Prediction scores or gastroenterologists' Gut Feeling for triaging patients that present with acute upper gastrointestinal bleeding.

INTRODUCTION: Several prediction scores for triaging patients with upper gastrointestinal (GI) bleeding have been developed, yet these scores have never been compared to the current gold standard, which is the clinical evaluation by a gastroenterologist. The aim of this study was to assess the added value of prediction scores to gastroenterologists' Gut Feeling in patients with a suspected upper GI bleeding. METHODS: WE PROSPECTIVELY EVALUATED GUT FEELING OF SENIOR GASTROENTEROLOGISTS AND ASKED THEM TO ESTIMATE: (1) the risk that a clinical intervention is needed; (2) the risk of rebleeding; and (3) the risk of mortality in patients presenting with suspected upper GI bleeding, subdivided into low, medium, or high risk. The predictive value of the gastroenterologists' Gut Feeling was compared to the Blatchford and Rockall scores for various outcomes. RESULTS: We included 974 patients, of which 667 patients (68.8%) underwent a clinical intervention. During the 30-day follow up, 140 patients (14.4%) developed recurrent bleeding and 44 patients (4.5%) died. Gut Feeling was independently associated with all studied outcomes, except for the predicted mortality after endoscopy. Predictive power, based on the AUC of the Blatchford and Rockall prediction scores, was higher than the Gut Feeling of the gastroenterologists. However, combining both the Blatchford and Rockall scores and the Gut Feeling yielded the highest predictive power for the need of an intervention (AUC 0.88), rebleeding (AUC 0.73), and mortality (AUC 0.71 predicted before and 0.77 predicted after endoscopy, respectively). CONCLUSIONS: Gut Feeling is an independent predictor for the need of a clinical intervention, rebleeding, and mortality in patients presenting with upper GI bleeding; however, the Blatchford and Rockall scores are stronger predictors for these outcomes. Combining Gut Feeling with the Blatchford and Rockall scores resulted in the most optimal prediction.

Symptomatic pectus excavatum in seniors (SPES): a cardiovascular problem? : A prospective cardiological study of 42 senior patients with a symptomatic pectus excavatum.

OBJECTIVES: There is no consensus among physicians as to whether or not pectus excavatum can produce symptoms sometimes even severe enough to justify a surgical procedure. The aim of this study was to assess the prevalence and severity of complaints and symptoms of senior patients with a pectus excavatum and to evaluate the results of surgical correction of the chest deformation. DESIGN: This is a prospective clinical study, case series. PARTICIPANTS: The participants are 42 senior patients with a pectus excavatum and somatic complaints. METHODS: Cardiological screening included medical history taking, physical examination, electrocardiography, transthoracic echocardiography and treadmill cardiography. Complaints, symptoms and test results were arranged in a clinical score. Indication for a therapeutic surgical correction by a modified Ravitch operation was a high clinical score in combination with radiological evidence of cardiac compression on CT or MRI. RESULTS: The clinical picture of the 42 senior patients with a pectus excavatum showed complaints of fatigue and low exercise tolerance, shortness of breath, palpitations, inspiratory obstruction and sometimes chest discomfort or pain. The serious and sometimes invalidating complaints of 19 patients (45%) had started only in their fourth or fifth decade of life and were labelled in 12 patients (63%) as 'Unexplained cardiovascular complaints'. To date, 11 patients have undergone surgical procedures. Symptoms were reduced substantially or had disappeared completely. All patients indicated that their health-related quality of life was significantly improved. CONCLUSION: Recognising the clinical picture of SPES is relevant because surgical reconstruction of the chest can provide substantial relief of symptoms.

Abnormal T cell differentiation persists in patients with rheumatoid arthritis in clinical remission and predicts relapse.

OBJECTIVES: An abnormal CD4+ T cell subset related to inflammation exposure (inflammation-related cells, IRC) has been identified in rheumatoid arthritis (RA). Patients with inflammatory and non-inflammatory diseases were used to examine the relationship between inflammation and this T cell subset in vivo. METHODS: Blood was collected from healthy controls and patients with RA (active disease or in clinical remission), Crohn's disease and osteoarthritis. IRC and chemokine receptors were quantified by flow cytometry. Thymic activity and apoptotic factors were measured by real-time polymerase chain reaction. Circulating cytokines were measured by enzyme-linked immunosorbent assay. CXCR4 and SDF1 in synovial biopsies were measured using immunohistochemistry. RESULTS: IRC were identified in patients with RA (p<0.0001) and Crohn's disease (p = 0.005), but not in those with osteoarthritis. In RA in remission, IRC persisted (p<0.001). In remission, hyperproliferation of IRC was lost, chemokine receptor expression was significantly lowered (p<0.007), Bax expression dropped significantly (p<0.001) and was inversely correlated with IRC (rho = -0.755, p = 0.03). High IRC frequency in remission was associated with relapse within 18 months (OR = 6.4, p<0.001) and a regression model predicted 72% of relapse. CONCLUSIONS: These results suggest a model in which, despite the lack of systemic inflammation, IRC persist in remission, indicating that IRC are an acquired feature of RA. They have, however, lost their hyper-responsiveness, acquired a potential for survival, and no longer express chemokine receptors. IRC persistence in remission confirms their important role in chronic inflammation as circulating precursors of pathogenic cells. This was further demonstrated by much higher incidence of relapse in patients with high IRC frequency in remission.

Castleman's disease: A rare lymphoproliferative disorder.

Castleman's disease (CD) is an atypical lymphoproliferative disorder. Since it was first described in 1956, it has been referred to as follicular lympho-reticuloma, angiofollicular mediastinal lymph node hyperplasia, and benign giant lymphoma. CD is a heterogeneous disease that can be either localized or systemic (multicentric). The localized form can be divided into two types: the hyaline-vascular (HV) type or the plasma cell (PC) type. The former usually produces few symptoms and histological features include abnormal follicles and increased interfollicular vascularity. The PC type, in which, histopathologically, the presence of sheets of mature plasma cells is the distinguishing feature, is more likely to produce clinical symptoms such as fever, night sweats, and lymphadenopathy. The multicentric form mimics the PC type of localized CD, and patients present with systemic symptoms. In this report, we discuss the spectrum of clinical and pathological findings in localized and multicentric CD.

High dose chemotherapy and syngeneic stem cell transplantation in a patient with refractory rheumatoid arthritis: poor response associated with persistence of host autoantibodies and synovial abnormalities.

BACKGROUND: Immunoablative therapy combined with haematopoietic stem cell transplantation (SCT) is a possible treatment for patients with severe rheumatoid arthritis (RA). CASE REPORT: A patient with rheumatoid factor positive, progressively erosive RA, refractive to treatment, was treated with high dose cyclophosphamide, followed by reinfusion of an unmanipulated peripheral blood graft derived from her identical twin sister. The clinical response was unsatisfactory, necessitating reinstitution of treatment with disease modifying antirheumatic drugs, which was associated with persistence of host serum autoantibodies and a cellular infiltrate in synovium, notably of plasma cells. DISCUSSION: The effectiveness of syngeneic SCT may be critically dependent on the degree of immunoablation achieved or on the composition of the graft.

Long-term followup of health status in patients with severe rheumatoid arthritis after high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation.

OBJECTIVE: High-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (HSCT) is a new treatment for patients with severe, refractory rheumatoid arthritis (RA). The present study was undertaken to assess the health status of patients with severe RA over a long-term followup period after treatment with HDC + HSCT. METHODS: Health status and utility scores were assessed in 8 patients before and after treatment with HDC + HSCT. Patients were followed up for 5 years posttransplantation. Health status was assessed by the Health Assessment Questionnaire (HAQ), the RAND-36 version of the Short Form 36 (SF-36) health survey, and the Arthritis Impact Measurement Scales (AIMS). Utility scores were calculated using the EuroQol (EQ-5D) questionnaire and the SF-36-derived utility index (called the SF-6D), from which quality-adjusted life years (QALYs) were derived. RESULTS: Most measures of health status improved compared with baseline in the first 2 years posttransplantation, notably HAQ and AIMS scores and scores on the functional status, general health, and health change summary scales of the RAND-36 version of the SF-36. Utility scores derived from the EQ-5D questionnaire and the SF-6D also increased significantly after transplantation. This was reflected in the 0.28 QALYs gained compared with baseline. For a putative 50-year-old RA patient with a life expectancy of 20 years, a threshold analysis revealed that HDC + HSCT yielded more QALYs than conventional therapy when treatment-related mortality (TRM) was <2.8%. CONCLUSION: HDC + HSCT temporarily increased the functionality and health status of patients with severe, refractory RA. With a reported TRM of 1.3%, HDC + HSCT can be considered a realistic treatment option for patients with severe RA.

Outcome of intensive immunosuppression and autologous stem cell transplantation in patients with severe rheumatoid arthritis is associated with the composition of synovial T cell infiltration.

OBJECTIVE: To determine clinical and immunological correlates of high dose chemotherapy (HDC) + autologous stem cell transplantation (ASCT) in patients with severe rheumatoid arthritis (RA), refractory to conventional treatment. METHODS: Serial samples of peripheral blood and synovial tissue were obtained from seven patients with RA treated with HDC and autologous peripheral blood grafts enriched for CD34+ cells. Disease activity was assessed with the Disease Activity Score (DAS), serum concentrations of C reactive protein (CRP), and human immunoglobulin (HIg) scans, and the extent of immunoablation was determined by immunophenotyping of peripheral blood mononuclear cells, and immunohistochemistry and double immunofluorescence of synovium. RESULTS: Clinical responders (n = 5) had a larger number of cells at baseline expressing CD3, CD4, CD27, CD45RA, CD45RB, and CD45RO in synovium (p < 0.05), higher activity on HIg scans (p = 0.08), and a trend towards higher concentrations of CRP in serum than non-responders (n = 2). Subsequent remissions and relapses in responders paralleled reduction and re-expression, respectively, of T cell markers. A relatively increased expression of CD45RB and CD45RO on synovial CD3+ T cells was seen after HDC + ASCT. No correlations were found between DAS and changes in B cells or macrophage infiltration or synoviocytes. CONCLUSIONS: HDC + ASCT results in profound but incomplete immunoablation of both the memory and naïve T cell compartment, which is associated with longlasting clinical responses in most patients. The findings provide strong circumstantial evidence for a role of T cells in established RA, and demonstrate a role for the synovium in post-transplantation T cell reconstitution.

High dose chemotherapy and autologous hematopoietic stem cell transplantation for rheumatoid arthritis: a review.

A new treatment approach, involving intense immunosuppression and autologous hematopoietic stem cell transplantation (SCT), has emerged in recent years for the treatment of severe, refractory rheumatic autoimmune diseases including rheumatoid arthritis (RA). The rationale of this strategy is based on the concept of immunoablation by intense immunosuppression with subsequent regeneration of naïve T lymphocytes derived from reinfused hematopoietic progenitor cells. Patients with a therapy-refractory, progressively erosive disease who are at risk of functional disability and early mortality are considered eligible for treatment with autologous SCT. The goal is long-term improvement of disease activity and quality of life. However, when offering SCT to RA patients these benefits should be balanced against toxicities and treatment-related mortality. In several patients with intractable RA, long-term remissions were observed with this strategy, but failures have been reported as well. Only small numbers of RA patients have been treated thus far. Although different treatment protocols have been used, high dose chemotherapy as a means to achieve immunoablation has been invariably used in all studies. In this review we discuss background, clinical results, protocols, and future prospects of high dose chemotherapy and autologous SCT for RA.

Intensive immunosuppression and autologous stem cell transplantation for patients with severe rheumatoid arthritis: the Leiden experience.

Ten patients with active, destructive rheumatoid arthritis refractory to antirheumatic therapy enrolled in a study to evaluate the effects of intensive immunosuppression followed by autologous stem cell transplantation. Intensive immunosuppression was achieved with high dose cyclophosphamide as part of the mobilization (4 g/m2) and conditioning (200 mg/kg) regimen. The autologous stem cell products were enriched for CD34+ cells to minimize the chance of reinfusing autoreactive lymphocytes. Eight patients completed all consecutive treatment steps, one patient withdrew after mobilization because of improvement, one patient was taken off study because of pulmonary embolism. The treatment appeared feasible and safe, and marked sustained clinical improvement was observed in 6 patients, 2 of whom were previously unresponsive to tumor necrosis factor blocking therapy. In 5 patients disease modifying antirheumatic drugs were successfully withdrawn after transplantation. The treatment induced significant lymphopenia, with low levels of naive CD4+ T cells in particular, without clinical sequelae. Titers of rheumatoid factor dropped but did not normalize.

High dose chemotherapy followed by autologous peripheral blood stem cell transplantation or conventional pharmacological treatment for refractory rheumatoid arthritis? A Markov decision analysis.

OBJECTIVE: To evaluate the effect of high dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (ASCT) in comparison to conventional pharmacological therapy in the treatment of patients with refractory, progressively erosive rheumatoid arthritis (RA). METHODS: Decision analysis using a Markov model with a 5.5 year time horizon. Probabilities of transition towards 5 different health states, ranging from 70% improvement to death, were derived from published case reports, patient series, and expert panels. Quality of life (QOL) estimates were obtained from 2 RA clinical trials. Patients were hypothetical cohorts of 50-year-old female patients with progressively erosive, active RA, who failed treatment with methotrexate, combination therapy, and tumor necrosis factor blocking agents. Interventions were HDC + ASCT versus conventional pharmacological treatment with a (combination) therapy of disease modifying antirheumatic drugs. As main outcome measures, we included the number of quality adjusted life years (QALY) after HDC + ASCT compared to conventional therapy. Sensitivity analysis was performed to investigate the influence of treatment related mortality (TRM) and the influence of QOL during HDC + ASCT, and to assess the minimal desired effectiveness of HDC + ASCT for a given TRM of 1% and 10%. RESULTS: HDC + ASCT and conventional pharmacological treatment were equally effective in the base-case analysis (3.48 vs 3.46 QALY). A TRM of less than 3.3% favored HDC + ASCT as the preferred treatment. The analysis showed that when TRM was set at 1%, a relatively short period of efficacy was sufficient to remain the preferred strategy, whereas a TRM of 10% would require a sustained response for several years. CONCLUSION: This model predicted equally favorable effects of HDC + ASCT and conventional therapy in the treatment of refractory RA in the base-case. The minor differences in terms of QALY seem to indicate that clinical decision making should be guided by patient preferences. However, better clinical efficacy might be achieved by adaptation of the treatment regimen of HDC + ASCT and patient selection. The model supports the need for randomized clinical trials and may contribute to an optimal study design.

High-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with rheumatoid arthritis: results of an open study to assess feasibility, safety, and efficacy.

OBJECTIVE: To assess the feasibility, safety, and efficacy of high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT) in patients with severe, refractory rheumatoid arthritis (RA). METHODS: Fourteen patients (3 male, 11 female, mean age 43 years, mean disease duration 10 years) with active, destructive, refractory RA entered the study. Autologous hematopoietic stem cells were collected by leukapheresis after mobilization with a single infusion of cyclophosphamide (CYC; 4 gm/m2) and subcutaneous injections of filgrastim (granulocyte colony-stimulating factor). Immunomagnetic selection of CD34+ cells from the leukapheresis products was performed to deplete potentially autoreactive lymphocytes. The conditioning regimen consisted of intravenous administration of high doses of CYC (cumulative dose 200 mg/kg), with subsequent reinfusion of the graft. Patients were monitored for disease activity, disability, adverse effects, and hematopoietic and immunologic reconstitution. RESULTS: All 14 patients completed the mobilization and leukapheresis procedures successfully, and 12 proceeded to receive conditioning and transplantation. Engraftment occurred in all of these patients, with rapid hematologic recovery. No major unexpected toxicity was observed. Marked improvement of disease activity was recorded in 8 of 12 patients at >50% of the visits, with a followup ranging from 7 months to 21 months. The clinical responders included 2 patients who had previously failed treatment with tumor necrosis factor (TNF) blocking agents. CONCLUSION: High-dose chemotherapy followed by autologous HSCT is feasible and safe, and can result in long-term improvement of disease activity in patients whose condition previously did not respond to conventional antirheumatic drugs or TNF blocking agents. The persistence of active disease in some patients may reflect the heterogeneity of the underlying disease process.

Ex vivo treatment of antigen-presenting cells with CTLA4Ig and encephalitogenic peptide prevents experimental autoimmune encephalomyelitis in the Lewis rat.

We used a novel approach to study the role of CD28-B7 T cell costimulatory blockade in experimental autoimmune encephalomyelitis (EAE) in the Lewis rat model. APCs were incubated in vitro with CTLA4Ig and the encephalitogenic peptide p71-90 of myelin basic protein. Systemic injection of APCs treated ex vivo with p71-90 and CTLA4Ig before immunization protected animals from clinical EAE. Systemic injection of APCs treated with CTLA4Ig alone, CTLA4Ig and control peptide, peptide alone, or peptide and control Ig was not protective. Injection of APCs treated ex vivo with CTLA4Ig and p71-90 on the day of immunization was also protective, but delaying the injection till day 7 after immunization impaired the protective effect. Immunohistologically, protected animals had decreased inflammatory responses, with inhibition of Th1 and sparing of Th2 cytokines in the brain. Preincubation of APCs with p71-90 and a mutant form of CTLA4Ig that binds only B7-1 also protected animals from developing EAE. These results suggest that ex vivo blockade of CD28-B7-1 leads to the generation of regulatory cells, presumably Th2, which inhibit the generation or priming of encephalitogenic T cells and suppress the autoimmune response to the specific Ag in vivo. These observations have therapeutic implications for autoimmune diseases and transplantation.

The effect of beryllium compound solubility on in vitro canine alveolar macrophage cytotoxicity.

Pulmonary alveolar macrophage cells (PAM), obtained by bronchopulmonary lavage of Beagle dogs, were exposed in vitro to beryllium oxide (BeO) particles calcined at either 500 or 1000 degrees C or to beryllium sulfate (BeSO4). Cell viability was determined by trypan blue dye exclusion after 20 h in culture. The most toxic material tested was BeSO4, followed by BeO calcined at 500 degrees C, then BeO calcined at 1000 degrees C. An in vitro dissolution technique was used to measure the relative solubility of the BeO particles. The BeO prepared at 500 degrees C exhibited greater solubility compared with BeO prepared at 1000 degrees C. This study extends previous work by examining the effects of beryllium compounds on canine PAM, and by relating PAM cytotoxicity with measured values of beryllium compound solubility.

The spectrum of clinical manifestation of anomalous origin of the left coronary artery and surgical management.

Intercoronary collaterals play a major role in determining whether patients with the symptoms of anomalous left coronary artery will suffer infarction early in life with resultant complications or will survive to an older age before becoming symptomatic with angina. We believe that the definitive surgical treatment should be performed at the earliest age possible to avoid further damage to myocardial muscle.