Wegener's granulomatosis: long-term follow-up of patients treated with pulse cyclophosphamide

Treatment with daily oral cyclophosphamide (CY) has improved survival in Wegener's granulomatosis (WG), but is associated with severe and potentially lethal adverse effects. Less toxic treatment regimens, such as pulse CY, have been used, but the effect has been questioned. We have treated 11 patients with WG with pulse CY (15 mg/kg initially every second week, gradually increasing the pulse interval). After 4.5 yr follow-up and a total of 501 pulses of CY, one patient died and eight patients (73%) were in complete remission. Remission was induced in 91% of the patients after a median period of 3.5 months and relapses were seen in 60%. With the same treatment protocol, a new complete remission was induced in 75% of those relapsing. Except for one patient who died, no patient developed end-stage renal failure. Haemorrhagic cystitis was not observed and no malignancies recorded. Severe infections were seen in 36%, but none caused by Pneumocystis carinii. Nausea was the most frequent side-effect, seen in 64% of the patients. We conclude that treatment with pulse CY every second week is safe and effective in inducing remission and treating relapses in WG. The relapse rate seems to be higher than with low-dose oral CY, but the cumulative dose of CY is less.      

Production and characterization of a bispecific IgG capable of inducing T-cell-mediated lysis of malignant B cells

Bispecific monoclonal antibodies (bsabs) recognizing both CD3 and a tumor antigen can redirect T-cell-mediated cytotoxicity toward cells bearing that antigen. Such bsabs have been shown to be more effective than monospecific monoclonal antibodies (MoAbs) at preventing tumor growth in animal models of B-cell malignancy. The current studies describe the production and preliminary evaluation of a bsab designed to induce the lysis of malignant human B cells by human T cells. The bsab was obtained from a hybrid-hybridoma cell line produced by fusing OKT3-secreting hybridoma cells with hybridoma cells that secrete 1D10. 1D10 is an MoAb that recognizes an antigen found on a majority of malignant human B cells that has not been detected to a significant degree on normal resting or activated lymphocytes. High performance liquid chromatography (HPLC) was used to separate bsab from monospecific antibodies that were also present in the hybrid-hybridoma antibody product. The bsab was then evaluated in vitro for its ability to induce lysis of malignant B cells by activated T cells. The bsab consistently induced extensive lysis in vitro of 1D10 (+) cells, including both cell lines and cells obtained from patients with a variety of B-cell malignancies. No such effect was seen with activated T cells alone or activated T cells with monospecific antibody. No increased lysis was seen with 1D10 (-) cell lines. The bsab also mediated lysis of malignant B cells by autologous T cells. We conclude bsab containing an OKT3 arm and a 1D10 arm can induce T-cell-mediated lysis in a manner that is both potent and specific. This supports further evaluation of this bsab as a potential immunotherapy of B-cell malignancy.     

Profile of Live-born Infants of In-vitro Fertilisation

Introduction

The Army Hospital (R&R) is the only service hospital providing in-vitro fertilisation (IVF) facility. Neonatal characteristics of live-born infants at this centre over a two-year period are analyzed in this study.

Methods

Data on 504 consecutive live-born IVF infants over a two-year period (01 Feb 2007 to 31 Jan 2009) were analysed.

Result

Of the 504 neonates, 190 (37.7%) were born by vaginal delivery, 156 (30.9%) by elective lower segment cesarean section (LSCS) and 127 (25.19%) following emergency LSCS. Maternal illness posing specific risk to the neonate was present in 165 out of 504 (32.7%). There were 239 (47.4%) preterm neonates. Males formed 51.8% of the cohort. Singletons accounted for 51.2%, while the rest (48.8%) were products of twin pregnancies. Small for gestational age neonates formed 22.6% (n = 114). A total of 20 (3.9%) infants had congenital malformations. There were 242 (48.1%) low birth weight neonates. A total of 128 (25.4%) neonates needed neonatal intensive care. Of the 504, there were 474 (94.1%) survivors while 30 (5.9%) did not survive. Twenty-nine (6.1%) neonates required readmission during the neonatal period.

Conclusion

In our setting, neonates born following IVF appeared to be at increased risk of prematurity, multiple births and low birth weight. Proper obstetric and neonatal management can result in good neonatal outcomes.Key Words: In-vitro fertilisation, Live-births, Low birth weight     

Intraepidermal nerve fiber densities in chronic inflammatory autoimmune diseases

BACKGROUND: Some patients with systemic lupus erythematosus have selective loss of small-diameter nerve fibers, while larger nerve fibers are unaffected. OBJECTIVE: To determine intraepidermal nerve fiber densities in patients with different chronic inflammatory autoimmune diseases. DESIGN: Cross-sectional study. SETTING: Stavanger University Hospital, Stavanger, and Haukeland University Hospital, Haukeland, Norway. PATIENTS: Sixty patients with systemic lupus erythematosus (SLE) (mean +/- SD age, 43.2 +/- 13.5 years), 61 patients with primary Sj?gren syndrome (age, 57.1 +/- 14.7 years), and 52 patients with rheumatoid arthritis (age, 57.4 +/- 12.3 years) were compared with 106 healthy subjects (age, 49.0 +/- 19.6 years). INTERVENTIONS: Skin biopsy specimens. MAIN OUTCOME MEASURES: To evaluate small-diameter nerve fiber loss, intraepidermal nerve fiber densities were measured in skin punch biopsy specimens obtained from the distal part of the leg. RESULTS: The mean +/- SD densities were 7.5 +/- 3.8 fibers/mm in patients with SLE, 9.2 +/- 3.8 fibers/mm in primary Sj?gren syndrome, and 10.9 +/- 5.4 fibers/mm in rheumatoid arthritis vs 12.4 +/- 4.6 fibers/mm in healthy subjects. Densities were significantly less in patients with SLE vs patients with rheumatoid arthritis and vs healthy subjects (P<.001 for both), as well as in patients with primary Sj?gren syndrome vs healthy subjects (P<.001). Eight patients (13%) with SLE, 2 patients (3%) with primary Sj?gren syndrome, and 2 patients (4%) with rheumatoid arthritis had densities below the lower reference limit of 3.4 fibers/mm, consistent with small-diameter nerve fiber neuropathy. CONCLUSION: The degree of loss of small-diameter nerve fibers differs among patients with these chronic inflammatory autoimmune diseases, likely reflecting differences in pathogenesis and organ affinity of the individual disease entities.     

Peripheral neuropathy in primary sjogren syndrome: a population-based study

BACKGROUND: Neurological manifestations appear to be frequently involved in patients with primary Sj?gren syndrome (PSS). OBJECTIVE: To investigate the involvement of the peripheral nervous system, including small-diameter nerve fibers, in an unselected cohort of patients who fulfilled the new international criteria for PSS. DESIGN: Cross-sectional study. SETTING: Stavanger University Hospital. Patients Sixty-two patients with PSS (mean +/- SD age, 57.1 +/- 14.6 years). INTERVENTIONS: Clinical neurologic examinations, conventional nerve conduction studies, and skin punch biopsies. MAIN OUTCOME MEASURES: Signs of large-diameter and small-diameter peripheral nerve fiber neuropathy as determined by clinical examination, nerve conduction studies, and densities of intraepidermal nerve fibers in skin punch biopsy specimens. RESULTS: Seventeen patients (27%) were diagnosed as having neuropathy after clinical examination. The results of nerve conduction studies were abnormal in 34 patients (55%): 19 patients (31%) had motor neuropathy, 8 (13%) had sensory neuropathy, and 7 (11%) had sensorimotor neuropathy. Two patients had intraepidermal nerve fiber densities less than 3.4 fibers per millimeter, fitting the morphologic criteria for small-diameter nerve fiber neuropathy. CONCLUSIONS: Peripheral neuropathy occurs in a large proportion of patients with PSS, in most cases as a subclinical demyelinating neuropathy. Small-diameter nerve fiber neuropathy is not a frequent finding in these patients.     

Detection of cerebral embolic signals in patients with systemic lupus erythematosus

Background

Involvement of the CNS in systemic lupus erythematosus (SLE) is caused by several pathogenic mechanisms including cerebral embolism.

Aim

To measure the frequency of microembolic signals (MES) by using transcranial Doppler (TCD) ultrasound and to assess their association with cerebral infarction, neuropsychological dysfunction, and biochemical, sonographic and clinical variables in an unselected group of patients with SLE.

Methods

A 1‐h TCD recording from the middle cerebral artery was carried out in 55 patients with SLE having a mean age of 46 (SD 13) years. MRI of the brain, carotid artery ultrasonography with intima–media thickness and atherosclerotic plaque assessments were carried out in addition to a broad biochemical and clinical assessment. All patients underwent a neuropsychological assessment.

Results

Of the 55 patients, MES were detected in 5 (9%) and cerebral infarcts were found in 9 (18%). A significant association was found between MES and cerebral infarcts and considerably more neuropsychological deficits were found in MES‐positive patients compared with the negative group. MES were not associated with other clinical, sonographic and biochemical factors believed to be associated with cerebral embolism.

Conclusions

Cerebral embolism may be one of the important mechanisms responsible for the high prevalence of cerebrovascular events and the neuropsychological deficits observed in patients with SLE. Although the number of MES‐positive patients was small, the lack of a significant association between MES and other known risk factors for MES suggests a complex pathogenesis for the embolisation in these patients.CNS symptoms and signs are common in systemic lupus erythematosus (SLE) and as many as 50% of patients with SLE may have neuropsychiatric involvement.^1,2 Well‐known complications include psychosis, seizures, cerebrovascular accidents and cognitive dysfunction. Women with SLE, aged 18–44 years, are eight times as likely to be admitted to hospital because of stroke as controls.³ The pathogenesis of CNS involvement in SLE has not been clarified, and multiple factors may be associated, such as microvascular damage, small‐vessel vasculopathy, antibodies to nervous tissue and immunologically mediated thromboembolism. Postmortem examinations have shown microinfarcts and microhaemorrhages in cortical and subcortical regions. Several factors are associated with the increased risk of stroke in these patients. These include antiphospholipid antibodies, use of corticosteroids, cardiac involvement and other well‐known risk factors for cerebrovascular disease.^2,4,5Transcranial Doppler (TCD) examination, a non‐invasive technique, can detect cerebral embolisation in the major intracranial arteries.⁶ Microembolic signals (MES) have been detected during cardiac surgery and carotid endarterectomy.^7,8 Long‐term TCD monitoring of the intracranial arteries has shown abnormal signals, indicating clinically silent MES in patients with high‐grade carotid stenosis, with prosthetic heart valves or after recent cerebrovascular events.^9,10,11 Cerebral microemboli may cause cognitive dysfunction if they enter the cerebral circulation in considerably large numbers. This has been studied in detail in patients who have had coronary artery bypass surgery.¹² Some instances showing a positive association between cerebral microemboli detected by TCD and postoperative neuropsychological outcome after cardiac surgery have been reported.^7,10Three studies^13,14,15 that used TCD for embolic detection in patients with SLE have showed conflicting results. It is therefore of interest to carry out further studies on the possible importance of cerebral microembolisation in SLE.We measured the occurrence of MES in a group of patients with SLE and assessed the possible association with cerebral infarcts, neuropsychological function, risk factors for cerebrovascular disease, including carotid atherosclerosis, and biochemical variables associated with cerebrovascular disease.     

Results of definitive radiotherapy in T1 and T2 glottic carcinoma: Institute of Rotary Cancer Hospital experience

Early glottic carcinomas (T₁ and T₂) constitute only 2% of all laryngeal cancers in our data. Seventy patients were seen between 1985 and 1992. All patients were treated by cobalt-60 small field radiotherapy using a beam directed shell. The total dose delivered was 60–65 Gy in 31 patients and 66–70 Gy in 39 patients. The follow-up period ranged from 5 to 126 months, with a mean follow up of 37 months overall and 55 months in the surgical salvage group. Radiation therapy controlled disease in 71% (50 of 70) of patients overall; 75% with T₁ and 67% with T₂ lesions. Total laryngectomy as salvage surgery was performed in 70% (14 of 20) of patients whose disease recurred. Ultimate control including surgical salvage occurred in 64 (91%) of 70 patients in the present study. The actuarial 5 year survival was 83 and 80% in T₁ and T₂ tumours, respectively (statistically insignificant). This report supports the policy of definitive irradiation, reserving surgical salvage for radiation failures in early laryngeal cancers.