High-risk fludarabine-pretreated B-cell chronic lymphocytic leukemia's high response rate following sequential DHAP and alemtuzumab administration though in absence of molecular remission

B-CLL patients with resistant/relapsed disease or adverse prognostic factors at presentation are suitable for alternative treatments. In the present pilot study we investigated a novel intensive chemo-immunotherapy approach for high-risk, fludarabine pretreated patients. Ten patients with resistant/relapsed, advanced stage BCLL were included. Age was 37-60 yr (median 53). All but one had an unmutated IgVH status. The treatment schedule included debulking with two DHAP courses followed by alemtuzumab (30 mg, eight doses), followed by peripheral blood progenitor cell (PBPC) mobilization with intermediate/high-dose cyclophosphamide and by autografting after high-dose mitoxantrone+L-Pam. The DHAP-alemtuzumab combination was highly effective. Eight patients out of 10 responded to DHAP, with a single complete remission. Following alemtuzumab, the number of overall responses increased to nine, and the complete remissions to five. After alemtuzumab PB double-positive clonal CD5+/CD19+ lymphocytes dropped, with median purification rate 99.95%. Owing to poor PBPC mobilization, only five patients underwent autografting, and three of these experienced post-graft recurrence. The six patients entering complete remission were free of disease 3-23 mo after study entry, and three of them were still in remission at 3, 7, and 22 mo. However, molecular evaluation regularly revealed persistence of minimal residual disease, both in all PBPC collections tested and in post-treatment follow-up samples. The use of DHAP/alemtuzumab appears useful to re-induce disease remission in relapsed/refractory, high-risk B-CLL patients. However, the addition of autograft was not usually feasible and of questionable clinical use. Other strategies should thus be considered for remission maintenance.     

Late onset cytomegalovirus disease in liver transplant recipients: de novo reactivation in recurrent hepatitis C virus hepatitis

Late onset cytomegalovirus (CMV) disease (occurring more than 1 year post-transplant] was documented in two liver transplant recipients with recurrent hepatitis C virus hepatitis in the absence of factors known to precipitate CMV disease, i. e., primary acquisition of CMV, allograft rejection, augmented immunosuppression, concomitant infections, or blood transfusions. Both patients had CMV enteritis (with CMV adrenalitis in one case]; however, other symptoms and signs of overt CMV infection, i. e., fever, leukopenia, or atypical lymphocytes, were lacking. Hepatitis C virus is an immunomodulatory virus; impaired CMV-specific T-cell responses may have accounted for the predisposition of our patients to unprovoked, late onset CMV disease. Given the high incidence of hepatitis C virus recurrence after liver transplantation, awareness of the occurrence and recognition of the unusual presentation of CMV disease in this setting is both clinically relevant and significant, particularly since CMV is treatable if recognized promptly. Received: 25 September 1997 Received after revision: 27 January 1998 Accepted: 2 March 1998     

Ebastine improves nasal symptoms and airflow and affects response to decongestion test in patients with persistent allergic rhinitis: a pilot study.

Nasal obstruction is the main symptom in patients with allergic rhinitis and it may be measured by rhinomanometry. Moreover, a decongestion test evaluates its reversibility. Some new antihistamines have been shown capable of improving this symptom. The aim of this pilot study was to evaluate nasal symptoms, nasal airflow, and the response to decongestion tests in patients with persistent allergic rhinitis (PER), before and after treatment with ebastine. Twenty patients with PER were evaluated, 15 male and 5 female patients (mean age, 28.2 +/- 6.7 years). All of the patients received ebastine (20 mg/day) for 3 weeks. Total nasal symptom score (including rhinorrhea, itching, sneezing, and obstruction), rhinomanometry, and decongestion tests were evaluated in all subjects before and after treatment. Patients evaluated weekly nasal and ocular symptoms by diary card. Ebastine treatment induced significant symptom relief (p = 0.0013), including obstruction (p = 0.0025) and significant increase of nasal airflow (p = 0.0001). Moreover, the response to the decongestion test was significantly affected by ebastine treatment (p = 0.0003). This pilot study showed the effectiveness of ebastine treatment in (i) improving nasal airflow and (ii) exerting decongestant activity in patients with PER. However, this pilot study was not suitable in assessing the effectiveness of ebastine on nasal symptoms. Additional controlled studies need to be conducted to confirm these findings.     

Esophageal achalasia: Is the herpes simplex virus really innocent?

This study was designed to test the hypothesis that mononuclear cells in the myenteric plexus of patients with achalasia may be activated by herpes simplex virus type 1 (HSV-1). Strips of esophageal muscle were obtained from patients with achalasia and multiorgan transplant donors who served as control subjects. After muscle digestion, mononuclear cells were purified through a Percoll gradient and cultured in medium, either alone or containing ultraviolet-inactivated HSV-1 or poliovirus (multiplicity of infection 1:1.5). As an indicator of HSV-1-induced lymphocyte activation, we determined T-cell proliferation by means of 3H-thymidine incorporation and interferon gamma release. DNA was extracted from esophageal muscle of achalasia patients and control subjects, and used as a template for PCR analysis using primer pairs specific for HSV-1. Circulating anti-HSV-1 and HSV-2 antibodies were detected by enzymelinked immunosorbent assay on serum samples. Fifteen patients with naive achalasia and eight control subjects were studied. The prevalence of circulating anti-HSV-1 and HSV-2 antibodies proved similar in the two groups, and no HSV-1 DNA was detected by polyermase chain reaction in the esophageal muscle samples. The proliferative index in mononuclear cells from achalasia patients stimulated with HSV-1 showed a 3.4-fold increase in comparison with control subjects (P < 0.01). In addition, a 1.4-fold increase in interferon gamma release after incubation with HSV-1 was observed in cells from achalasia patients but not control subjects. The results of this study indicate that HSV-1-reactive immune cells are present in lower esophageal sphincter muscles of patients with achalasia. We hypothesize that the HSV-1-reactive lymphocytes in lower esophageal sphincter muscles of achalasia patients may contribute to damage of the neurons in the myenteric plexus and lead to the motor dysfunction. Presented at the Forty-Fourth Annual Meeting of The Society for Surgery of the Alimentary Tract, Orlando, Florida, May 18–21, 2003 (oral presentation). Supported in part by a grant from the University of Padova Research Fund.     

Blink reflex abnormalities in Tourette syndrome.

OBJECTIVE: Tourette syndrome (TS) is a not uncommon disorder which represents the most complex manifestation of the spectrum of tic disorders, with onset during childhood or early adolescence. There are no definitive tests for diagnosis of TS. The objective of this study has been to demonstrate whether neurophysiological abnormalities of the blink reflex can be observed in patients affected with TS and correlate with the severity of TS. METHODS: We enrolled 17 patients with Tourette syndrome, diagnosed according to DSM IV Diagnostic Criteria, and 10 healthy volunteers. Tic severity was assessed using a self rating scale (Tourette Syndrome Symptom List, TSSL) and examiner ratings (Yale Global Tic Severity Scale (YGTSS), and Tourette-Syndrome Global Scale (TSGS)). The blink reflex was elicited by stimulating the supraorbital nerve in order to measure the early response (R1), homolateral and contralateral R2 (late) responses, amplitude of R1 and duration of R2. RESULTS: We observed a mean duration of R2 significantly longer in the patient group than in the control group (P<0.01, Student t test), without any statistically significant differences of R1 and R2 latencies and of R1 amplitude between the patient group and the control group. Correlations between changes in clinical rating scores and R2 duration were tested by simple linear regression analysis, which has not demonstrated a significant correlation between TSSL scores, clinical rating scores (measured by TSGS and YGTSS) and duration of R2. CONCLUSIONS: A pattern as to excitability of the blink reflex can be a frequent abnormality in TS patients, not correlated with its severity.     

Localization of angiotensinogen messenger RNA in rat aorta

The distribution of angiotensinogen messenger (mRNA) was determined in the rat aorta. Other investigators have demonstrated the presence of angiotensinogen mRNA in whole rat aorta; however, its precise location in the blood vessel wall has not been defined. When various layers of the vessel wall were separated by dissection or cell dispersion, angiotensinogen mRNA levels were greatest in the periaortic adipose tissue. Angiotensinogen mRNA was present in very small levels in the adventitia, with no detectable levels in the muscle layer. In addition to periaortic adipose tissue, angiotensinogen mRNA was also present in the interscapular brown fat pad of the rat. The high levels of angiotensinogen mRNA in periaortic brown adipose tissue suggests that angiotensin may be synthesized there and responses may exist in this tissue or adjacent sympathetic nerve terminals.     

Clinical xenotransplantation

Abstract: Two baboon liver xenografts transplanted to patients with B virus hepatitis supported life for 70 and 26 days but did not function optimally despite minimum or no histopathologic findings of overt humoral or cellular rejection in serial biopsies. However, there was evidence of complement activation in both cases, which in retrospect was thought to explain the unsatisfactory outcome. Strategies to deal with this problem are discussed.     

Pharmacological management of undifferentiated spondyloarthropathies

Among undifferentiated spondyloarthropathies (uSpA) are included incomplete forms or early phases of definite seronegative spondyloarthritides and cases of spondyloarthritides that remain undifferentiated. The treatment of all spondyloarthritides is more conditioned by the disease localisation, number of involved districts and severity of inflammation rather than by the subtype of the spondyloarthritides itself. Specific studies focused on the pharmacological approach to uSpA are scarce. As a consequence, many drugs are used on the basis of the experiences that have been gained in the treatment of other spondyloarthritides. At present, non-steroidal anti-inflammatory drugs/COX-2 inhibitors and disease-modifying antirheumatic drugs are the main therapeutic agents for the involvement of peripheral joints in uSpA. In those cases in which severe symptoms persist despite these treatments or when there is a severe axial involvement, antitumour necrosis factor agents represent an effective choice. In these patients, antitumour necrosis factor treatment raises the important possibility of blocking a shift from uSpA to differentiated severe forms of spondyloarthritides such as ankylosing spondylitis. Local administration of corticosteroids is useful when a small number of joints are involved, as is also the case for the extra-articular localisations of soft tissues.