009 Blackwell Publishing Ltd.
Manichanh C.,Hospital General Vall dHebron |
Eck A.,Hospital General Vall dHebron |
Varela E.,Hospital General Vall dHebron |
Roca J.,Molecular Biology Institute of Barcelona |
And 12 more authors.
Gut | Year: 2014
Objective To characterise the influence of diet on abdominal symptoms, anal gas evacuation, intestinal gas distribution and colonic microbiota in patients complaining of flatulence. Design Patients complaining of flatulence (n=30) and healthy subjects (n=20) were instructed to follow their usual diet for 3 days (basal phase) and to consume a high-flatulogenic diet for another 3 days (challenge phase). Results During basal phase, patients recorded more abdominal symptoms than healthy subjects in daily questionnaires (5.8±0.3 vs 0.4±0.2 mean discomfort/ pain score, respectively; p=<0.0001) and more gas evacuations by an event marker (21.9±2.8 vs 7.4±1.0 daytime evacuations, respectively; p=0.0001), without differences in the volume of gas evacuated after a standard meal (262±22 and 265±25 mL, respectively). On flatulogenic diet, both groups recorded more abdominal symptoms (7.9±0.3 and 2.8±0.4 discomfort/ pain, respectively), number of gas evacuations (44.4±5.3 and 21.7±2.9 daytime evacuations, respectively) and had more gas production (656±52 and 673±78 mL, respectively; p<0.05 vs basal diet for all). When challenged with flatulogenic diet, patients' microbiota developed instability in composition, exhibiting variations in the main phyla and reduction of microbial diversity, whereas healthy subjects' microbiota were stable. Taxa from Bacteroides fragilis or Bilophila wadsworthia correlated with number of gas evacuations or volume of gas evacuated, respectively. Conclusions Patients complaining of flatulence have a poor tolerance of intestinal gas, which is associated with instability of the microbial ecosystem.
Azpiroz F.,Hospital General Vall Dhebron |
Azpiroz F.,Research Center Biomedica En Red Of Enfermedades Hepaticas gestivas Ciberehd |
Azpiroz F.,Autonomous University of Barcelona |
Malagelada C.,Hospital General Vall Dhebron |
And 2 more authors.
Diabetologia | Year: 2016
The activity of the digestive tract is usually regulated to match its content: physiological stimuli in the gut induce modulatory reflexes that control digestive function so that digestion is normally not perceived. However, under certain circumstances, digestive stimuli may activate sensory afferents and give rise to conscious sensations. Both reflex and sensory signals are modulated by a balance of excitatory and inhibitory mechanisms. Patients with diabetes may develop a neuropathy affecting the control of gastric and/or intestinal motor function and the sensory innervation as well. During fasting the stomach is contracted and relaxes to accommodate a meal. After ingestion the stomach progressively recontracts and this contraction gently produces gastric emptying. Impairment of excitatory pathways affects the contraction of the stomach, which may result in delayed gastric emptying and vomiting of retained food. Conversely, alteration of the inhibitory neural pathways results in impaired relaxation of the stomach in response to a meal; in this case increased wall tension may produce early satiation, fullness and nausea. Diabetic neuropathy may distort the control of intestinal motility, which can lead to diverse symptoms such as diarrhoea, constipation, intestinal distension and abdominal pain. Neuropathy in diabetes may also affect the sensory nerves of the gut, and depending on which pathways are involved, perception may be increased or reduced. In summary, in patients with diabetic neuropathy, disorders of gut motor function are associated with sensory abnormalities, and the combination of impaired pathways determines the clinical consequences. This review summarises a presentation given at the ‘Diagnosis and treatment of autonomic diabetic neuropathy in the gut’ symposium at the 2015 annual meeting of the EASD. It is accompanied by another mini-review on a topic from this symposium (by Hans Törnblom, DOI: 10.1007/s00125-015-3829-9) and a commentary by the Session Chair, Péter Kempler (DOI: 10.1007/s00125-015-3826-y). © 2015, Springer-Verlag Berlin Heidelberg.
PubMed | Hospital General Vall dHebron
Type: Journal Article | Journal: Diabetologia | Year: 2016
The activity of the digestive tract is usually regulated to match its content: physiological stimuli in the gut induce modulatory reflexes that control digestive function so that digestion is normally not perceived. However, under certain circumstances, digestive stimuli may activate sensory afferents and give rise to conscious sensations. Both reflex and sensory signals are modulated by a balance of excitatory and inhibitory mechanisms. Patients with diabetes may develop a neuropathy affecting the control of gastric and/or intestinal motor function and the sensory innervation as well. During fasting the stomach is contracted and relaxes to accommodate a meal. After ingestion the stomach progressively recontracts and this contraction gently produces gastric emptying. Impairment of excitatory pathways affects the contraction of the stomach, which may result in delayed gastric emptying and vomiting of retained food. Conversely, alteration of the inhibitory neural pathways results in impaired relaxation of the stomach in response to a meal; in this case increased wall tension may produce early satiation, fullness and nausea. Diabetic neuropathy may distort the control of intestinal motility, which can lead to diverse symptoms such as diarrhoea, constipation, intestinal distension and abdominal pain. Neuropathy in diabetes may also affect the sensory nerves of the gut, and depending on which pathways are involved, perception may be increased or reduced. In summary, in patients with diabetic neuropathy, disorders of gut motor function are associated with sensory abnormalities, and the combination of impaired pathways determines the clinical consequences. This review summarises a presentation given at the Diagnosis and treatment of autonomic diabetic neuropathy in the gut symposium at the 2015 annual meeting of the EASD. It is accompanied by another mini-review on a topic from this symposium (by Hans Trnblom, DOI: 10.1007/s00125-015-3829-9 ) and a commentary by the Session Chair, Pter Kempler (DOI: 10.1007/s00125-015-3826-y ).