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Pregnancy is a high-risk event in women with essential thrombocythemia (ET). This observational study evaluated pregnancy outcome in ET patients focusing on the potential impact of aspirin (ASA) or interferon alpha (IFN) treatment during pregnancy. We retrospectively analyzed 122 pregnancies in 92 women consecutively observed in the last 10 years in 17 centers of the Italian thrombocythemia registry (RIT). The live birth rate was 75.4% (92/122 pregnancies). The risk of spontaneous abortion was 2.5-fold higher than in the control population (P < 0.01). ASA did not affect the live birth rate (71/93, 76.3% vs. 21/29, 72.4%, P = 0.67). However, IFN treatment during pregnancy was associated with a better outcome than was management without IFN (live births 19/20, 95% vs. 73/102, 71.6%, P = 0.025), and this finding was supported by multivariate analysis (OR: 0.10; 95% CI: 0.013-0.846, P = 0.034). The JAK2 V617F mutation was associated with a poorer outcome (fetal losses JAK2 V617F positive 9/25, 36% vs. wild type 2/24, 8.3%, P = 0.037), and this association was still significant after multivariate analysis (OR: 6.19; 95% CI: 1.17-32.61; P = 0.038). No outcome concordance between first and second pregnancies was found (P = 0.30). Maternal complications occurred in 8% of cases. In this retrospective study, in consecutively observed pregnant ET patients, IFN treatment was associated with a higher live birth rate, while ASA treatment was not. In addition, the JAK2 V617F mutation was confirmed to be an adverse prognostic factor., ((c) 2009 Wiley-Liss, Inc.)

Background & Aims: Narrow band imaging (NBI) is an imaging technique that allows a better definition of capillary pattern and improves the contrast between adenomas and the surrounding mucosa. Conflicting data exist on the ability of NBI to improve detection of colonic neoplasm; the impact of NBI is being tested in several screening scenarios. We evaluated whether the routine use of NBI, compared with white light (WL), during the withdrawal phase of screening colonoscopy improved adenoma detection., Methods: This randomized controlled study included consecutive 50- to 69-year-old patients with positive immunologic fecal occult blood tests. They were randomly assigned to groups that were examined with WL (n = 108) or NBI (n = 103) during the withdrawal phase of their colonoscopies. The primary end point was the adenoma detection rate. The prevalence of non-polypoid and the total number of adenomas were also evaluated., Results: The number of total and mean per-patient adenomas were 201 (1.95 +/- 2.3) and 198 (1.83 +/- 2.1) in the NBI and WL groups, respectively (P = .69). The adenoma detection rates were 57.3% for patients examined by NBI and 58.3% for those examined by WL (P = .88). A total of 41 non-polypoid adenomas were identified (26 in the NBI and 15 in the WL groups, P = .16). The flat adenoma detection rates were 21.4% and 9.3% in the NBI and WL groups, respectively (P = .019)., Conclusions: The routine use of NBI in screening colonoscopy did not increase the adenoma detection rate. NBI seems to improve the detection of flat adenomas, although additional studies are necessary.

Compelling evidence indicates the role of sphingosine kinase 1 (SPHK1) deregulation in the processes of carcinogenesis and acquisition of drug resistance, providing the rationale for an effective anti-cancer therapy. However, no highly selective inhibitors of SPHK1 are available for in vitro and in vivo studies, except for the newly discovered 'SK inhibitor' (SKI). The present study showed that, in a panel of myeloid leukaemia cell lines, basal level of SPHK1 correlated with the degree of kinase inhibition by SKI. Exposure to SKI caused variable anti-proliferative, cytotoxic effects in all cell lines. In particular, SKI induced an early, significant inhibition of SPHK1 activity, impaired cell cycle progression and triggered apoptosis in K562 cells. Moreover, SKI acted synergistically with imatinib mesylate (IM) to inhibit cell growth and survival. Finally, the inhibitor affected the clonogenic potential and viability of primary cells from chronic myeloid leukaemia (CML) patients, including one harbouring the IM-insensitive Abl kinase domain mutation T315I. Due to the fact that the phenomenon of resistance to IM remains a major issue in the treatment of patients with CML, the identification of alternative targets and new drugs may be of clinical relevance.

Constipation is a highly prevalent and bothersome disorder that negatively affects patients' social and professional lives and places a great economic burden on both patients and national health services. An accurate determination of the prevalence of constipation is difficult because of the various definitions used, but many epidemiological studies have shown that it affects up to 20% of the population at any one time. Although constipation is not a physiological consequence of normal aging, decreased mobility and other co-morbid medical conditions may contribute to its prevalence in older adults. Functional constipation is diagnosed when no secondary causes can be identified. Patients have some unusual beliefs about their bowel habits. Systematic attention to history, examination and investigation, especially in older people, can be highly effective in resolving problems and in enhancing quality of life. There is a considerable range of treatment modalities available for patients with constipation, but the clinical evidence supporting their use varies widely. However, if constipation is not managed proactively, patients can experience negative consequences, such as anorexia, nausea, bowel impaction or bowel perforation. The clinical benefits of various traditional pharmacological and non-pharmacological agents remain unclear. The first steps in the treatment of simple constipation include increasing intake of dietary fibre and the use of a fibre supplement. Patients with severe constipation or those unable to comply with the recommended intake of fibre may benefit from the addition of laxatives. More recently, newer agents (e.g. tegaserod and lubiprostone), have been approved for the treatment of patients with chronic constipation. Additional work is needed to determine what role, if any, these agents may play in the treatment of patients with chronic constipation. The purpose of this review is to identify evidence-based interventions for the prevention and management of constipation in the elderly.

Background: Examining the current practice is important for the benchmarking of quality of colonoscopy and the comparison with the standards and recommendations expected by professional societies., Aim: To describe colonoscopy practice in Italy, on the basis of prospective analysis of a large number of examinations performed by operators with different levels of expertise in a wide range of unselected centres., Design and Setting: Cross-sectional, prospective and multicentre study., Methods: The main features of each endoscopy centre (structure indicators) were collected through the use of a standardised questionnaire. A second questionnaire was used to prospectively record details of all the consecutive colonoscopies performed in a 2-week study period., Results: Data from 278 centres and 12,835 consecutive colonoscopies were evaluated. Centres were uniformly distributed throughout Italy - north, centre and south - as was their organizational complexity and workload. Overall, adequate facilities (i.e. cleaning area for disinfection/reprocessing, equipped recovery room), and safety equipment (i.e. pulse oximetry, equipment for emergency cardiopulmonary resuscitation) were lacking in a considerable amount of centres, especially in those with a lower degree of organizational complexity. Written informed consent was routinely required in 87% of the centres, but a specific consent for colonoscopy, including detailed information on adverse events, was adopted by 66%. Regular programs for recording some quality indicators (i.e. cecal intubation, quality of bowel cleansing, patients' satisfaction and complications) were implemented in a minority of centres. About 93% of the colonoscopies were performed for diagnostic purpose; screening and surveillance accounted for 13.7% and 25.3% of the indications, respectively. Sedation and/or analgesia was administered in about half of the patients. Overall, colonoscopies were completed to the cecum in 80.7% of cases, and only 22.1% of the centres reported a cecal intubation rate >or=90%; this figure was reported in 33.1% of centres with high-organizational complexity and in 14.4% of outpatient units. The overall incidence of immediate complications was low (2 perforations, 26 bleedings and 32 serious cardiorespiratory complications)., Conclusions: This study documented a wide variation in colonoscopy practice between centres and highlighted problem areas where interventions are needed to improve performance and safety of the examinations.

It has been suggested that polycythemia vera (PV) could be preceded by an "early" phase of the disease (e-PV), in which the increase in the red cell parameters is lower than required for a PV diagnosis. In this study, we compared the clinicopathologic and molecular features of 17 patients with e-PV with those of 14 patients with essential thrombocythemia (ET) and 19 with PV. The results for e-PV were more similar to those for PV than for ET. In fact, patients with e-PV were characterized by an increase in the red cell parameters, splenomegaly (P<.05), and hepatomegaly (P=.038), together with hypercellular bone marrow due to increased erythropoiesis and granulopoiesis, associated with megakaryocytic hyperplasia, with pleomorphic aggregates (P<.001). The frequency of the JAK2V617F mutation was similar in e-PV (16 cases tested [100%]) and PV (18/19 [95%]) but was significantly lower (7/13 [54%]) in ET (P=.0007). We propose a diagnostic algorithm helpful to distinguish ET from the early prepolycythemic phase of PV.

Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by an indolent clinical course, with a median survival exceeding 20 years. A minority of patients undergo thrombohemorrhagic complications, which might be prevented by cytoreductive treatment in high risk categories. Alkylating agents (ALK) have been demonstrated to increase the risk of acute leukemia and myelodysplastic syndromes in patients with myeloproliferative disorders, whereas the potential oncogenicity of hydroxyurea (HU) remains a matter of debate. In this study, we retrospectively investigated long-term development of hematological and non-hematological second malignancies in 331 patients with ET, analyzing possible associations with chemotherapy treatments. Median follow-up was 108 months. Of the 194 patients who were treated with chemotherapy, 116 (60%) received only HU, 38 (19.5%) only ALK (busulfan or melphalan) and 40 (20.5%) ALK followed by HU. After a median time of 87 months from the diagnosis of ET, 43 patients developed a second malignancy, hematological in 15 and non-hematological in 28, for an overall cumulative incidence of 13%. According to the type of treatment, second malignancies were documented in 11.2% of patients treated with only HU, in 26.3% of patients who received only ALK, and in 25% of those treated with ALK followed by HU. Ten cases (7.3%) were recorded among the 137 patients who did not receive any treatment. Our analysis revealed a significant association between treatment with alkylating agents and an increased risk of developing second hematological malignancies, whereas no such association was detected with regard to treatment with hydroxyurea single agent in our ET population. In addition, different treatment strategies did not affect the risk of developing second solid cancers.

Background: It is essential to identify the factors in clinical practice that influence the technical performance of colonoscopy as a basis for quality improvement programs., Aims: To assess the factors linked to two key indicators of colonoscopy performance, i.e., cecal intubation and polyp diagnosis., Design and Setting: Consecutives colonoscopies performed over a 2-wk period in 278 unselected practice sites throughout Italy were prospectively evaluated. A multivariate model was developed to identify determinants of the performance indicators of colonoscopy., Results: In total, 12,835 patients (mean age 60.5 yr, standard deviation [SD] 15.1, 53% men) were studied. Sedation and/or analgesia was administered in 55.3% of procedures: 28.8% of patients received intravenous (IV) benzodiazepines, 15.4% received benzodiazepines in combination with narcotics, 3.1% received propofol, and 7.5% received other sedation regimens. Overall, cecal intubation was achieved in 80.7% of procedures, and the polyp detection rate was 27.3%. Multivariate analysis showed that the strongest predictors of cecal intubation were the quality of bowel preparation (inadequate vs excellent: odds ratio [OR] 0.013, 95% confidence interval [CI] 0.009-0.018; fair vs excellent: OR 0.246, 95% CI 0.209-0.290; and good vs excellent: OR 0.586, 95% CI 0.514-0.667) and the use of sedation (IV benzodiazepines vs no sedation: OR 1.460, 95% CI 1.282-1.663; IV benzodiazepines and narcotics vs no sedation: OR 2.128, 95% CI 1.776-2.565; and propofol vs no sedation: OR 2.355, 95% CI 1.590-3.488). The colonoscopy setting (workload and organizational complexity of the center) and the endoscopist colonoscopy volume were other factors independently correlated with completion of the procedure. Detection of polyps partially depended on the quality of bowel cleansing (inadequate vs excellent: OR 0.511, 95% CI 0.404-0.647) and use of sedation (OR 1.172, 95% CI 1.074-1.286)., Conclusion: In usual clinical practice, the use of sedation/analgesia, the colon-cleansing quality, the endoscopist experience, and some features related to the colonscopy setting decisively influence the quality of colonoscopy. These factors indicate the targets of future corrective measures to boost the quality of this examination.

Various clinical prognostic scoring systems (PSSs) have been suggested as means of selecting high-risk chronic idiopathic myelofibrosis (CIMF) patients at diagnosis. The WHO has recently proposed strict diagnostic criteria for CIMF, and the European consensus for bone marrow fibrosis (BMF) grading recommends 4 classes. It has been suggested that BMF grading may play a prognostic role in CIMF, but it has never been compared with the other PSSs in the same patients. We tested a prognostic model for overall survival (OS) based on the WHO criteria and BMF grading in 113 consecutive patients with chronic myeloproliferative disorders (98 with CIMF and 15 with postpolycythemic myelofibrosis), and compared the findings with those of PSSs. The results showed that our model is significantly associated with different OSs and, unlike the other PSSs, clearly discriminates the OS of intermediate- and high-risk patients.

Imatinib mesylate (IM) is used in the targeted therapy of chronic myelogenous leukemia and gastrointestinal stromal tumors. It is well tolerated and leads to no higher incidence of hemorrhagic events than other therapies. Of 87 patients we treated with IM for a minimum of 3 months, 10 patients (11%) developed unilateral or bilateral conjunctival hemorrhage (CH). No other hemorrhagic events were observed during follow-up, except for CH recurrence in 6 cases (7%). Because there was no other obvious reason for such a high incidence of CH, we hypothesize drug hypersensitivity or ocular irritation induced by IM treatment.

We examined microvessel density (MVD) and immunohistochemical expression of vascular endothelial growth factor (VEGF) in the bone marrow biopsy specimens of 98 patients with Philadelphia chromosome-negative (Ph-) chronic myeloproliferative disorders (CMPDs). There were significantly more MVD "hot spots" in chronic idiopathic myelofibrosis (CIMF; mean +/- SD, 25.6 +/- 6.3) and polycythemia vera (PV; 20.7 +/- 10.2) cases than in essential thrombocythemia (ET) cases (10.1 +/- 4.5) and normal control (NC) samples (7.5 +/- 3.6) (P < .05). Similar results were found using a semiquantitative method (P < .0001). A calculated VEGF index (VEGF(i)) was higher in CIMF (0.29 +/- 0.15) and PV (0.28 +/- 0.20) cases than in ET (0.12 +/- 0.05) and NC (0.08 +/- 0.04) cases (P < .0001). MVD and VEGF(i) were higher in the myelofibrotic phases of CIMF and PV. There was a direct correlation between VEGF(i) and MVD when considering the Ph- CMPDs together (r = 0.67; P < .001) and when considering PV (r = 0.79; P < .001) and CIMF (r = 0.40; P = .013) as individual entities. Our data could provide a rationale for directly targeting VEGF or endothelial cells in CIMF and PV.

Thrombotic and haemorrhagic complications are the main causes of morbidity in Essential Thrombocythemia (ET). We investigated the clinical and laboratory characteristics associated with the occurrence of these events with the aim of identifying subgroups of patients who might benefit from anti-aggregant and/or cytoreductive therapy. The study involved 306 consecutive ET patients (median age 58 years and median follow-up 96 months); the investigated variables were age, gender, platelet count, previous history of thrombotic or haemorrhagic events, disease duration and cardiovascular risk factors. Forty-six patients (15%) experienced thrombotic complications during the follow-up: 26/64 patients with a previous history of thrombosis (40.6%) and 20/242 patients without (8.3%; p < 0.0001). Thirty-one patients (10%) experienced major haemorrhagic complications, mainly gastrointestinal tract bleeding: 3 with and 28 without a history of haemorrhagic events (p = 0.052). When the patients with a negative history of thrombosis were stratified on the basis of the number of cardiovascular risk factors (none vs. one vs. more than one), there was a significant correlation with the occurrence of thrombotic events (p < 0.05). ET patients with a positive history of thrombosis are at high risk of thrombotic complications, and should receive cytoreductive and anti-aggregant treatment. Asymptomatic patients with a negative thrombotic history and no cardiovascular risk factors are at low risk, and should not be treated. Patients with a negative thrombotic history and one or more cardiovascular risk factors are at intermediate risk, and should be treated with anti-aggregant and/or cytoreductive therapy. The need for treatment should be periodically re-evaluated. Age and platelet count, generally accepted as very important risk factors for thrombosis, did not seem in our series associated with an increased risk for thrombosis., (2007 John Wiley & Sons, Ltd.)

Background and Study Aim: Continuous quality improvement (CQI) is recommended by professional societies as part of every colonoscopy program, but little is known with regard to its effectiveness for colonoscopy outcomes. We prospectively assessed whether the implementation of a CQI program in routine clinical practice influences the quality performance of colonoscopy., Methods: In an open-access endoscopy unit at a secondary care center in Northern Italy, 6-monthly audit cycles were carried out over a 4-year period, to identify reasons for poor colonoscopy outcomes and institute appropriate changes to improve performance. The colonoscopy completion rate and the polyp detection rate as detected by endoscopists were considered to be key measures for improvement., Results: The initial crude colonoscopy completion rate was 84.6%, with a range for individual endoscopists 80.4%-94%. Four endoscopists had a completion rate lower than 90%. The overall polyp detection rate was 34%, with a wide variation among endoscopists (range 14%-42%). Poor patient tolerance and differences in colonoscopist expertise were the main determinants of lack of completion and variation in polyp detection rate. Changes to sedation practice, greater access to endoscopy sessions for the endoscopists with the lowest performance rates, and other organizational arrangements, were implemented to improve quality performance. The crude completion rates improved consistently, up to 93.1%, over the study period. This trend was confirmed even when adjusted completion rates were calculated. All endoscopists reached a crude completion rate of 90% or more and a polyp detection rate of over 20%. The introduction of CQI did not significantly change the overall incidence of procedure-related complications., Conclusions: The effectiveness of colonoscopy can be improved by implementing a CQI program in routine colonoscopy practice.

Purpose: ABL kinase domain mutations have been implicated in the resistance to the BCR-ABL inhibitor imatinib mesylate of Philadelphia-positive (Ph+) leukemia patients., Experimental Design: Using denaturing high-performance liquid chromatography and sequencing, we screened for ABL kinase domain mutations in 370 Ph+ patients with evidence of hematologic or cytogenetic resistance to imatinib., Results: Mutations were found in 127 of 297 (43%) evaluable patients. Mutations were found in 27% of chronic-phase patients (14% treated with imatinib frontline; 31% treated with imatinib post-IFN failure), 52% of accelerated-phase patients, 75% of myeloid blast crisis patients, and 83% of lymphoid blast crisis/Ph+ acute lymphoblastic leukemia (ALL) patients. Mutations were associated in 30% of patients with primary resistance (44% hematologic and 28% cytogenetic) and in 57% of patients with acquired resistance (23% patients who lost cytogenetic response; 55% patients who lost hematologic response; and 87% patients who progressed to accelerated phase/blast crisis). P-loop and T315I mutations were particularly frequent in advanced-phase chronic myeloid leukemia and Ph+ ALL patients, and often accompanied progression from chronic phase to accelerated phase/blast crisis., Conclusions: We conclude that (a) amino acid substitutions at seven residues (M244V, G250E, Y253F/H, E255K/V, T315I, M351T, and F359V) account for 85% of all resistance-associated mutations; (b) the search for mutations is important both in case of imatinib failure and in case of loss of response at the hematologic or cytogenetic level; (c) advanced-phase chronic myeloid leukemia and Ph+ ALL patients have a higher likelihood of developing imatinib-resistant mutations; and (d) the presence of either P-loop or T315I mutations in imatinib-treated patients should warn the clinician to reconsider the therapeutic strategy.

We reviewed a large series of patients with essential thrombocythemia diagnosed on the basis of the Polycythemia Vera Study Group criteria, and reclassified them by evaluating their major morphologic features and clinical course using the World Health Organization classification. The morphologic review of the bone marrow biopsies of 116 patients (44 males and 72 females; aged 19 - 83 years, median 55 years; median follow-up 121 months) led to 22 cases (19%) being classified as essential thrombocythemia (ET), 24 (21%) as chronic idiopathic myelofibrosis (CIMF)-0, 44 (37%) as CIMF-1, 13 (12%) as CIMF-2, 9 (8%) as latent phase polycythemia vera, and four (3%) as chronic myeloproliferative disorder, unclassifiable. There was a significant difference in the median age of the ET and fibrotic CIMF patients (54.7 +/- 13.55 vs. 59.13 +/- 15.05 years; P = 0.03). Histologic analysis showed that the simultaneous presence of loose clusters of large/giant megakaryocytes and nuclear hyperlobulation was significantly different between the ET and the prefibrotic CIMF (P<0.01) and fibrotic CIMF patients (P<0.01), and that the association of dense clusters of megakaryocytes with maturation defects and bulbous nuclei also distinguished the prefibrotic CIMF (P<0.05) and fibrotic CIMF patients (P<0.001) from those with ET. The association of cellularity, granulocytic proliferation and reticulin fibers was helpful in distinguishing prefibrotic from fibrotic CIMF (P<0.001).

Objective: To compare the efficacy and patient acceptance of an oral high dose of senna to conventional polyethylene glycol-electrolyte lavage solution (PEG-ES) in adults undergoing elective colonoscopy., Methods: Consecutive outpatients referred for elective colonoscopy were prospectively randomly assigned to receive, the day before the procedure, either 24 tablets of 12 mg senna, divided into two doses at 1 p.m. and 9 p.m. (senna group, n=191), or standard 4-L PEG-ES (PEG-ES group, n=92). The overall quality of colon cleansing (primary outcome measure) and cleansing in the right colon were evaluated using the Aronchick scoring scale (1=excellent to 4=inadequate) by the investigator/endoscopist who was blinded to the treatment assignment. Patient acceptance and the safety of the preparation were assessed by a nurse, using a structured questionnaire covering compliance with the dosing, overall tolerance of the preparation (1=none or mild discomfort to 4=severely distressing), and adverse events., Results: The quality of colon cleansing, overall tolerance of the preparation, and compliance were significantly better with senna; overall cleansing was excellent or good in 90.6% of patients in the senna group and in 79.7% in the PEG-ES group (p= 0.003). The percentage of procedures rescheduled because of insufficient colon cleansing was 7.3% in the PEG-ES group and 2.6% in the senna group (p=0.035). Multivariate logistic regression modeling showed the PEG-ES preparation as negative independent predictor of unsuccessful bowel cleansing. The incidence of adverse reactions was similar in the two groups; patients who received senna experienced significantly less nausea and vomiting, but more abdominal pain., Conclusions: An oral high dose of senna is a valid alternative to standard PEG-ES for outpatient colonoscopy preparation.

Background and Study Aims: Endoscopic retrograde cholangiopancreatography (ERCP) is usually performed with the patient lying in the prone position, on the assumption that this position is optimal for cannulation of the papilla and for obtaining good-quality radiographic images. The supine position, however, may be more comfortable for the patient and may facilitate airway management, and this study aimed to compare the two positions in terms of procedure outcome, safety, and patient tolerance., Patients and Methods: Consecutive patients who were undergoing ERCP were randomized to start the procedure in either the prone position or the supine position. Patients under the age of 18 years, intubated patients, and those who had already undergone endoscopic sphincterotomy were excluded. The difficulty of cannulation was assessed using the Freeman score (1=one to five attempts; 2=six to 15 attempts; 3=more than 15 attempts; 4=failure of cannulation). Total procedure time, patient tolerance, willingness to undergo ERCP in the future, and procedure-related adverse cardiorespiratory events (oxygen desaturation, tachycardia, bradycardia) were also recorded., Results: A total of 34 patients were evaluated (21 men, 13 women; mean age 68, range 20-96), 17 patients in each group. Demographic and clinical features, and the indications for the procedure were similar for the two patient groups. The median Freeman score was significantly lower in the prone group compared with the supine group (1 vs. 3, P=0.0047, rank sum test). Biliary cannulation was achieved in all patients in the prone group, but was not achieved in five patients (29%) in the supine group (P=0.052). In four of these five patients, biliary cannulation was successfully achieved after turning the patient into the prone position. The percentage of patients unwilling to repeat the ERCP procedure in the future was higher in the supine group (29% vs. 6%, P=0.087); the mean tolerance score and mean total procedure time were similar in the two groups. Seven patients in the supine group experienced at least one adverse cardiorespiratory event, compared with only one patient in the prone group (41% vs. 6%, P=0.039)., Conclusions: ERCP performed with the patient in the supine position is technically more demanding for operators used to working with patients in the prone position and carries a greater risk of adverse cardiorespiratory events in nonintubated patients.

Background and Study Aims: The association between gastrointestinal symptoms and headache is frequently unrecognized. The aim of the present study was to determine the prevalence of migraine in dyspeptic outpatients referred for upper gastrointestinal endoscopy., Patients and Methods: Patients aged 18 - 55 years undergoing upper gastrointestinal endoscopy for dyspeptic symptoms in three endoscopic units were recruited consecutively. All of the patients were given a validated questionnaire on headache symptoms in order to determine the prevalence of migraine. Patients were divided into four groups (ulcer-like dyspepsia, reflux-like dyspepsia, dysmotility-like dyspepsia, only nausea and/or vomiting). Age-matched blood donors were given the same questionnaires and served as controls., Results: A total of 378 patients (mean age 40 +/- 11, 52 % men) and 310 controls (mean age 39 +/- 11, 56 % men) were enrolled. No differences were observed between the two groups in the prevalence of migraine (15 % vs. 11 %; P = 0.12). A higher prevalence of migraine was found among women in both groups (P < 0.006). In patients with reflux-like and ulcer-like dyspepsia, the prevalence of migraine did not differ from that in the control individuals (8 % and 7 %, respectively), whereas a higher prevalence of migraine was noted in patients with dysmotility-like dyspepsia (23 %; P < 0.02 vs. controls, those with ulcer-like dyspepsia and those with reflux-like dyspepsia) and in patients with nausea and/or vomiting alone (53 %; P < 0.002 vs. all other groups). The multivariate analysis confirmed that the symptom pattern and sex were the only variables independently associated with migraine., Conclusions: A diagnosis of migraine should be considered in young patients referred for upper gastrointestinal endoscopy due to nausea and/or vomiting or for dysmotility-like dyspepsia.

Rofecoxib is a selective cyclooxygenase-2 inhibitor that has been approved for the treatment of osteoarthritis and management of acute pain. Recent debate has emerged regarding the prothrombotic potential and the cardiovascular safety of this new drug, especially at doses greater than 25mg. We describe two extensively investigated cases of self-limited ischemic colitis in patients who were briefly treated with 50mg rofecoxib daily for acute pain. In both cases, the onset of symptoms correlated temporally with rofecoxib use and symptoms abated with drug discontinuation. There was no evidence of other possible causes of colon ischemia. A causal relationship between the start of rofecoxib treatment and the colon ischemia cannot be definitely established on the basis of the evidence, but the temporal relationship is striking and the pathophysiological rationale could be founded.

Objectives: To evaluate the referral patterns and indications for esophageal pH monitoring in an open-access system and to determine whether these indications conform to practice guidelines of the American Gastroenterological Association (AGA)., Methods: A total of 851 consecutive patients referred for ambulatory pH monitoring to nine open-access gastrointestinal units over a 12-month period received a structured interview. The indication for the examination was decided by the physician performing the procedure, on the basis of the patient's clinical history and main complaint., Results: Three hundred and twenty-three (38%) examinations were for indications in accordance with the guidelines. The proportion of appropriate requests in each center ranged from 34% to 47%. This figure was not significantly different in larger gastrointestinal units (more than 150 examinations per year) and smaller ones (35% and 40%; p= 0.14). The proportion of appropriate requests was 45% for gastroenterologists, 38% for surgeons, 32% for other specialists, and 24% for primary care physicians (PCPs) (p < 0.001). The percentage of appropriateness was significantly different between gastrointestinal specialists and PCPs (p < 0.001 vs gastroenterologists, p= 0.015 vs GI surgeons), and between gastroenterologists and other specialists (p= 0.006). The underuse of an empirical trial of acid-suppression therapy in patients with suspected reflux disease and the overuse of this test to confirm a diagnosis in patients with erosive esophagitis and in endoscopy-negative cases with typical symptoms responding completely to antisecretory therapy accounted for most of the referrals, which was not in accordance with the guidelines., Conclusions: In an open-access system, a high proportion of esophageal pH studies are done for indications not consistent with published guidelines, particularly among the examinations not requested by gastrointestinal specialists. Further education is still needed on the appropriate use of esophageal pH monitoring and management of gastroesophageal reflux disease (GERD).

The practice of sedation and analgesia is under increasing scrutiny by numerous regulatory agencies, with the aim of making these procedures safer and reducing the incidence of cardiopulmonary complications during GI endoscopy. As we move toward more evidence-based medicine, new technologies will have to be assessed in a manner that demonstrates their efficacy and utility in clinical practice. Although there have been no controlled studies examining whether more intensive monitoring during endoscopy improves outcomes, extended monitoring with capnography seems to offer an advantage over conventional monitoring in that, by providing a real-time indication of any change in adequate ventilation before oxygen desaturation occurs, it can detect early phases of respiratory depression, which can allow a more precise and safer titration of medications. There is a close agreement among experts that capnography may reduce the risk of adverse outcomes during deep sedation; therefore, its use should be required for patients undergoing advanced endoscopic procedures with the potential for deep sedation. Extended monitoring with capnography should also be endorsed whenever propofol is considered as an alternative to standard sedation with a benzodiazepine or narcotic. Our understanding of the clinical application of techniques for monitoring of depth of sedation is in its infancy, and its full contribution to the practice of endoscopy has yet to be determined. Their potential role in improving sedation practice during endoscopy needs to be confirmed by controlled trials. If we consider the lack of proven efficacy of these emerging monitoring techniques in reducing the adverse outcomes associated with sedation and analgesia, the importance of appropriate monitoring cannot be overemphasized. However, it is vital for the endoscopist to be thoroughly familiar with the type of sedation chosen, to be able to recognize the various levels of sedation, and, above all, to rescue patients should they unintentionally progress to a deeper level of sedation than intended.

Background: The aim of this study was to determine whether a single bolus of meperidine in addition to midazolam improves patient tolerance during colonoscopy., Methods: Consecutive patients undergoing outpatient colonoscopy were randomly assigned in double-blind fashion to receive a single rapid intravenous bolus of 5 mg of midazolam and placebo (Group A, n = 125) or 5 mg midazolam plus 50 mg meperidine (Group B, n = 128). Tolerance (4-point scale: 1 excellent, 4 unbearable), pain (4-point scale: 1 none, 4 severe) and willingness to undergo another colonoscopy were assessed 24 to 48 hours later in a telephone interview conducted by an independent observer blinded to the regimen of sedative medication., Results: Significantly more patients in Group A reported moderate or severe pain (28% vs. 9%; p < 0.001), poor or unbearable tolerance (18% vs. 6%; p < 0.01) and unwillingness to undergo colonoscopy again in the future (14% vs. 5%; p < 0.05). By multivariate analysis, randomization to the midazolam group and younger age were the only variables independently associated with the risk of reporting at least one of these outcomes. Recovery time, frequency of oxygen desaturation, and need for supplemental oxygen were not significantly different between the 2 groups., Conclusions: The addition of a single bolus of meperidine to midazolam improves patient tolerance and lessens pain during colonoscopy without significantly increasing the frequency of side effects or prolonging recovery time.

Essential thrombocythemia (ET) is a chronic myeloproliferative disorder that can rarely undergo leukemic transformation either in treated (3-7%) or untreated patients (1%). Evolution to myeloblastic or myelomonoblastic acute leukemia is commonly described in the literature, whereas lymphatic and megakaryocytic forms are considered unusual. Here, we report three cases of acute megakaryocytic leukemia (LMA-M7) among 11 acute leukemic transformations observed in our series of 321 ET patients. LMA-M7 was diagnosed employing immunophenotyping according to FAB criteria. These recurrences of LMA M7 suggest that this kind of evolution cannot be considered rare or casual in ET.

Background: The safety and tolerance of routine sedation and analgesia versus "on demand" sedation were compared in patients undergoing colonoscopy., Methods: Two hundred forty-nine outpatients were randomly assigned to one of two groups. Group A (n = 125) received midazolam, 0.07 mg/kg intravenously plus meperidine, 0.77 mg/kg intravenously immediately preceding the colonoscope insertion. Group B (n = 124) received the same medication upon request during the procedure. Tolerance was assessed 24 hours later by phone interview performed by a nurse blinded to the medication regimen administered., Results: Eighty-three patients (66%) in Group B required sedation during colonoscopy. Among men in Group B more than 60 years of age, only 23% required sedation. The proportion of patients reporting moderate or severe pain (34% vs. 12.1%, p < 0.001) and of those stating they would not be willing to undergo colonoscopy again in the future (22% vs. 9.7%, p < 0.005) was significantly higher in the "on demand" sedation group. By multivariate analysis the randomization group was the single variable independently associated with both such outcomes. The frequency of side effects was similar in the two groups., Conclusions: Administration of sedative and analgesic drugs routinely before colonoscopy is superior to "on demand" sedation in terms of tolerance and is not associated with an increase in side effects.

Objectives: High hepatocyte proliferation has been recently proposed as a risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to assess whether hepatocyte proliferation is an independent risk factor for HCC when considered together with clinical and demographic characteristics., Methods: We retrospectively evaluated 97 consecutive patients with a histological diagnosis of cirrhosis and preserved liver function, enrolled in a surveillance program for early diagnosis of HCC. Hepatocyte proliferation was evaluated by flow-cytometric analysis in liver samples collected at the time of histological diagnosis of cirrhosis. All patients were followed with abdominal US and serum alpha-fetoprotein (AFP) assays every 6 months., Results: During a mean follow-up of 53 months (range, 12-120 months), 12 patients developed HCC, giving an annual incidence of 2.8%. The mean S-phase fraction was 2.5%+/-1.6 in patients who developed HCC and 0.9%+/-0.6 in those who did not (p < 0.0001). By univariate analysis, S-phase fraction 1.8% or higher and AFP higher than 20 ng/ml were the only two variables significantly correlated with the development of HCC (p < 0.0001, p < 0.0001). Multivariate analysis found that both variables were independently associated with HCC development (p < 0.003 and p < 0.005, respectively), with hazard ratios of 8.0 and 7.3 (confidence intervals, 2.1-31.2 and 1.8-29.2). Among patients with high AFP and/or high S-phase fraction, 11 (39%) developed HCC, compared with only one (1%) with a low S-phase fraction and normal AFP, corresponding to HCC yearly incidences of 9.5% and 0.3% (p < 0.00009)., Conclusions: Patients with high S-phase fraction and/or above-normal serum AFP are at higher risk of developing HCC and should be offered a close surveillance program.

Background and Objectives: Splenectomy is the treatment of choice in the majority of patients affected by idiopathic thrombocytopenic purpura refractory to corticosteroid therapy, but it is not free from early and late complications. As the available literature does not seem to contain any precise indications concerning possible factors predicting the response to splenectomy, the aim of this retrospective study of 65 splenectomized patients was to attempt to identify potentially predictive clinical or laboratory parameters., Design and Methods: For the purposes of statistical analysis, the patients were divided into two groups: the first included those with a complete (platelets > 100x10(9)/L) or partial response (platelets 50-100 x10(9)/L) to splenectomy; the second, the non-responders (platelets < 50x10(9)/L). The non-parametric tests were based on the Kruskal-Wallis method for independent samples, and the independent samples were compared using the Chi-square test according to Pearson., Results: Univariate analysis did not reveal any significant correlation between successful splenectomy and age, sex, platelet count at diagnosis, anti-platelets antibody positivity, the site of platelet sequestration, the time between diagnosis and surgery, or the response to high intravenous immunoglobulin doses. However, the probability of success was greater in the patients with a complete or partial pre-operative response to steroid therapy (p<0.05)., Interpretation and Conclusions: The factor most frequently associated with the success of splenectomy is the site of autologous platelet sequestration. Our study did not identify any clinical or laboratory parameter clearly predictive of post-splenectomy cure other than a transient response to steroid treatment. This finding needs further confirmation in larger patient populations.

Background: Loss or reduction of duodenal folds, scalloping of Kerkring folds and a micronodular or mosaic duodenal mucosal pattern have been described in celiac disease (CD), endoscopic findings that are considered reliable in the diagnosis of this disorder. However, most data have been obtained in patients with suspected or certain disease. We assessed the accuracy of the above markers in diagnosing CD in patients with nonulcer dyspepsia., Methods: In this prospective study, in 705 consecutive dyspeptic patients (284 men, 421 women, mean age 51 +/- SD 15.8 years) duodenal biopsies were obtained only in the presence of typical endoscopic markers, whereas in another 517 (207 men, 310 women, mean age 49.9 +/- SD 16 years) duodenal biopsies were done irrespective of macroscopic findings. CD was diagnosed histologically and on the basis of positive antiendomysium antibody., Results: Endoscopic markers were found in 4 patients of the first group but CD was ruled out. In the second group 5 patients had an endoscopic pattern that was consistent and CD was diagnosed in 3, whereas 3 others with normal endoscopic findings were eventually diagnosed as having CD. Endoscopic markers had a sensitivity of 50% and a specificity of 99.6% (95% CI [11.8, 88.2 and 98.6, 99.9], respectively) with positive and negative predictive values of 60% and 99.4%, respectively., Conclusion: The accuracy of endoscopic markers in the diagnosis of CD must be reevaluated in relation to the characteristics of the population studied.

Background: Although 30% to 40% of patients with celiac disease (CD) (which affects 1 in 200 individuals) have dyspeptic symptoms, there is a lack o data concerning the prevalence of CD in patients with dyspepsia., Methods: In this prospective series, we enrolled all consecutive outpatients undergoing endoscopy of the upper gastrointestinal tract for dyspepsia at our centers between January and June 1998. The exclusion criteria were age younger than 12 years, workup or follow-up of an already known disease of the gastrointestinal tract, suspected CD, malabsorption, and/or iron-deficiency anemia., Results: Of the 3019 patients who were evaluated, 517 (17%) were eligible for the study. Endoscopic findings suggested CD in 5 cases. Celiac disease was histologically diagnosed in 6 patients (5 women and 1 man; mean age, 31.3 years; age range, 20-46 years), 3 of whom had a normal endoscopic pattern and 3 of whom had an endoscopic pattern that was consistent with CD. In the patients with histologically diagnosed CD, antiendomysium antibody positivity supported the diagnosis. The relative risk for CD was 2.32 (95% confidence interval, 1.06-5.07) in comparison with the general population and higher among females (3.22; 95% confidence interval, 1.37-7.56)., Conclusions: The present results indicate that the prevalence of CD in patients with dyspepsia is twice that of the general population. Thus, serological screening for CD should be considered in the early workup of these patients to allow diagnosis and treatment of an eminently treatable disease.

We report a case of acute self-limiting ulcerative jejunitis of unknown aetiology in a 72-year-old female patient in which a subsequent diagnosis of microscopic polyangiitis and Sjogren's syndrome was made. All known causes of jejunal ulceration and inflammation were excluded. Previously reported cases of acute self-limiting jejunitis are reviewed and the possibility that acute jejunitis in this patient had been the first manifestation of systemic vasculitis is discussed.

Objective: To evaluate the prevalence and the clinical evolution of patients with an initial diagnosis of indeterminate colitis., Design: Retrospective, observational study., Setting: Fifteen gastrointestinal units in northern Italy., Participants: Patients with an initial diagnosis of indeterminate colitis seen between 1988 and 1993., Interventions: Patients were traced through a common database and centres were requested to update their clinical follow-up., Main Outcome Measures: Frequency of patients with an initial diagnosis of indeterminate colitis among those with IBD; rate of patients who subsequently had a definite diagnosis of either Crohn's disease or ulcerative colitis., Results: Fifty out of 1113 IBD patients (4.6%) had been diagnosed as having indeterminate colitis. During follow-up, 37 patients (72.5%) had a definite diagnosis of either Crohn's disease or ulcerative colitis. The cumulative probability of having a definite diagnosis of either ulcerative colitis or Crohn's disease was 80% 8 years after the first one (i.e. the first diagnosis). The probability of having a diagnosis of Crohn's disease was increased in patients with fever at onset, segmental endoscopic lesions or extra-intestinal complications and in current smokers. The probability of having a diagnosis of ulcerative colitis was increased in patients who had not undergone appendectomy before diagnosis., Conclusions: In our area, indeterminate colitis accounts for about 5% of initial diagnoses of IBD. In about 80% of patients, a diagnosis of either ulcerative colitis or Crohn's disease is made within 8 years. Several clinical and demographic features can help in identifying those patients more likely to have a subsequent diagnosis of Crohn's disease and those more likely to have a subsequent diagnosis of ulcerative colitis.

Background and Objective: The diagnostic and prognostic value of bone marrow biopsy (BMB) has been widely investigated in patients with chronic myeloproliferative disorders (CMPD). The present study is based on a review of the results of routine BMBs taken from 93 essential thrombocythemia (ET) patients at the time of diagnosis., Design and Methods: The common BMB histologic parameters and clinico-hematologic variables were considered for diagnostic and prognostic purposes. Clinico-pathologic correlations were looked for univariately. Moreover, the diagnostic significance of the histologic findings was tested by means of cluster analysis. Overall survival and event-free survival were considered as prognostic endpoints., Results: There were no correlations between the clinic and pathologic findings, and none of the histologic and clinical parameters was predictive of survival or the occurrence of major clinical events. Cluster analysis of the BMB findings revealed two distinct morphologic patterns: one was clearly myeloproliferative; the other had somewhat dysplastic features. The event-free and overall survival rates in the latter group were significantly worse (p = 0.0377 and p = 0.0162 respectively), with major ischemic events accounting for most of the difference in event-free survival., Interpretation and Conclusions: These results have no clearcut counterpart in the literature, but we feel that dysplastic BMB findings could be included in the definition of ET prognostic scores in order to allow therapeutic strategies to be adapted to the level of risk.

The clinico-pathologic entity of idiopathic granulomatous gastritis is a form of granulomatous gastritis, distinct from Crohn's disease, sarcoidosis, infections, foreign bodies, malignancy or vasculitis. The case of a 61-year-old female is described who was admitted on account of progressive weight loss, diffuse abdominal pains, post-prandial vomiting. Gastroscopy revealed a pyloric stenosis managed surgically. Pathological examination of the resected stomach showed numerous non-caseating granulomas in the lamina propria. No definite aetiological factor could be detected. A diagnosis of idiopathic granulomatous gastritis was made. She remains well 5 years later and has not developed regional enteritis, sarcoidosis, or any other generalized diseases.

Hydroxyurea is a usually well-tolerated cytostatic agent, but its side effects include cutaneous lesions that appear after several years of maintenance therapy with hydroxyurea. The reported incidence of such adverse reactions varies from 10 to 35%; in our Center it is 2%. We describe a patient with essential thrombocythemia who presented with ulcers of the hands only 15 days after hydroxyurea treatment.

A new case of congenital short pancreas (partial agenesis or hypoplasia of the dorsal pancreas) is reported. The patient was a 61-year-old caucasian man, referred for two episodes of non-severe acute biliary pancreatitis. Clinical and laboratory findings and the presence of ultrasound biliary sludge in the gallbladder supported the biliary origin of pancreatitis. Computerized tomography revealed a slightly enlarged and hypodense head of the gland but could not identify any pancreatic tissue in the region of the body and tail. Endoscopic retrograde pancreatography showed a short pancreas with a duct system in communication both with the accessory and main papilla. Laparoscopic cholecystectomy was performed and no further episodes of abdominal pain occurred. Short pancreas is a rare congenital abnormality consisting in the parenchyma and ductal system restricted to the head with some residual dorsal tapering and arborizing ducts communicating with the minor papilla. This anomaly can be an incidental finding and its association with episodes of recurrent pancreatitis needs to be proven.

A panel of 51 cases of essential thrombocythaemia (ET), in chronic or leukaemic phase, was investigated for p53 gene and RAS oncogenes mutations by PCR-SSCP-direct sequencing. No RAS oncogenes mutations were detected, but p53 mutations were identified in three cases: 1/27 cases (approximately 4%) in chronic phase not undergoing chemotherapy, 1/19 cases (approximately 5%) in chronic phase undergoing chemotherapy, and 1/5 cases (20%) which had progressed to leukaemia. Our results suggest that: (1) p53 gene mutations occur sporadically in the chronic phase of ET, independent of chemotherapy, and may contribute to the progression to the leukaemic phase in a limited number of ET patients; (2) the RAS genes family does not seem to be involved in the pathogenesis of ET, unlike other bcr/abl negative chronic myeloproliferative diseases (CMPDs).

We report four pregnancies in four patients with essential thrombocythemia (ET). In two cases pregnancy resulted in spontaneous abortion at 6 and 11 weeks of gestation, respectively. The other two had a full-term, normal delivery; one of them received no therapy during the pregnancy, whereas the other was treated with acetylsalicylic acid from 11 weeks for signs of threatened abortion. No thrombotic or hemorrhagic complications were observed in any of the patients during pregnancy or the post-partum period. We believe that pregnancy in patients with ET represents a risk. Close monitoring is therefore indispensable and antiaggregant therapy might be of benefit.

The paper reports a number of cases of uncommon metastasis confirmed by histological tests in surgical biopsies; following a brief discussion of the literature on this topic and in particular on the basis of an earlier study by one of the authors, the paper affirms that metastasis is related to general and local biological factors, that the diffusion of neoplastic cells is an early and generalised phenomenon opposed by organic defence mechanisms, and that the concept of uncommon metastasis should be revised, without resorting to fixed anatomical references, according to a general "impregnation" of tumour cells.

A vincristine, melphalan, cyclophosphamide, and prednisone (VMCP) multi-drug regimen was used in 85 previously untreated patients with multiple myeloma (MM) (symptomatic Durie Stages II and III) until they became refractory. The prognostic significance of various pretreatment characteristics was evaluated in terms of therapeutic response (according to Southwest Oncology Group [SWOG] and Chronic Leukemia-Myeloma Task Force [TF] criteria) and survival. Therapeutic responses, obtained in 31.2% (SWOG) and 68.7% (TF) of patients, had a significant inverse correlation with myeloma cell mass, serum calcium, and bone status. Median survival time of Stage II and Stage III patients was 39 and 34 months, respectively. Serum B2 microglobulin greater than or equal to 6 micrograms/ml was the only variable correlating unfavorably with survival duration after multi-variate analysis (increased risk = 2.79), although therapeutic response as a time-dependent variable had no effect on survival. These data suggest no correlation between response and survival, partially because of inadequate response assessment criteria and partially because no existing treatment is curative (although current therapeutic approaches may prevent death from complications).

A retrospective study of 103 patients with essential thrombocythemia was carried out to evaluate the incidence of thrombohemorrhagic complications and establish whether there were any correlations between these events and clinical or laboratory data. At onset or during the course of the disease, 26 patients (25.2%) presented thrombotic and 12 (11.6%) hemorrhagic complications: among the latter, six patients had gastrointestinal bleeding during antiaggregant therapy. No significant correlations were observed between thrombohemorrhagic complications and platelet count, age, sex, platelet function, bleeding time, or therapeutic regimen. However, there was a statistically significant correlation between a positive patient history for thrombotic events and an increase in thromboses. In agreement with other authors, it is believed that the best approach in asymptomatic patients is strict surveillance without treatment. Chemotherapy and/or treatment with antiaggregant agents should be reserved for symptomatic patients or patients with a positive history for thrombotic events.

Legionella pneumonia is an increasingly frequently reported complication in immunocompromised patients, particularly patients with hairy cell leukemia (HCL) in active phase. The most important predisposing factor seems to be the quantitative and qualitative defect of the monocytic-macrophagic system characteristic of HCL. We report a case of severe Legionella pneumophila infection with multisystem involvement in a patient with HCL in stable partial remission obtained after therapy with interferon. In our patient recovery of a normal monocyte count did not protect against a legionella infection, indicating that this pathogen should always be sought in HCL patients even those in clinical and hematologic remission. Early diagnosis and appropriate treatment may reduce the mortality of this serious complication.

Between January 1983 and December 1988 67 patients presenting with solitary cerebral recurrence from lung cancer were observed in our Institution. Resection was possible in 21 cases (31%). The surgical treatment included craniotomy with radical thoracotomy in 10 patients, craniotomy alone (with thoracotomy not including radical lung resection) in 5 patients and craniotomy performed within months of the initial elective thoracic surgery in 6 patients. In our series routine brain CT was carried out as a part of the staging procedure for lung cancer. Based on our results, we recommend an aggressive surgical approach to both cerebral recurrence and lung primary (scheduling craniotomy before thoracotomy), followed by whole brain RT, in order to prolong survival and improve the quality of life.