bluuebunny/crossref_metadata_2025 huggingface dataset:
Lansoprazole 15 and 30 mg daily in maintaining healing and symptom relief in patients with reflux oesophagitis
Authors: HATLEBAKK J. G. , BERSTAD A.
Published: October 2003

Background: In patients with reflux oesophagitis, endoscopic healing and symptom relief are considered important treatment goals in long‐term care.

Aim: To compare the effect of lansoprazole 15 and 30 mg daily on maintaining endoscopic healing and symptom relief in patients with moderate reflux oesophagitis.

Patients and methods: In a single‐centre, double‐blind randomized clinical trial, 103 patients with grade 1 or 2 reflux oesophagitis who were endoscopically healed and asymptomatic after lansoprazole 30 mg daily for 12 weeks, were randomized to maintenance therapy with either lansoprazole 15 mg or 30 mg o.m. Endoscopy was repeated after 3, 6 and 12 months, and symptom relief assessed after 3, 6, 9 and 12 months. Relapse of oesophagitis or symptoms were considered end‐points.

Results: After 12 months, 14/50 patients (28%) receiving lansoprazole 15 mg daily had suffered an endoscopic relapse compared to 8/53 patients (15%) treated with lansoprazole 30 mg daily. A life table analysis showed no statistically significant difference between the two groups (P=0.086). Significantly more patients were kept in complete symptomatic remission in the 30 mg group (P<0.01). In the 15 mg group, 23/50 (46%) had suffered either an endoscopic or symptomatic relapse on completion of the study, compared to 12/53 (23%) in the 30 mg group. A life table analysis showed this difference to be statistically significant (P=0.010). Lansoprazole 15 and 30 mg daily were equally well tolerated.

Conclusion: No statistically significant differences were found in endoscopic relapse rate or occurrence of adverse events, while lansoprazole 30 mg proved superior to 15 mg in maintaining patients in symptomatic relief and combined endoscopic and symptomatic remission.
Clinical economics review: Helicobacter pylori‐associated peptic ulcer disease
Authors: BODGER K. , DALY M. J. , HEATLEY R. V.
Published: October 2003

The high prevalence and chronic nature of peptic ulcer disease have traditionally resulted in a major economic burden on health care systems. In 1991, for example, peptic ulcer disease was estimated to account for over one‐third of all National Health Service expenditure on gastrointestinal diseases. It is now well established that elimination of Helicobacter pylori can lead to a dramatic reduction in gastroduodenal ulcer relapse, with obvious clinical benefits. This review considers the economic implications of the use of H. pylori eradication therapy in peptic ulcer disease.
Recurrence of duodenal ulcer after Helicobacter pylori eradication is related to high acid output
Authors: HARRIS A. W. , GUMMETT P. A. , PHULL P. S. , JACYNA M. R. , MISIEWICZ J. J. , BARON J. H.
Published: October 2003

Background: Helicobacter pylori eradication reduces the recurrence of duodenal ulcers. It is unclear why duodenal ulcers rarely recur in the absence of reinfection with H. pylori or NSAID treatment.

Methods: Basal, gastrin‐releasing peptide‐ and pentagastrin‐stimulated peak acid outputs in patients with ulcer relapse after H. pylori eradication were measured, and compared with patients without ulcer relapse after H. pylori eradication.

Results: Pentagastrin‐stimulated peak acid output was significantly higher in H. pylori‐positive patients with duodenal ulcers than in H. pylori‐negative controls, and fell significantly after H. pylori eradication. In H. pylori‐negative patients with recurrent duodenal ulcers, pentagastrin‐stimulated peak acid output was significantly higher than in controls and similar to H. pylori‐positive patients with duodenal ulcers.

Conclusions: These findings suggest that duodenal ulcer relapse after eradication of H. pylori may be related to high pentagastrin‐stimulated peak acid output. In this subset of patients with duodenal ulcers, maintenance anti‐secretory treatment may be necessary to prevent relapse.
Acyclovir‐induced colitis
Authors: WARDLE T. D. , FINNERTY J. P. , SWALE V. , BEER T.
Published: October 2003

Three patients developed acute colitis, either de novo, or as an exacerbation of pre‐existing colitis, following the use of oral acyclovir, prescribed for Herpes zoster or Herpes simplex infection. Rechallenge with oral acyclovir was performed in one patient, and resulted in a recurrence of colitic symptoms. It is speculated that acyclovir can have a direct irritant effect on large bowel mucosa.
Review article: controversy in the therapy of gastro‐oesophageal reflux disease—long‐term proton pump inhibition or laparoscopic anti‐reflux surgery?
Authors: WALKER S. J. , BAXTER S. T. , MORRIS A. I. , SUTTON R.
Published: October 2003

The treatment of gastro‐oesophageal reflux disease is controversial. Whilst medical treatment is successful in patients with mild to moderate disease, the threshold of severity above which an operation should be contemplated remains a matter for debate. Laparoscopic anti‐reflux surgery may be lowering this threshold, as this form of therapy provides several advantages over its open counterpart, but it is not without risk, and few long‐term results are available. This article reviews treatment options for reflux disease and examines the relative position of current medical and surgical therapies.
Review article: update on the role of transjugular intrahepatic portosystemic stent‐shunt (TIPSS) in the management of complications of portal hypertension
Authors: STANLEY A. J. , REDHEAD D. N. , HAYES P. C.
Published: October 2003

In the 8 years since its introduction into clinical practice, initial enthusiasm for the transjugular intrahepatic portosystemic stent‐shunt (TIPSS) has been tempered by a more critical appraisal of its role in the management of portal hypertension. TIPSS has established its role as a rescue procedure for variceal haemorrhage uncontrolled by endoscopic means and as a treatment for ectopic or recurrent variceal bleeding. Randomized trials comparing TIPSS with endoscopic methods in the secondary prophylaxis of oesophageal variceal haemorrhage have shown reduced rebleeding after TIPSS but no effect on survival. Its exact role in this situation awaits further assessment, including quality of life and cost analyses, and consideration of the current limited availability of the technique.

Experience of TIPSS in patients with refractory ascites or hepatorenal syndrome has been disappointing. Little data currently exist, but results of further randomized studies comparing TIPSS with paracentesis for refractory ascites are awaited. Ideally these should be multicentre studies, and should include quality of life data for this poor prognostic group.

Development of shunt insufficiency remains a major problem and occurs in ≈50% patients at 1 year. The need for continued shunt surveillance by Doppler sonography and direct portography is the major limitation of TIPSS, but hopefully the development of covered stents will address this problem.
One‐week low‐dose triple therapy for Helicobacter pylori is sufficient for relief from symptoms and healing of duodenal ulcers
Authors: LABENZ J. , IDSTRÖM J.‐P. , TILLENBURG B. , PEITZ U. , ADAMEK R. J. , BÖRSCH G.
Published: October 2003

Aim: To test the hypothesis that 1‐week low‐dose triple therapy for H. pylori is sufficient for relief from dyspeptic symptoms and healing of duodenal ulcers.

Methods: Fifty‐nine out‐patients with duodenal ulcers and positive rapid urease test participated in this randomized, double‐blind, two‐centre study. All patients were treated for 1 week with omeprazole 20 mg b.d., clarithromycin 250 mg b.d. and metronidazole 400 mg b.d. In a double‐blind fashion, patients were then randomly treated for another 3 weeks with either omeprazole 20 mg once daily or an identical‐looking placebo. Patients were investigated endoscopically before treatment for H. pylori, after 2 weeks and after 4 weeks. H. pylori infection was assessed by a 13C‐urea breath test at the time of enrolment and 4 weeks after cessation of any study medication.

Results: Fifty‐two patients were included in the ‘all patients treated’ analysis of efficacy. The overall H. pylori cure rate was 96% (95% CI=87–100%), with no difference between the treatment groups. After 2 weeks duodenal ulcer healing was confirmed in 91% (95% CI=80–100%) of patients treated with omeprazole and in 76% (95% CI=60–91%) in the placebo group (P=0.14). After 4 weeks all ulcers had healed. Relief from dyspeptic symptoms and adverse events (13.8 and 16.7%) did not differ between the treatment groups.

Conclusions: One‐week low‐dose triple therapy consisting of omeprazole, clarithromycin and metronidazole is a highly effective and well‐tolerated approach to the cure of H. pylori infection in patients with a duodenal ulcer. Our data suggest that continuation of antisecretory drug therapy beyond anti‐H. pylori therapy is actually excessive regarding relief from dyspeptic symptoms and healing of duodenal ulcers.
Review article: irritable bowel syndrome
Authors: CAMILLERI M. , CHOI M.‐G.
Published: October 2003

Irritable bowel syndrome is a disease that can be diagnosed positively on the basis of an established series of criteria and limited exclusion of organic disease. It is the most common disease diagnosed by gastroenterologists and affects about 20% of all people at any one time. Symptoms fluctuate, and the overall prevalence rate is relatively constant in Western communities. Ten per cent of patients present to their physicians; the illness has a large economic impact on health‐care utilization and absenteeism. Irritable bowel syndrome is a biopsychosocial disorder in which three major mechanisms interact: psychosocial factors; altered motility; and/or sensory function of the intestine. Management of patients is based on positive diagnosis of the symptom complex, limited exclusion of underlying organic disease and institution of a therapeutic trial. If patient symptoms are intractable, further investigations are needed to exclude significant motility or other disorders. Symptomatic treatment includes fibre for constipation, loperamide for diarrhoea and low‐dose antidepressants or infrequent use of antispasmodics for pain; novel pharmacological agents, psychotherapy and hypnotherapy are being evaluated.
A one‐week quadruple eradication regimen for Helicobacter pylori in routine clinical practice
Authors: VAUTIER G. , SCOTT B. B.
Published: October 2003

Background: The addition of omeprazole to 1 week of standard triple therapy (tripotassium dicitrato bismuthate, tetracycline and metronidazole) has given a 98% eradication rate in 54 patients at 4–6 weeks in a research setting. We report the result of a similar 1‐week regimen in 52 patients in routine clinical practice assessed at a mean of 8 months.

Methods: Fifty‐two patients with peptic ulcer disease and antral biopsies containing Helicobacter pylori sensitive to metronidazole were given a 7‐day course of treatment: omeprazole 20 mg b.d., tetracycline 500 mg q.d.s. and tripotassium dictitrato bismuthate chelate tablets 120 mg q.d.s., with metronidazole 400 mg five times daily for the last 3 days only. Completeness of eradication was assessed by a 13C‐urea breath test at 4–26 months (mean 8 months).

Results: Forty‐eight patients (92%) had a negative breath test. Three patients vomited on the last day of the course, otherwise the treatment was well tolerated with the expected minor side‐effects of tongue discoloration, nausea and unpleasant taste.

Conclusions: The efficacy of a modified 1‐week standard triple therapy with omeprazole is confirmed and shown to be almost as effective in routine clinical practice as a similar regimen in a research setting.
Review article: the dietary management of Crohn's disease
Authors: KING T. S. , WOOLNER J. T. , HUNTER J. O.
Published: October 2003

Enteral feeding has been shown to be as effective as primary therapy for Crohn's disease, but it requires high patient motivation, may be unpalatable and is expensive. However, in adolescents with growth failure and when corticosteroid therapy is contra‐indicated or has failed, it may become the treatment of choice. Furthermore, dietary therapy allows circumvention of the adverse side‐effects of repeated courses of steroids.

A number of different hypotheses have been proposed to explain the effect of enteral feeds but none has reached universal acceptance. Prospective trials suggest that the exclusion of whole protein is not necessary. Comparison of feeds with differing composition suggests that a low fat content increases efficacy and various explanations have been offered. The reduction of colonic bacterial load may also be important.

Because symptoms of Crohn's disease may be provoked by eating, there is a risk of falsely attributing symptoms to specific foodstuffs. However, in many individuals foods can be identified which affect disease activity, and their exclusion leads to prolongation of disease remission. Dietetic supervision during food testing is important to avoid detrimental effects on nutrient and micronutrient intake.
Antiemetic activity of ondansetron in acute gastroenteritis
Authors: CUBEDDU L. X. , TRUJILLO L. M. , TALMACIU I. , GONZALEZ V. , GUARIGUATA J. , SEIJAS J. , MILLER I. A. , PASKA W.
Published: October 2003

Background: The mechanism of nausea and vomiting associated with gastroenteritis is unknown. The role of 5‐HT3 receptors in emesis associated with gastroenteritis was investigated in paediatric patients.

Methods: A randomized, double‐blind, placebo‐controlled, parallel‐group study was conducted in three groups of 12 patients each, receiving either a single i.v. dose of ondansetron (0.3 mg/kg), metoclopramide (0.3 mg/kg) or placebo (sterile saline). Food was restricted and oral rehydration was administered for 4 h.

Results: During 0–24 h, the number of emetic episodes experienced was significantly greater (P=0.048) with placebo (mean=5) than ondansetron (mean=2) and the proportion of patients experiencing no emesis was significantly greater (P=0.039) with ondansetron (58%) than placebo (17%). A numerical difference, in favour of ondansetron, was observed between ondansetron and metoclopramide groups for both of the above parameters. Fewer treatment failures were observed with ondansetron (17%) than placebo (33%) and metoclopramide (42%). More diarrheal episodes were observed in the groups receiving anti‐emetic treatment. All three treatments were well tolerated.

Conclusions: Ondansetron, a 5HT3 receptor antagonist, was significantly superior to placebo in preventing emesis associated with acute gastroenteritis, in paediatric patients. Therefore, serotonin, acting through 5HT3 receptors, may play a role in this form of emesis.
In vivo effects of the 5‐HT3 antagonist alosetron on basal and cholera toxin‐induced secretion in the human jejunum: a segmental perfusion study
Authors: BEARCROFT C. P. , ANDRÉ E. A. , FARTHING M. J. G.
Published: October 2003

Background:

5‐hydroxytryptamine type 3 receptor antagonists have been shown to reduce fluid and electrolyte secretion or promote absorption in experimental models of small intestinal secretion. The aim of this study was to compare the effects of a single dose (4 mg) of the 5‐hydroxytryptamine type 3 receptor antagonist alosetron and placebo on jejunal fluid and electrolyte movement in humans under basal conditions (n=7) and following cholera toxin‐induced secretion (n=5) in a randomized, double‐blind, crossover design over two separate study periods.

Methods:

One hour after oral alosetron or placebo, jejunal intubation was performed. A 30 cm segment of jejunum, isolated by two occluding balloons, was exposed to 15 μg of purified cholera toxin for 2 h prior to triple lumen perfusion with a plasma electrolyte solution containing []> 14C]‐polyethylene glycol as a non‐absorbable volume marker. In the basal study, intestinal perfusion was performed without exposure to cholera toxin. Collection and analysis of the effluent from the jejunal segment allowed fluid and electrolyte movement to be calculated.

Results:

Alosetron treatment increased basal jejunal fluid absorption (median 5.1 mL/cm/h [interquartile range 4.2 to 7.1] compared with placebo (3.8 [3.6 to 4.3] P=0.028, two sided Wilcoxon matched pairs signed rank test)). However, following establishment of a secretory state by cholera toxin, alosetron failed to significantly promote absorption or reduce secretion (0.3 [−1.2 to 1.2] compared to placebo (−4.3 [−7.7 to −1.3] P=0.14)). Adverse events during the study, which included anorexia, nausea, dizziness and loose bowel movements, were not considered to be clinically important. There were no clinically significant changes in laboratory parameters.

Conclusion:

The 5‐hydroxytyptamine type 3 receptor antagonist, alosetron increased basal fluid absorption in normal human small intestine but failed to have a beneficial effect in cholera toxin‐induced secretion.
Peripheral blood progenitor cell collections in multiple myeloma: predictors and management of inadequate collections
Authors: Prince H. Miles , Imrie Kevin , Sutherland D. Robert , Keating Armand , Meharchand Jacinta , Crump R. Michael , Girouard Caroline , Trip Kathy , Stewart A. Keith
Published: October 2003

Thirty‐seven patients with previously treated multiple myeloma (MM) underwent peripheral blood progenitor cell (PBPC) collection following high‐dose cyclophosphamide and GM‐CSF or sequential IL‐3 and GM‐CSF. Patients with an inadequate collection were considered for a second or third collection. 25 patients underwent subsequent autotransplant. The only variable predictive of CFU‐GM yield was the extent of prior melphalan therapy. All repeat collections were unsuccessful and patients infused with an autograft obtained from multiple sets of collections had a high incidence of delayed engraftment. We conclude that melphalan should be avoided or PBPC collection performed early in the disease course in patients who are potential transplant candidates.
Bone marrow assessment in B‐cell chronic lymphocytic leukaemia: aspirate or biopsy? A comparative study in 258 patients
Authors: Montserrat Emilio , Villamor Neus , Reverter Juan‐Carlos , BruguÉs Rosa‐MarÍa , TÀssies Dolors , Bosch Francesc , Aguilar Josep‐LluÍs , Vives‐Corrons Joan‐Lluis , Rozman Maria , Rozma Ciril
Published: October 2003

To evaluate the relative merits and prognostic value of bone marrow aspirate and bone marrow biopsy in the assessment of bone marrow infiltration in B‐cell chronic lymphocytic leukaemia (CLL), two observers independently reviewed the percentage of lymphocytes in bone marrow aspirate (lymphocytic infiltration, LI) and the bone marrow histological pattern (BMP) in 258 patients. The inter‐observer reproducibility and agreement was higher for BMP than for LI. BMP was an independent prognostic factor for survival in the whole series, whereas LI only had independent predictive value in stage A patients. In the entire series, disease progression was predicted by either BMP and LI, whereas in stage A patients only by BMP. Regarding low‐risk CLL (smouldering CLL or A′′1 substage), BMP led to a more reproducible identification of these clinical forms than LI. In conclusion, although both BMP and LI are of value to estimate bone marrow infiltration in CLL and to predict the outcome of the disease, BMP is more reliable and reproducible than LI.
Humanized CD52 monoclonal antibody campath‐1H as first‐line treatment in chronic lymphocytic leukaemia
Authors: ÖSterborg Anders , Fassas Athanasios S. , Anagnostopoulos Achilles , Dyer Martin J. S. , Catovsky Daniel , Mellstedt Håkan
Published: October 2003

The humanized CD52 monoclonal antibody Campath‐1H was used as first‐line therapy in nine patients with progressive chronic lymphocytic leukaemia (CLL). Intravenous (n = 5) or subcutaneous (n = 4) injections (up to 30 mg/inj.) were given three times a week for a maximum of 18 weeks. Three patients achieved a complete remission (CR) and five patients a partial remission (PR) (response rate 89%). CLL cells were cleared from blood in all patients and from the bone marrow in seven patients. The response duration time was 8+–24+ months. Adverse events were mild except for one patient who developed CMV pneumonitis. All patients developed lymphocytopenia (B and T cells) but other haematological toxicities were negligible. Campath‐1H is a highly effective and well‐tolerated agent in patients with previously untreated CLL and further studies are warranted.
Correction of aplastic anaemia complicating paroxysmal nocturnal haemoglobinuria: absence of eradication of the PNH clone and dependence of response on cyclosporin A administration
Authors: STOPPA Anne Marie , VEY Norbert , SAINTY Danielle , ARNOULET Christine , CAMERLO Jacques , CAPPIELLO Maria Antonietta , GASTAUT Jean Albert , MRANINCHI Dominique
Published: October 2003

Paroxysmal nocturnal haemoglobinuria (PNH) is defined as a somatic mutation of a clonal population of stem cells. Consequently, when aplastic anaemia (AA) occurs in patients with a history of PNH, allogeneic bone marrow transplantation is considered as the only effective treatment. The impact of immunosuppressive therapy has not been reported in this situation. We present observations of three PNH patients who developed AA and were effectively treated with cyclosporin A (CSA).

Because of lack of improvement with other treatments, CSA alone was given at a dose of 5–10 mg/kg/d. Complete response (CR) was obtained in two patients after 6 and 24 months respectively. A partial response (PR) was observed in the third patient after 12 months. Transient elevated LDH and haemosiderinuria persisted in all cases. DAF and MIRL deficiency were still documented in the two patients in CR.

Two patients (one CR, one PR) ceased CSA therapy after 12 months and relapsed within 3–6 months. CSA was reinitiated and led to platelet recovery in one patient after 6 months.

The persistence of the abnormal PNH clone is coherent with the hypothesis that CSA does not act directly on the PNH clone but probably acts through regulation of the inhibitory effects of immunocompetent cells on haemopoiesis.

These observations suggest that patients suffering from severe AA complicated PNH should not be excluded from immunosuppressive therapy.
T‐cell form of chronic lymphocytic leukaemia: a reaffirmation of its existence
Authors: Wong K. F. , Chan J. K. C. , Sin V. C.
Published: October 2003

Early in the 1980s three categories of T‐cell chronic lymphocytic leukaemia were recognized: CD4+ CD8− knobby type, CD4− CD8+ azurophilic type and CD4+ CD8− adult T‐cell leukaemia (ATL) type. Both azurophilic and ATL types were later shown to be distinctive disorders, whereas the knobby type has been largely neglected and even considered non‐existent by some authors. In this report we describe two patients with leukaemia of CD3+ CD4+ CD8− post‐thymic T lymphocytes presenting with marked lymphocytosis, generalized lymphadenopathy and hepatosplenomegaly. We believe that CLL of post‐thymic T‐lymphocytes is a distinct entity, and merits a separate designation from other T‐cell leukaemias.
Sustained trilineage recovery and disappearance of abnormal chromosome clone in a patient with myelodysplastic syndrome following combination therapy with cytokines (granulocyte colony‐stimulating factor and erythropoietin) and high‐dose methylprednisolone
Authors: Imai Yasufumi , Fukuoka Toshihiko , Nakatani Atsushi , Ohsaka Akimichi , Takahashi Atshushi
Published: October 2003

We report a case of hypoplastic myelodyplastic syndrome (MDS) (refractory anemia (RA)) in which sustained trilineage haematological response and persistent disappearance of an abnormal chromosome clone were achieved after treatment with combination therapy of cytokines (granulocyte colony‐stimulating factor (G‐CSF) and erythropoietin (Epo)) and methylprednisolone (mPSL) pulse dose. The patient's haematological recovery was rapid and maintained even after cessation of the therapy. In addition, the predominant chromosome clone 13q− in bone marrow cells disappeared in the fourth week. The patient's improved bone marrow haemopoiesis and disappearance of the abnormal chromosome has continued to the present, 13 months after treatment. The occurrence of both trilineage response and abnormal chromosome disappearance in MDS patients treated with cytokine(s) or steroids in rare. Combination therapy might therefore be advantageous in MDS.
Cytokine levels in platelet concentrates: quantitation by bioassays and immunoassays
Authors: Wadhwa M. , Seghatchian M. J. , Lubenko A. , Contreras M. , Dilger P. , Bird C. , Thorpe R.
Published: October 2003

Some adverse reactions to the transfusion of platelet concentrates (PCs) cannot be attributed to antibodies against blood cells or to subclinical microbial agents. It has been suggested that leucocyte‐derived inflammatory cytokines such as interleukin (IL)‐1, IL‐6 and tumour necrosis factor (TNF) may contribute to a large number of unexplained non‐antibody‐mediated adverse reactions. Three types of PCs, containing different levels of leucocytes, are currently produced. Filtration is used on demand to further reduce leucocyte contamination of these components. We have monitored the plasma of PCs prepared by the platelet‐rich plasma method (PRP), the buffy‐coat method or by apheresis for IL‐6, IL‐1, transforming growth factor‐beta (TGF‐β), TNF and interferon γ (IFNγ). Biologically active IL‐6 increased in stored PRP‐PCs from a mean of 140 pg/ml on day 1 to 2395 pg/ml on day 5/6. Elevated levels of IL‐8, as detected by immunoassay, were evident in PRP‐PCs during routine storage under blood bank conditions. Small amounts of immunoreactive IL‐1 with only minimal biological activity were present in some PRP‐PCs by day 5/6. No significant increase in the levels of IL‐8, IL‐6 or IL‐1 were seen in buffy‐coat PCs during storage for 5/6 d. For apheresis PCs, an increase in IL‐8 content, but not in IL‐6 over 6 d was observed. In all three types of PCs, elevated amounts of both bioactive and immunoreactive TGFβ were present, but there was no evidence of any biologically active or immunoreactive TNFα. Pre‐storage filtration of PRP‐PCs for depletion of leucocytes prevented the increase in IL‐8 and IL‐6 levels of these PCs. Our results show that leucocyte reduction by buffy‐coat method reduces cytokine levels to a comparable level to filtered or apheresis PCs, containing low levels of leucocytes, but use of these PCs in minimizing the severity and incidence of reactions in recipients will require clinical evaluation. This is the first comprehensive and comparative study which, on the basis of biological activity of cytokines, directly indicates that the mode of platelet production grossly influences the levels of cytokines.
Glycophorin A mutations and risk of secondary leukaemia in patients treated for childhood acute lymphoblastic leukaemia
Authors: Boyse Jayne , Hewitt Martin , Mott Martin G.
Published: October 2003

Survivors of childhood acute lymphoblastic leukaemia (ALL) have a higher than expected risk of developing secondary acute myeloid leukaemia (AML). The glycophorin A (GPA) mutation assay measures the frequency of variant NO and NN erythrocytes in MN heterozygotes. A raised variant frequency (Vf) has been shown in patients treated with chemotherapy known to be at risk of secondary leukaemia. ALL patients were investigated for increased Vf using the GPA assay. Vf's at diagnosis were not significantly different from controls (NO Vf P = 0.193; NN Vf P = 0.790). During treatment Vf's increased significantly (NO Vf P = 0.001; NN Vf P = 0.001). NO Vf returned to control values (P = 0.169) within 5 years from diagnosis but NN Vf remained significantly raised (P = 0.014). Three study patients developed secondary AML. At diagnosis of AML all three had significantly increased Vf. The first had a significantly raised Vf at routine follow‐up 19 years following diagnosis of ALL then developed AML 3.5 years later. The second had a significantly raised NN Vf at diagnosis of ALL indicating possibly prior exposure to a mutagen or defective DNA repair involving erythroid stem cells. We conclude that a raised Vf detected by the GPA assay can act as a marker for the development of secondary induced leukaemia and can be used to screen individuals at a known high risk of this complication.
Analysis of natural killer‐associated antigens in peripheral blood and bone marrow of multiple myeloma patients and prognostic implications
Authors: García‐Sanz R. , González M. , Orfão A. , Moro MA. J. , Hernández J. M. , Borrego D. , Carnero M. , Casanova F. , Bárez A. , Jiménez R. , Portero J. A. , San Miguel J. F.
Published: October 2003

The aim of this study was to analyse the expression of NK‐associated antigens in both peripheral blood and bone marrow lymphocytes from a large series of newly diagnosed multiple myeloma patients. 112 patients with untreated multiple myeloma (MM) were included in the study. 36 sex‐ and age‐matched healthy volunteers were used as controls for peripheral blood (PB) studies and 14 for the bone marrow (BM) studies. Simultaneous stainings with the CD3/CD56, CD2/CD16 and CD8/CD57 monoclonal antibodies were systematically performed in PB and CD3/CD56 and CD2/CD16 in BM in order to analyse their relationship with the clinical and biological characteristics of the disease and survival. The expression of NK‐associated antigens (CD56, CD16 and CD57) assessed within the lymphoid gate, was significantly increased (P < 0.001) in the PB of MM patients both in relative and absolute numbers. In the BM a significant increase in the percentage of CD56+ lymphocytes (P < 0.001) was also observed; in contrast, the proportion of CD16+ cells did not differ significantly from that of normal BM samples. The number of CD56+CD3− lymphocytes increased significantly within high‐risk patients (869 ± 671) as compared to intermediate (388 ± 212) and low‐risk patients (274 ± 199) (P = 0.04). Moreover, patients with high values of CD56+CD3− lymphocytes showed a statistically significant association with several adverse prognostic factors including anaemia, hypoalbuminaemia, renal failure, high β2M, DNA diploidy and high S‐phase plasma cells. In addition, patients with higher absolute numbers of PB CD56+CD3− lymphocytes displayed a poorer prognosis, whereas patients with higher values of CD57+CD8− cells had a better outcome.
Association of acquired Pelger‐Huet anomaly with taxoid therapy
Authors: JUNEJA S. K. , MATTHEWS J. P. , LUZINAT R. , FAN Y. , MICHAEL M. , RISCHIN D. , MILLWARD M. J. , TONER G. C.
Published: October 2003

We describe the occurrence of acquired Pelger‐Huet anomaly (APHA) in 23 patients treated with paclitaxel (13) or docetaxel (10). A consistent peak of Pelger‐Huet cells (PHC) within a range of 3–9d after treatment with taxoids was noted. The APHA generally disappeared by day 21 after treatment. Peak PHC values for the first course were significantly different in paclitaxel versus docetaxel versus control groups (P<0.0001) with the maximum PHC counts being significantly higher for docetaxel compared with paclitaxel (P<0.001) and for paclitaxel compared with controls (P=0.007). We conclude that taxoid therapy produces transient APHA which peaks between days 3 and 9 and is more pronounced with docetaxel than with paclitaxel.
Demonstration of developing myelodysplasia/acute myeloid leukaemia in haematologically normal patients after high‐dose chemotherapy and autologous bone marrow transplantation using X‐chromosome inactivation patterns
Authors: Gale R. E. , Bunch C. , Moir D. J. , Patterson K. G. , Goldstone A. H. , Linch D. C.
Published: October 2003

Autologous bone marrow or peripheral blood stem cell transplantation may carry an increased risk of secondary myelodysplasia (MDS) and acute myeloid leukaemia (AML), which are already recognized as complications of conventional treatment for lymphoid malignancies. In order to ascertain whether it is possible to detect the evolution of such a clone at an early stage in its development we have studied X‐chromosome inactivation patterns (XCIPs) in three informative females who developed abnormal myelopoiesis after high‐dose chemotherapy and ABMT. In one patient transplanted for relapsed Hodgkin's disease a leukaemic clone comprising approximately 50% of the patient's myeloid cells was detectable by comparison of peripheral blood granulocyte and T‐cell XCIPs when the full blood count and morphology were normal. She presented with AML 7 months later. In two patients transplanted for AML, XCIP analysis was complicated by constitutively skewed Lyonization patterns, nevertheless a progressive alteration could be demonstrated by serial analyses. In one patient a difference was detectable 28 months before presentation with MDS. In the other patient, despite evident mild pancytopenia and alterations in her XCIPs over the past 4 years, she has developed no definitive myelodysplastic features and oligoclonality due to stem cell failure cannot be excluded. These studies show that XCIPs can be used to predict development of MDS/AML in some patients, but the technique is limited by technical variability and frequent constitutional skewing in the haemopoietic system.
Treatment of newly‐diagnosed acute myelogenous leukaemia in patients aged 80 years and above
Authors: DELIMA MARCOS , GHADDAR HABIB , PIERCE SHERRY , ESTEY ELIHU
Published: October 2003

In order to assess outcome following treatment of acute myeloid leukaemia (AML) in patients aged 80 years and above, we have studied 33 patients aged ≥80 years treated between 1980 and 1994; 29 of these received treatment. The median age was 82 years (range 80–89). Three patients received daunorubicin (≥60mg/m2 daily × 3) alone or with low‐dose ara‐C, two patients received ‘3+7’ with post‐treatment GM‐CSF; 24 patients had higher doses of ara‐C, generally with anthracyclines or fludarabine, and in nine cases with G or GM‐CSF.

The median survival of the treated patients was 3–4 weeks and only two were alive after 1 year (at 66 and 79 weeks). Complete remission (CR) occurred in 9/29 (31%). Only one of the nine remains alive in remission, at 76 weeks after the date of CR, whereas the other eight died in remission or had disease recurrence at a median of 11 weeks (range 5–37 weeks) after CR. The median survival of the four untreated patients was 10 weeks (range 3–38). Patients aged ≥80 had, on average, worse outcomes than those observed in patients aged 70–79.

Our results confirm that currently available chemotherapy is generally not indicated in patients aged 80 or over with AML.
Molecular characterization of the 7q deletion in myeloid disorders
Authors: Lewis Sian , Abrahamson Gail , Boultwood Jacqueline , Fidler Carrie , Potter Alison , Wainscoat James S.
Published: October 2003

Deletion of the long arm of chromosome 7 is a common karyotypic finding in myeloid disorders and in particular is found in association with secondary leukaemias. We have used restriction fragment length polymorphisms and gene dosage experiments to assess the loss or retention of sequences localized to chromosome 7q in five patients with clonal myeloid disorders and a 7q deletion. The deletion was interstitial in all cases with retention of the anonymous marker pS194 located at 7q36‐qter. Three out of five cases also retained the more proximal gene T‐cell receptor β (TCRβ) located at 7q35. The proximal breakpoints of all five cases were localized to 7q22 by cytogenetic analysis. In two cases the proximal breakpoint lay between the genes for elastin (ELN) and collagen type 1α (COL1A2) and in three cases distal to this region between the genes for erythropoietin (EPO) and acetylcholinesterase (ACHE). The genes for ACHE, plasminogen activator inhibitor 1 (PLANH1), CCAAT displacement protein (CUTL1) and Met proto‐oncogene (MET) were deleted in all cases. Molecular analysis of the 7q deletion in myeloid leukaemias demonstrates heterogeneity of the breakpoints, supporting a recessive mechanism of tumourigenesis.
Isolation and characterization of cysteine proteinase in thrombotic thrombocytopenic purpura
Authors: Kelton John G. , Moore Jane C. , Warkentin Theodore E. , Hayward Catherine P. M.
Published: October 2003

Thrombotic thrombocytopenic purpura (TTP) is an uncommon disorder characterized by thrombocytopenia, schistocytic haemolytic anaemia, fever, neurologic lesions, and renal failure. A platelet aggregating factor has been postulated to be responsible for this disorder, but its precise identity remains debated. Two different groups of investigators have provided evidence that the platelet aggregating factor is a cysteine proteinase. We have suggested that it was calpain, whereas others have suggested that it was cathepsin L. To help resolve this issue, we have studied the platelet activating activity found in the acute serum samples from 10 different TTP patients as well as purified calpain and cathepsin L. The TTP activity was measured functionally (platelet serotonin release assay and casein lysis assay) and antigenically (immunodepletion using anti‐calpain and anti‐cathepsin L antibodies and antigenic analysis using SDS PAGE). The TTP serum parallelled the activity of the purified calpain and had optimal pH activity of 7.5. The purified cathepsin L activity had optimal activity at low pH (5.5) and activity was no longer measurable at pH 7.5. Similarly, a specific cathepsin L inhibitor (Z‐Phe‐Phe‐CHN2) had no effect on the activity of the TTP samples nor on purified calpain, but it did abolish the activity of purified cathepsin L. The platelet activating activity of the TTP samples was detectable in the microparticle pellet following ultracentrifugation of TTP serum, and could be immunodepleted using antibodies to calpain but not to cathepsin L.

These studies indicate that the microparticle‐associated platelet activating factor in TTP corresponds to calpain.
Direct and reversible inhibition of platelet factor 4 on megakaryocyte development from CD34+ cord blood cells: comparative studies with transforming growth factor β1
Authors: Xi Xiaodong , Caen Jacques P. , Fournier Sylvie , Schlegel Nicole , Miral Jean , Sibony Olivier , Blot Philippe , Han Zhong C.
Published: October 2003

Mechanisms of the action of platelet factor 4 (PF4) on the growth of megakaryocyte (MK) progenitor cells in CD34+ cord blood (CB) cells were studied in comparison with transforming growth factor β1 (TGFβ1). Development of MK from CD34+ CB cells in both plasma clot culture and liquid culture was significantly inhibited by either purified human PF4 and by recombinant human TGFβ1. Inhibition of MK colony formation by PF4 was reversible, because CD34+ cells preincubated with PF4 could regenerate colonies after washing and replating into secondary cultures. In contrast, TGFβ1‐preincubated CD34+ cells gave rise to few colonies following replating. Moreover, incubation of CD34+ cells with PF4 in liquid culture caused the increased number of both stem cell factor (SCF)‐binding cells and CD34 antigen‐bearing cells. In addition, PF4‐preincubated CD34+ cells exibited a higher potential in MK colony formation in the presence of 5‐fluorouracil (5FU). These results demonstrate that both PF4 and TGFβ1 inhibit MK development from CD34+ CB cells by different mechanisms, and suggest that PF4, unlike TGFβ1, exerts its inhibitory effect on the growth of the target cells in a reversible manner which results in a preservation of a more immature and 5FU‐resistant cell population.
NA‐phenotype‐dependent differences in neutrophil FcγRIIIb expression cause differences in plasma levels of soluble FcγRIII
Authors: Koene Harry R. , Haas Masja de , Kleijer Marion , Roos Dirk , Von Dem Borne Albert E. G. Kr
Published: October 2003

Soluble FcγRIII in plasma is primarily derived from neutrophils and is a measure of the total body neutrophil mass. We have developed a new, sensitive ‘sandwich’ ELISA to measure soluble FcγRIII in plasma and released FcγRIII in cell supernatants. Both sFcγRIIIa, derived from NK cells and sFcγRIIIb, derived from neutrophils are detected in the assay. However, plasma analysis of FcγRIIIB gene‐deficient donors suggested that sFcγRIIIa contributes only marginally to the total amount measured in healthy individuals. Furthermore, we observed that plasma of homozygous NA1‐positive donors contained lower amounts of sFcγRIII than plasma of homozygous NA2‐positive donors. Heterozygous donors were found to have intermediate levels of sFcγRIII in their plasma. Hemizygous FcγRIIIB gene‐deficient donors were found to have half the amount of sFcγRIII in their plasma compared to donors with two FcγRIIIB alleles. These NA phenotype‐dependent differences in plasma sFcγRIII could not be contributed to either an assay artefact or NA‐dependent differences in shedding of FcγRIIIb upon neutrophil activation. Calibration curves constructed with plasma of homozygous donors did not reveal NA‐dependent differences in antibody affinity. Measurement of released FcγRIIIb in supernatants of neutrophils stimulated with PMA, and inhibition of this signal with human IgG revealed no NA‐dependent differences. However, NA‐dependent differences in neutrophil FcγRIIIb expression were present, comparable to the differences found in plasma levels of sFcγRIII. Differences in the amounts of released FcγRIII in supernatants of NA‐typed apoptotic neutrophils were similar to initial differences in FcγRIIIb expression, again being lower in NA1‐positive than in heterozygous and NA2‐positive donors. In conclusion, NA‐dependent differences in plasma levels of soluble FcγRIII seem to be caused by differences in expression of the receptor on the neutrophil membrane.
Comparison of lyophilized plasmas with fresh plasmas for calibration of thromboplastin reagents in oral anticoagulant control
Authors: Van Den Besselaar A. M. H. P.
Published: October 2003

In a multicentre study of four thromboplastin reference materials (three from rabbit brain and one from bovine brain combined with adsorbed bovine plasma), three types of lyophilized plasmas were included. One was a pooled normal plasma, another was made by pooling plasmas of coumarin‐treated patients, and the third was prepared by adsorption of vitamin K dependent clotting factors (artificially depleted). The purpose of this study was to investigate whether these lyophilized plasmas could be used for reliable calibration of the four thromboplastins. Calibration line slopes were calculated for the lyophilized plasmas and compared to the slopes based on fresh plasmas. When a rabbit thromboplastin was calibrated against a similar but not identical reagent (like‐to‐like comparison), the slopes for lyophilized plasmas and for fresh plasmas were the same. However, significant differences between lyophilized and fresh plasmas were observed in the calibration of unlike thromboplastins. The deviation of the slope with artificially depleted plasma was greater than that with lyophilized coumarin plasma. Indiscriminate use of these lyophilized plasmas for thromboplastin calibration should be avoided.
2‐Chlorodeoxyadenosine in the treatment of hairy cell leukaemia: differences in response in patients with and without abdominal lymphadenopathy
Authors: MERCIECA J. , MATUTES E. , EMMETT E. , COLES H. , CATOVSKY D.
Published: October 2003

We treated 26 patients with hairy cell leukaemia (HCL) with 2‐chlorodeoxyadenosine, including nine with abdominal lymphadenopathy and of whom two had HCL‐variant; 18 were previously treated. The overall response in 23 evaluable HCL patients was 100% with 87% complete remission (CR). The CR rate was 57% in patients with abdominal lymphadenopathy. Neither of the patients with HCL‐variant achieved CR. Of four patients who had become refractory to 2′‐deoxycoformycin, two achieved CR and one partial remission (PR). The lower response in HCL with abdominal lymphadenopathy supports the view that this represents a more resistant form of the disease.
Comparison of benzimidazole nucleosides and ganciclovir on the in vitro proliferation and colony formation of human bone marrow progenitor cells
Authors: Reza Nassiri M. , Emerson Stephen G. , Devivar Rodrigo V. , Townsend Leroy B. , Drach John C. , Taichman Russell S.
Published: October 2003

Recently we have shown that certain benzimidazole ribonucleosides are potent and selective inhibitors of human cytomegalovirus (HCMV) replication. Because antiviral drugs used to treat HCMV and human immunodeficiency virus (HIV) infections can suppress marrow progenitors, we have evaluated the most promising of the new benzimidazoles for their effects on human bone marrow cells in vitro. In an initial study of the bone marrow toxicity of one of the most active compounds, 100 μm 2‐bromo‐5,6‐dichloro‐1‐(β‐d‐ribofuranosyl)‐benzimidazole (BDCRB) inhibited cell proliferation by 20% over a 10 d period compared to 52% inhibition by 100 μm ganciclovir, the drug currently most used to treat HCMV infections. The effects of these drugs and selected other benzimidazole nucleosides were evaluated more extensively in haemopoietic progenitor cell colony formation assays. Colony formation was determined at 2 weeks and scored as either burst forming units‐erythroid (BFU‐E), or colony forming units‐granulocyte/macrophage (CFU‐GM). At the highest concentration tested, 100 μm BDCRB only moderately affected BFU‐E or CFU‐GM formation (31% and 47% inhibition, respectively). This concentration is 10‐fold higher than that required to produce a 10 000‐fold reduction in virus titre. Evaluation of the 2‐chloro analog of BDCRB (TCRB) which is less potent against HCMV, its 5′‐deoxy analog (5′‐dTCRB) which is more potent, and the 2‐unsubstituted compound (DRB) gave the following order of haemopoietic toxicity: DRB > TCRB≥ 5′‐dTCRB > BDCRB. In contrast to the benzimidazoles, ganciclovir decreased colony formation by 84% for BFU‐E and 86% for CFU‐GM at 100 μm. These results establish that certain benzimidazole nucleosides are less toxic to haemopoietic progenitors than the preferred drug now being used clinically for HCMV infections. The results also establish that different structure–activity relationships exist for antiviral activity and progenitor cell toxicity, thereby suggesting that different mechanisms are involved in the two types of drug action.
Large‐cell variants of mantle cell lymphoma: cytologic characteristics and p53 anomalies may predict poor outcome
Authors: Zoldan Maria Cristina , Inghirami Giorgio , Masuda Yuichi , Vandekerckhove Filip , Raphael Bruce , Amorosi Edward , Hymes Kenneth , Frizzera Glauco
Published: October 2003

Large‐cell variants are uncommon in mantle cell lymphoma (MCL). Here we describe the pathologic and clinical findings in five patients with large‐cell lymphoma related to MCL (L‐MCL), and compare them to a group of classic small‐cell MCL (s‐MCL) cases.

Histologically, the MC origin of the large cells was evinced by their association with a small mantle cell component in the same tissue, or their distribution in a classic mantle zone pattern, or their development in a patient with previous s‐MCL. The large cells were either pleomorphic mantle cells (case 1) or transformed blast‐like cells (cases 2–5). The median nuclear diameter, median nuclear area and proliferation index of L‐MCLs and s‐MCLs, were statistically different. Immunophenotypic characterization of four specimens of L‐MCL and 10 of s‐MCLs with a large panel of antibodies showed the classic findings of MCL, i.e. the IgM+ D+/−, CD5+, CD10−, CD23− phenotype in all cases except two (one CD5− and one CD23+), and the association with a loose follicular dendritic cell network. Two of four L‐MCLs and 5/10 s‐MCLs demonstrated rearrangements of the bcl‐1 gene by Southern blot or by polymerase chain reaction (PCR); 2/4 L‐MCLs and 1/9 s‐MCLs had p53 mutations on single‐strand conformation polymorphism analysis; none of the 14 specimens showed rearrangement of bcl‐2 by PCR or bcl‐6 and c‐myc by Southern blot. All patients with ‘transformed’ histology (versus 37% of all others) died of lymphoma; their survival (15–18 months; median 17) was much shorter than that of all the others (28–117+ months; median 43) (P = 0.0035). All three patients with p53 anomalies, two of whom had tumours with transformed histology, died of their disease in a short time (15, 18 and 28 months). In contrast, the presence of bcl‐1 rearrangements did not have prognostic implications.

This study documents the existence of large‐cell variants of MCL and the poor prognosis associated with the ‘transformed’ cytologic type and/or p53 abnormalities.