Features of transient hypogammaglobulinaemia in infants screened for immunological abnormalities

The incidence of transient hypogammaglobulinaemia of infancy (THI) detected in a major paediatric centre over a 10 year period was examined. A total of 2468 subjects less than 2 years of age had an IgG measurement taken between July 1979 and March 1990. Subjects with known immunodeficiencies were excluded. Fifteen patients were classified as having THI with an initial IgG level less than the fifth centile followed by a second measurement within the normal range. A further 24 patients were identified as having possible THI with a single low IgG concentration. There were 60,174 live births each year in Victoria in the years 1979-88. This gives an incidence of proved THI of 23 per 10(6) births, and including proved and probable THI an incidence of 61 per 10(6) live births. Of those patients with proved THI 12/15 had symptoms of either atopic disease or food allergy/intolerance and three had gastrointestinal symptoms without any evidence of atopic disease. At presentation 12/15 (80%) were IgA deficient and 9/15 had IgM concentrations less than the 20th centile for age. It is suggested that in view of the preponderance of atopic and food intolerant patients that subclinical protein loss from the bowel due to allergic inflammation may be a contributing factor to the development of THI in some patients.     

Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma

BACKGROUND: Doxil (ALZA Corp., Mountain View, CA) is a formulation of doxorubicin in polyethylene-glycol coated liposomes with a prolonged circulation time and unique toxicity profile. As yet, the effect of the dose schedule on toxicity and the correlation of toxicity with pharmacokinetics have not been directly addressed. METHODS: The objectives of this study were to examine the toxicity profile and pharmacokinetics of various dose schedules of Doxil in a group of patients with metastatic breast carcinoma (MBC) previously treated with chemotherapy. Forty-five patients received a total of 268 courses of Doxil (median per patient, 5; range, 1-19). Six dose schedules were investigated: 35 mg/m2 every 3 weeks (11 patients), 45 mg/m(2) every 3 weeks (5 patients), 50 mg/m(2) every 4 weeks (5 patients), 60 mg/m(2) every 4 weeks (6 patients), 65 mg/m(2) every 5 weeks (6 patients), and 70 mg/m(2) every 6 weeks (12 patients). Doxil pharmacokinetics was examined in 24 of these patients at the dose levels of 35, 45, 60, and 70 mg/m(2). RESULTS: Stomatitis was dose related, with higher incidence and severity at doses of 60-70 mg/m(2). Skin toxicity in the form of palmar-plantar erythrodysesthesia (PPE) developed usually after two or more courses of treatment and was schedule dependent with shorter dosing intervals leading to increased frequency and severity of skin manifestations. Myelosuppression, mainly as leukopenia/neutropenia, was dose dependent but mild and uncomplicated in most cases. Hair loss was infrequent (< 7%) and always of limited extent. Despite high cumulative doses up to 1500 mg/m(2), cardiac toxicity was observed in only 1 patient who received prior mitoxantrone and mediastinal radiotherapy. Objective responses, improvements, and durable stabilizations were observed in 9, 6, and 14 patients, respectively, indicating significant antitumor activity of Doxil in previously treated MBC patients. Doxil pharmacokinetics was well described by a monoexponential elimination curve with a long T(1/2) (median, 79 hours), a slow clearance (median, 40 mL/hour), and a small volume of distribution (median, 3.9 L). Cmax (peak plasma concentration) and AUC (area under the concentration*time curve) increased linearly with dose with a statistically significant correlation. Correlation analysis of dose and pharmacokinetic parameters with Doxil toxicites revealed that stomatitis grade and leukocyte nadir were correlated strongly with dose and Cmax, and weakly with AUC, whereas PPE grade was correlated significantly with only 1 parameter, T(1/2). CONCLUSIONS: The toxicity of Doxil is dose and schedule dependent and well correlated with pharmacokinetic parameters. Pharmacokinetic guidance of Doxil dosing may be a useful tool.     

Adjuvant chemotherapy with and without radiotherapy in stage II breast cancer

The influence of several variables on the effectiveness of adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) chemotherapy given to 87 patients with stage II breast cancer was retrospectively analyzed. CMF was given in optimal doses (greater than or equal to 85% of the planned dose) to 17% of the patients; in intermediate doses (66-84% of the planned dose) to 50% of the patients; and in low doses (less than or equal to 65% of the planned dose) to 33% of the patients. Radiotherapy before CMF was given to 68% of the patients; simultaneous radio- and chemotherapy to 17% of the patients; and the remaining 15% received CMF only. At a median follow-up of 8 yr, 61% of the patients were still alive; 54% of them were disease-free. Patients receiving radio- and chemotherapy concomitantly had a higher relapse-free survival (RFS) than those given both treatments sequentially (77% versus 46%; P = 0.05). Dose levels of CMF did not influence RFS. Delay in initiation of CMF, mainly due to the administration of prior radiotherapy was deleterious: patients started on CMF within 3 months of diagnosis had a 77% 8 yr RFS, as compared with 44% for those with a delay of over 3 months (P = 0.01). No differences in local relapse rates were observed between irradiated and non-irradiated patients, although 87% of all distant failures occurred in patients who received radio- and chemotherapy sequentially. The data of this study indicate that delay in onset of CMF is deleterious, and can be avoided by the simultaneous administration of both treatment modalities, since this approach was well tolerated, without significant myelotoxicity.     

Dynamic computed tomography of the head and neck: differential diagnostic value

A retrospective review of the dynamic CT studies performed in our institution on head and neck lesions, excluding the brain, was carried out. Five basic types of density vs. time curves were obtained. Dynamic CT scanning is valuable in the differential diagnosis, management, and followup of such cases; its usefulness as an imaging modality in diagnosis and followup of hemangiomas is stressed.     

Routine Cyclosporine concentration - C2 level Monitoring. Is it helpful during the early post Transplant Period?

Background

Pre dose or trough blood cyclosporine (CSA) concentration is routinely monitored and the result is used to alter patient''s drug dosing. Patients with identical pre dose blood CSA may have very different systemic exposure to the drug. Recently CSA 2 hour post dose level [C2] has been reported to correlate better with drug exposure. We undertook this study to evaluate the influence of trough and C2, CSA concentration monitoring on short-term renal allograft outcomes.

Methods

25 patients of renal transplant receiving a triple drug regimen of CSA micro emulsion (Panacea Biotec) 8mg/kg, azathioprine 1mg/kg and prednisolone 0.5mg/kg were analyzed prospectively for graft outcomes. CSA levels were monitored in whole blood by radioimmunoassay using monoclonal antibodies, at 72 hours after the transplant.

Results

The mean age of patients was 37.08 + 9.1 years. There were 20 males and 5 females. The mean age of donors was 40.2 + 8.2 years. There were 11 related donors with at least a haplomatch, 4 spousal and 10 unrelated donors with a nil antigen match. The mean pre dose CSA concentration was 289.22 + 171.9ng/ml; range (98.8 + 783.41ng/ml). The CSA concentration at 2 hours after the CSA administration was 838 + 310.87ng/ml (range, 169 + 1268ng/ml). 3 (12%) patients had acute rejection. In these patients the mean pre dose CSA concentration was 328.67ng/ml and the mean C2, CSA concentration was 1006.26ng/ml. CSA induced hemolytic uraemic syndrome was diagnosed in one patient. The trough and C2, CSA concentration levels were 174 and 870.83ng/ml respectively in this patient.

Conclusion

In our study CSA levels, trough and peak showed significant inter patient variability. The trough and C2 concentration levels did not correlate with the episodes of acute rejection. We conclude that in a triple drug regimen with fixed dosing schedules routine trough CSA level monitoring is not helpful in the acute post renal transplant period.Key Words: Cyclosporine levels, Cyclosporine trough levels, C2 levels     

Sonovue improves endocardial border detection and variability in assessing wall motion score and ejection fraction during stress echocardiography

Background Stress echocardiography is useful for assessing patients with coronary artery disease unable to undergo formal exercise testing. Considerable skill is required to avoid large intra- and inter-observer variability due to poor endocardial definition. Intravenous ultrasound contrast agents are now available which may improve this variability. Aim To study intravenous Sonovue in assessing wall motion score and ejection fraction (EF) during stress echocardiography. Methods Thirty-eight patients undergoing arbutamine stress echocardiography for known or suspected coronary artery disease were studied. Echocardiographic analysis of wall motion score index, endocardial border detection (EBD) and EF was performed at rest and at peak stress before and after intravenous injection of Sonovue, by experienced and inexperienced observers. Results All three observers noted an improvement in endocardial border definition following Sonovue (p=<0.001). At baseline, there was a significant difference in wall motion score index between experienced and inexperienced observers at rest (p=0.01) and at peak stress (p=0.001). Following Sonovue administration this was no longer significant (p=0.07, p=0.114). Intra-observer variability of end diastolic, end systolic volumes (ESV) and EF improved following contrast (p<0.05) at rest and during stress. Conclusion Sonovue significantly improved EBD and reduced intra-observer variability of EF at rest and during peak arbutamine infusion.