Evaluation of whole blood catalase estimation for diagnosis of malignancy

Whole blood catalase levels were estimated using a disc flotation method in 209 random patients with a wide variety of malignancies. Fifty patients had received no treatment, and the remainder, although having undergone prior therapy, had recurrent or metastatic disease at the time of the study. No relationship was found between the presence of cancer and catalase levels. A direct relationship was found for catalase with hemoglobin levels in both normal and patients' samples. Whole blood catalase is of no value in diagnosis and monitoring of cancer. The decreased catalase values found here and reported previously by others are the result of low hemoglobin levels found in many patients with cancer.     

Downregulation of neuronal cdk5/p35 in opioid addicts and opiate-treated rats: relation to neurofilament phosphorylation.

Neuronal cyclin-dependent kinase-5 (Cdk5) and its neuron-specific activator p35 play a major role in regulating the cytoskeleton dynamics. Since opioid addiction was associated with hyperphosphorylation of neurofilament (NF) in postmortem human brains, this study was undertaken to assess the status of the cdk5/p35 complex and its relation with NF-H phosphorylation in brains of chronic opioid abusers. Decreased immunodensities of cdk5 (18%) and p35 (26-44%) were found in the prefrontal cortex of opioid addicts compared with matched controls. In the same brains, the densities of p25 (a truncated neurotoxic form of p35), phosphatase PP2Ac and mu-calpain were found unaltered. Acute treatment of rats with morphine (30 mg/kg, 2 h) increased the density of cdk5 (35%), but not that of p35, in the cerebral cortex. In contrast, chronic morphine (10-100 mg/kg for 5 days) induced marked decreases in cdk5 (40%) and p35 (47%) in rat brain. In brains of opioid addicts, the density of phosphorylated NF-H was increased (43%) as well as the ratio of phosphorylated to nonphosphorylated NF-H forms (two-fold). In these brains, phosphorylated NF-H significantly correlated with p35 (r=0.58) but not with cdk5 (r=0.03). The results suggest that opiate addiction is associated with downregulation of cdk5/p35 levels in the brain. This downregulation and the aberrant hyperphosphorylation of NF-H proteins might have important consequences in the development of neural plasticity associated with opiate addiction in humans.     

In vivo imaging of apoptosis by 99mTc-Annexin V scintigraphy: visual analysis in relation to treatment response.

BACKGROUND AND PURPOSE: Anticancer therapy induces apoptosis in a dose- and time-dependent fashion. (99m)Tc-Hynic-rh-Annexin V scintigraphy (TAVS) enables non-invasive in vivo imaging of treatment-induced apoptosis. We identified the visual patterns of (99m)Tc-Hynic-rh-Annexin V tumour uptake and related these to treatment response. PATIENTS AND METHODS: Thirty-three patients with malignant lymphoma (n=26), leukaemia (n=1) NSCLC (n=5), H&NSCC (n=1), scheduled for radiotherapy (n=27), platinum-based chemotherapy (n=5) or concurrent chemoradiation (n=1), underwent TAVS before and early after the start of treatment. Planar and SPECT images were visually examined to assess changes in tumour (99m)Tc-Hynic-rh-Annexin V uptake. Twenty-nine patients were eligible for further analysis. Annexin V uptake before (U(baseline)) and early after (U(post)) the start of treatment was graded using a four-step scale: 0, absent; 1, weak; 2, moderate and 3, intense. The difference between these values (Delta U) was calculated and correlated to tumour response after therapy (Spearman rank correlation test). RESULTS: Weak to moderate U(baseline) was detected in 13/15 patients with a complete response and U(post) was markedly increased in all these cases (Delta U range 1-3). Partial response (n=7) was associated with weak to moderate U(baseline) and a moderately increased U(post) (Delta U range 1-2). In patients with stable disease (n=5), U(baseline) was predominantly weak, without considerable changes in uptake after the start of treatment (Delta U range 0-1). Finally, in case of progressive disease (n=2), either no tumour uptake or a decrease in U(post) was detected (Delta U=-1). A statistically significant correlation was found between changes in (99m)Tc-Hynic-rh-Annexin V tumour uptake and clinical response (correlation coefficient=0.62; P<0.001). CONCLUSIONS: Complete or partial tumour response was associated with a marked increase of (99m)Tc Hynic-rh-Annexin V accumulation early during treatment compared to baseline values. In case of stable or progressive disease, pretreatment scans demonstrated predominantly low (99m)Tc Hynic-rh-Annexin V tumour uptake and no significant increase early after treatment. These results indicate that TAVS might be useful as a predictive test for treatment response.     

Liposomal irinotecan: formulation development and therapeutic assessment in murine xenograft models of colorectal cancer.

PURPOSE: The purpose is to demonstrate whether an appropriately designed liposomal formulation of irinotecan is effective in treating mice with liver-localized colorectal carcinomas. EXPERIMENTAL DESIGN: Irinotecan was encapsulated in 1,2-distearoyl-sn-glycero-3-phosphocholine/cholesterol (55:45 molar ratio) liposomes using an ionophore (A23187)-generated transmembrane proton gradient. This formulation was evaluated in vivo by measuring plasma elimination of liposomal lipid and drug after i.v. administration. Therapeutic activity was determined in SCID/Rag-2M mice bearing s.c. LS180 tumors or orthotopic LS174T colorectal metastases. RESULTS: Drug elimination from the plasma was significantly reduced when irinotecan was administered in the liposomal formulation. At 1 hour after i.v. administration, circulating levels of the liposomal drug were 100-fold greater than that of irinotecan given at the same dose. High-performance liquid chromatographic analysis of plasma samples indicated that liposomal irinotecan was protected from inactivating hydrolysis to the carboxylate form. This formulation exhibited substantially improved therapeutic effects. For the LS180 solid tumor model, it was shown that after a single injection of liposomal irinotecan at 50 mg/kg, the time to progress to a 400-mg tumor was 34 days (as compared with 22 days for animals treated with free drug at an equivalent dose). In the model of colorectal liver metastases (LS174T), a median survival time of 79 days was observed after treatment with liposomal irinotecan (50 mg/kg, given every 4 days for a total of three doses). Saline and free drug treated mice survived for 34 and 53 days, respectively. CONCLUSIONS: These results illustrate that liposomal encapsulation can substantially enhance the therapeutic activity of irinotecan and emphasize the potential for using liposomal irinotecan to treat liver metastases.     

Radiation-Induced Apoptosis: The Ceramide-SAPK Signaling Pathway and Clinical Aspects

Apoptosis, or programmed cell death is an important regulatory mechanism that is involved in a variety of homeostatic processes. Decreased cellular sensitivity or inappropriate responses to apoptotic stimuli may be important factors in tumorigenesis and resistance to anticancer treatments. It is generally accepted that all mammalian cells constitutively express the biochemical machinery to execute apoptosis. It is, however, not clear which signal transduction pathways are involved, or to which extent various stimuli activate independent or partially overlapping pathways. In this paper we discuss the involvement of a ceramide-mediated stress-activated protein kinase (SAPK) signaling cascade in radiation-induced apoptosis. Furthermore, examples are presented of pharmacological intervention in specific signal transduction pathways that lead to modulation of the apoptotic response. Finally, data are presented to illustrate the potential clinical relevance of apoptosis.     

Visualization and quantification of coronary calcifications with electron beam and spiral computed tomography

This contribution reviews the pathology and morphology of coronary calcifications. It summarizes the indications for investigation of the coronary arteries. The standard protocols for scan acquisition using electron beam and conventional computed tomography are described as well as various methods for evaluation such as the traditional Agatston scoring method and the newer three-dimensional scoring algorithms. Guidelines for interpreting scores are also reviewed. Major limitations of the reproducibility of the calcium score measurement are summarized. Future aspects of multirow-detector spiral computed tomography with retrospective electrocardiographic triggering for quantifying coronary calcium are discussed. Received: 13 August 1999; Accepted: 30 September 1999     

Withholding or starting antibiotic treatment in patients with dementia and pneumonia: prediction of mortality with physicians' judgment of illness severity and with specific prognostic models.

BACKGROUND: To help decision makers plan treatment, the authors assessed clinical predictors of mortality from nursing home-acquired pneumonia in patients with dementia. METHODS: Pneumonia patients treated without (n = 165) or with antibiotics (n = 541) were enrolled in a prospective cohort study in 61 nursing homes. RESULTS: In both groups, clinical judgment of illness severity was a strong predictor for 1-week mortality. Despite large differences in frailty and mortality (83% in untreated patients and 15% in treated patients), separate multivariable logistic models included similar specific predictors. DISCUSSION: Despite profound differences between the 2 independent groups, predictors for short-term mortality were largely similar. We found that, when combined with physicians' clinical judgment, 3 readily assessed predictors (respiratory rate, fluid intake, and eating dependency) helped predict mortality. Our results, if confirmed in an independent population, can help make decision making about antibiotic treatment of pneumonia in patients with dementia more evidence-based.     

Antiprotozoal activities of new bicyclo[2.2.2]octan-2-imines and esters of bicyclo[2.2.2]octan-2-ols.

Several bicyclo[2.2.2]octan-2-imines and esters of bicyclo[2.2.2]octan-2-ols were prepared. Their antitrypanosomal and antiplasmodial activities against Trypanosoma brucei rhodesiense (STIB 900) and the K1 strain of Plasmodium falciparum (resistant to chloroquine and pyrimethamine) were determined using microplate assays. Two of the synthesized bicyclo[2.2.2]octan-2-one 4'-phenylthiosemicarbazones showed the highest antitrypanosomal activity (IC(50)<0.3 microM) of the so far prepared 4-amino-6,7-diarylbicyclo[2.2.2]octane derivatives, but they are distinctly less active than suramine (IC(50)=0.0075 microM). Most of the 4'-phenylthiosemicarbazones and a single bicyclo[2.2.2]octan-2-yl benzoate exhibit attractive antimalarial activity (IC(50)=0.23-0.72 microM). Two bicyclooctanone oximes are even as active as chloroquine (IC(50)=0.08-0.15 microM, chloroquine: IC(50)=0.12 microM against sensitive strains).