Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors.

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors. EXPERIMENTAL DESIGN: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle. RESULTS: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the dose-limiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received > or = 2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 +/- 6.17 ng/mg tissue. CONCLUSION: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.     

Effect of impurities on estradiol crystallization in a sustained-release implant.

During the development of a silicone rubber implant for the delivery of estradiol 17-beta some batches of implants made from a certain lot of commercial estradiol inexplicably developed surface crystals of estradiol after several days of storage. An impurity profile was obtained for 28 lots of estradiol by a newly developed HPLC method. One or more impurities may have had a role in the spontaneous crystal growth on the surface of the implants, because the one lot of estradiol that initially had surface crystals on aging produced acceptable implants after multiple recrystallizations. Attempts to isolate suspected impurities for characterization were unsuccessful. During the manufacture of the implants, temperatures sufficient to melt the estradiol (mp, 173-179 degrees C) were used. It was expected that, upon implant cooling, melted impure estradiol would form a thermodynamically more active (i.e., noncrystalline) physical form. This metastable form could have migrated to the implant surface, where ambient conditions favored crystallization. Because melted estradiol of a higher purity tended to crystallize more readily, it was less likely to form a glass upon cooling. The phenomenon of surface crystallization was limited to one lot of estradiol with the highest level of impurities. Data from differential scanning calorimetry studies supported this conclusion.     

Natural history of the benign breast lump

A prospective study of 112 patients with clinically discrete benign breast lumps has shown that 68 per cent of patients experienced resolution of their lumps over a period of up to 2 years. Resolution of both fibro-adenomas and discrete areas of fibro-adenosis was observed. Diagnosis was achieved by clinical examination and fine needle aspiration cytology. Four patients thought clinically to have benign disease were proven by cytology to have a carcinoma, but no patient with a cytopathological diagnosis of benign disease has developed cancer during or subsequent to this study. We recommend that patients under 35 years of age with clinically and cytologically benign breast lumps can be offered the option of non-excision in the reasonable expectation of resolution of their lesion.     

Chlorinated hydrocarbon levels in human serum: Effects of fasting and feeding

Twenty healthy adult humans had serum samples drawn on four occasions within a 24-hr period: after a 12 hr overnight fast, 4–5 hr after a high fat breakfast, at midafternoon, and the next morning after another 12 hr fast. Nonfasting samples had 22% to 29% higher mean concentrations (p < 0.05) than did fasting samples for polychlorinated biphenyls (PCBs, 4.81 vs 3.74 ng/g serum wt), hexachlorobenzene (HCB, 0.163 vs 0.134 ng/g serum wt), andp,p-dichlorodiphenyldichloroethylene (p,p-DDE, 6.74 vs 5.37 ng/g serum wt) measured by electron capture gas liquid chromatography. Total serum lipids were estimated from measurements of total cholesterol, free cholesterol, triglycerides, and phospholipids and were 20% higher in nonfasting samples than in fasting samples (7.05 g/L vs 5.86 g/L). When PCBs, HCB, andp,p-DDE concentrations were corrected by total serum lipids, results from fasting and nonfasting samples were not statistically different. Because of the differences in these chlorinated hydrocarbon concentrations observed with different sample collection regimens, meaningful comparison of analytical results requires standardizing collection procedures or correcting by total serum lipid levels.     

Comparison of conventional stool concentration and preserved-smear methods with Merifluor Cryptosporidium/Giardia Direct Immunofluorescence Assay and ProSpecT Giardia EZ Microplate Assay for detection of Giardia lamblia.

Giardiasis is the most common parasitic infection in the United States. Variation in the numbers of cysts and/or trophozoites that are present along with the need for a skilled microscopist offer challenges in diagnosis. We compared the sediment wet preparation and permanent stained smear results (concentration in formalin-ethyl acetate and preparation of a smear prepared from a polyvinyl alcohol-preserved specimen) from 512 consecutive specimens with the results obtained by using the Merifluor Cryptosporidium/Giardia Direct Immunofluorescence Assay (DFA; Meridian Diagnostics, Inc., Cincinnati, Ohio) and the ProSpecT Giardia EZ Microplate Assay (EIA; Alexon, Inc., Sunnyvale, Calif.). The Merifluor DFA detected 33 of 33 positive specimens, and the ProSpecT EIA detected 32 of 33 positive specimens. The diagnostic sensitivities of the Merifluor DFA and the ProSpecT EIA were 100 and 97%, respectively. The specificities of the assays were 99.8%. The Merifluor DFA and the ProSpecT EIA appear to be equally sensitive, and both are more sensitive than conventional microscopy.     

Influence of feeding and starvation on the persistence and transmission of Quaranfil virus by Argas (Persicargas) arboreus (Acari: Argasidae)

Viral antigen was detected in the cytoplasm and in associated membranes of salivary gland acinus cells by indirect immunofluorescence and immunoperoxidase staining. Viral ribonucleoproteins (indicated histochemically by presence of pyroninophilic granules) which had accumulated in the cytoplasm of salivary gland type B (granular) acini of unfed Argas (Persicargas) arboreus Kaiser, Hoogstraal & Kohls were no longer visible 24 h after feeding. Virus in tick salivary glands increased from 300 to 500 plaque-forming units during the brief feeding interval (approximately 1 h), but virus was not detectable by 72 h. Overall salivary gland, ovarian, and synganglion tissue levels of Quaranfil virus decreased in the 96 h after feeding, except for synganglion samples in which virus titers increased during 24 h after feeding. Starvation for 105 d resulted in a sevenfold increase in salivary gland viral content compared with those starved 45 d, whereas synganglion tissue titers for Quaranfil virus became undetectable, and ovarian tissue values were similar to those starved for 45 d. Feeding had a greater effect on viral persistence in tissues for ticks starved 60 additional d (comparing 45 with 105 d) in that no Quaranfil virus was detected in any tissue after 48 h (compared with 72 h). Feeding infected ticks (with short extrinsic incubation) on chicks resulted in a peak of host mortality on days 7 and 8, whereas long extrinsic incubation resulted in sporadic mortality over 20 d of monitoring.     

Antibody levels in mothers colonised with group B streptococci during pregnancy and in their newborn infants,as measured by an enzyme linked immunosorbent assay

An enzyme-linked immunosorbent assay (ELISA) was developed to measure serum antibodies to group B streptococci in 20 healthy pregnant women before delivery and in their newborn infants. The sera from 10 of these women who were colonised with group B streptococci and umbilical cord sera from their infants, had higher levels of type-specific lgG antibody than the 10 non-colonised controls and their neonates. All the babies remained well. The results demonstrate that infants from colonised mothers receive type-specific antibody. The possibility that this antibody may provide some degree of protection at birth against this potentially lethal organism warrants investigation.     

Sensititre autoreader for same-day breakpoint broth microdilution susceptibility testing of members of the family Enterobacteriaceae.

The Sensititre Autoreader system is an instrument-assisted broth microdilution susceptibility test procedure based on the detection of fluorogenic growth substrate metabolism by test bacteria with different concentrations of antimicrobial agents. In the current investigation, this system was assessed as a means for predicting the in vitro activity of 17 antimicrobial agents versus numerous species of the family Enterobacteriaceae and Pseudomonas aeruginosa by using a breakpoint broth microdilution test format. Same-day and overnight determinations of susceptibility were made with the Sensititre Autoreader system, and in both cases, the results were compared with those obtained with a manual overnight breakpoint broth microdilution susceptibility test. Among a total of 6,086 organism-antimicrobial agent comparisons with Enterobacteriaceae, concordance was noted between the results of the same-day Autoreader system and the manual overnight test in 94.4% of cases. The same-day Autoreader results with members of the Enterobacteriaceae other than Proteus spp. were determined after 4 h of incubation; with Proteus spp. the same-day Autoreader results were determined after 5 h of incubation. When the Enterobacteriaceae Autoreader results were determined after 18 h of incubation, concordance was noted in 97.2% of comparisons. Among a total of 1,377 organism-antimicrobial agent comparisons with P. aeruginosa after 18 h of incubation, agreement of results from the manual overnight test and the Autoreader system was achieved in 92.2% of cases.     

Identification of women at high genetic risk of breast cancer through the National Health Service Breast Screening Programme (NHSBSP).

Breast cancer is a multifactorial disease with an inherited predisposition being implicated in around 5% of all cases. Using previous epidemiological data assessing risks for the relatives of women with breast cancer, we have identified 154 women (from a screened population of 35,505) and 289 of their relatives between 50 and 64 years who have more than twice the age related risk of developing breast cancer. This constitutes 1.24% of the breast screening population attending the North East Scotland NHSBSP. For each woman identified to be at high risk, we have found 1.87 female relatives between 50 and 64 years and 1.85 relatives under 50 years also to be at high risk. Around 78% of the women identified with a significant family history of breast or other cancer have attended for counselling about their risks. The breast screening programme can be used to identify women at high risk of breast cancer in order to offer them (and their relatives) access to genetic counselling and appropriate screening.