The haemotoxicity of azathioprine in repeat dose studies in the female CD-1 mouse

Azathioprine (AZA) is a cytotoxic immunosuppressive drug used in the prevention of rejection in organ transplants and the treatment of auto-immune diseases. However, AZA is haemotoxic causing significant bone marrow depression. The present studies were to characterize the haemotoxicity of AZA in the female CD-1 mouse. In Experiment 1, a dose-ranging study, with AZA gavaged daily for 10 days, clinical evidence of toxicity was evident at 125 mg/kg and above. Experiment 2 was a dose–response study with AZA gavaged daily for 10 days at 40–120 mg/kg. At day 1 after the final dose, AZA induced a dose-related pancytopaenia, reduced femoral marrow cellularity, increases in serum levels of the cytokine fms-like tyrosine kinase 3 ligand, reduction in granulocyte-monocyte colony-forming units and erythroid colonies, and increased bone marrow apoptosis. Histology demonstrated hepatocyte hypertrophy, thymic atrophy, reduced splenic extramedullary haemopoiesis, and reduced cellularity of sternal bone marrow. In Experiment 3, AZA was dosed for 10 days at 100 mg/kg with autopsies at 1, 3, 9, 22, 29, 43 and 57 days postdosing. At 1, 3 and 9 days, haematological parameters reflected changes in Experiment 2. At 22/29 days, many blood parameters were returning towards normal; at 43/57 days, most parameters compared with controls. However, there was some evidence of a persistent (i.e. residual/late-stage) mild reduction in RBC and erythroid progenitor cell counts at day 43/57. We conclude that the CD-1 mouse provides an acceptable model for the haemotoxicity of AZA in man.     

Assessment of adjuvant trials in breast cancer

In this paper, we discuss the analytic problems associated with the evaluation of overall survival for breast cancer adjuvant studies and results of pooling data from the published literature to determine if there is evidence showing an overall survival advantage to adjuvant therapy. An investigation of the effect of competing causes of death shows that trials on older patients have low statistical power. Hence many of the current trials have low statistical power and may fail to find overall survival advantage for adjuvant therapy even when a benefit exists. The implications of the assessment of short-term follow-up are discussed in the context of the heterogeneous distribution of residual disease after primary treatment. Short-term follow-up (less than 5 yr) precludes anyone from making any conclusions about benefit for patients with small residual tumor burdens who constitute the patient subgroup most likely to benefit from adjuvant therapy. We reviewed 15 published randomized trials (each having a control group receiving no systemic therapy) to determine if overall survival has been increased by adjuvant therapy. We conclude that there is a benefit from some chemotherapy regimens given to node-positive premenopausal women. However, the published data for tamoxifen are mixed, with some trials showing benefit and others not. As more follow-up time is accumulated, this matter should be settled.     

A pilot study of three-dimensional conformal radiotherapy in unresectable hepatocellular carcinoma

BACKGROUND: The purpose of this study was to determine the potential role of three-dimensional (3-D) conformal radiotherapy (RT) in treatment of unresectable hepatocellular carcinoma (HCC). METHODS: Thirteen patients were included in this study, which was conducted between 1993 and 1996. Nine patients (group A) were treated with 3-D conformal RT alone because of main portal vein thrombosis, inferior vena cava thrombosis, obstructive jaundice and failure of previous transcatheter arterial chemoembolization (TACE) to control the disease. The remaining four patients (group B) were treated with a combination of TACE and 3-D conformal RT. RESULTS: The greatest dimension of the main tumour in the whole group of patients ranged from 6 to 25 cm (median 15 cm). The radiation dose ranged from 40 to 60 Gy. The tumour response was evaluated by computed tomography scans of the liver 6-8 weeks after completion of radiotherapy. Partial response was observed in 58% of the patients (seven of 12) and minimal response in another 25% of patients (three of 12). One patient could not be evaluated because of the development of hepatic failure 1 month after completion of RT. All patients in group B lived for more than 1 year (range 16-40 months). In group A, one patient who had a large tumour (11 x 10 x 21 cm) with portal vein thrombosis was converted to become resectable after 45 Gy of radiation. The resection specimen revealed no residual cancer cells. This patient is alive longer than 15 months after treatment without the evidence of disease. CONCLUSIONS: Our experience indicates that HCC is more radiosensitive than it was traditionally expected. Three-dimensional reconstruction of tumour and surrounding organs helps to avoid excessive exposure of the liver and adjacent organs to RT and makes it a safer treatment modality for unresectable HCC. Our preliminary data show promise and are worthy of further study to explore the potential role of radiotherapy in the treatment strategy for HCC at various stages of involvement.     

SUBOCCIPITO-VAULT SKULL DIAMETER: AN EARLY INDICATOR OF VENTRICULAR DILATATION IN PRETERM BABIES

The distance between the inferior surface of the occiput and the superior surface of the vault of the skull was measured weekly during the first nine weeks of life in 56 preterm but appropriately grown babies with birthweights less than 1850g. For seven babies with dilatation of the cerebral ventricles (shown by ultrasonography) the suboccipito-vault height increased above the 97th centile within the first five weeks of life, although over the same period the occipitofrontal head circumference did not exceed the 75th centile. In the only other baby with ventricular dilatation the suboccipito-vault height did not increase while therapy with frequent removal of lumbar cerebrospinal fluid was performed. Suboccipito-vault height is a sensitive early indicator of progressive dilatation of the cerebral ventricles, and may be of value in centres without ultrasound facilities.     

Referrals for vascular hypertension in a group of 45-64-year-old patients

Two hundred and ten consecutive 45-66-year-old patients underwent a routine eye examination and a decision was made whether to refer each patient on the basis of fundus appearance and other non-sphygmomanometric criteria. Blood pressure was then measured and the referral decision was reviewed. Of the 33 (15.7%) patients finally referred, only 5 (2.4%) would have been referred on the non-sphygmomanometric findings. It is suggested that optometrists include a protocol of blood pressure measurement as part of the eye examination routine.     

Increased serum C-reactive protein levels are associated with shorter survival and development of second cancers in chronic lymphocytic leukemia

Background: Chronic lymphocytic leukemia (CLL) is characterized by a heterogeneous clinical course, ranging from stable to more aggressive disease. Herein, we determined the prognostic significance of serum C-reactive protein (CRP) levels in patients with CLL

Methods: A retrospective cohort study reviewing the records of 107 consecutive treatment naïve patients with CLL and a control group comprised of apparently healthy individuals attending for periodic health examinations.

Results: The median CRP level of patients with CLL was 0.19?mg/dL (0–2.9). In univariate analysis, high-CRP levels (≥0.4 mg/dL) were significantly associated with an increased risk of mortality (HR?=?3.97, 95%CI 1.64–9.62, p?=?.002) and development of second solid cancers (HR?=?4.54, 95%CI 1.57–13.11, p?=?.005), compared to low-CRP values (<0.4 mg/dL). In multivariate analysis, high-CRP retained statistical significance for all-cause mortality (HR?=?2.81, 95%CI 1.04–7.57, p?=?.04) and the development of second solid malignancies (HR?=?4.54, 95%CI 1.57–13.11, p?=?.005). Moreover, when compared to an apparently healthy population, CLL patients with high CRP levels had more than an eightfold risk of cancer.

Conclusions: Elevated baseline CRP levels are associated with shorter survival and development of second cancers in patients with CLL. We suggest that increased CRP in patients with CLL may justify a more rigorous search for second cancers.

• KEY MESSAGES

• Elevated CRP levels are associated with a shorter overall survival in CLL.

• Elevated CRP levels are associated with an increased risk of second cancers in CLL.

• Increased CRP in patients with CLL may justify a more rigorous search for second cancers.

     

A nondenaturing solid phase pharmaceutical carrier comprised of surface-modified nanocrystalline materials.

Numerous carrier systems have been developed for the controlled delivery of biologically active molecules such as drugs and diagnostic agents. The biophysical interactions between the biologically active molecules and their carriers, however, may denature the former and lead to reduced biological activity. In this study, a model nondenaturing carrier comprised of a nanocrystalline (10 -7 m) tin oxide core and a surface-charge-reducing organic bonding layer (GF292) was synthesized. A subsequently bound protein (human transferrin) showed significant retained conformation by immunoelectron microscopy. In the synthesis of targeted drug systems and vaccines, nanocrystalline cores treated with appropriate surface-modifying agents may be suitable carriers.