Phase I trial of a novel matrix metalloproteinase inhibitor batimastat (BB-94) in patients with advanced cancer

Summary Degradation of basement membrane and extracellular matrix by matrix metalloproteinases (MMPs) is believed to be required for tumor invasion, tumor-induced angiogenesis and vascular invasion. A synthetic hydroxamate, batimastat (also known as BB-94), inhibits MMPs by binding the zinc ion in the active site of the MMP. Batimastat inhibits at least 50% of MMP activity at concentrations less than or equal to 10 ng/ml in vitro. Batimastat retarded ascites accumulation and increased survival in mice with human ovarian tumor xenografts. Acute and long-term toxicological studies revealed no major toxicity in animals. Batimastat is poorly soluble and was administered intraperitoneally (i.p.) as a suspension. Previous studies in patients with malignant ascites have shown no major toxicities at doses as high as 1350 mg/m².     

Mine Blast Injuries - Our Experience

Background

The sudden increase in incidence and magnitude of mine blast injuries prompted us to highlight the problem and its management.

Methods

The cases of mine blast injuries occurring during mining and demining in a particular geographical area were analysed. Total 27 cases of mine blast injuries occurred during mining or demining operations in a period of 13 months.

Results

Various body regions were involved in the mine blast injuries but the main brunt was borne by feet and legs followed by multiple body regions due to splinters. 14 patients underwent below knee (BK) amputation while 4 patients required through knee (TK) amputations. The effect of blast was so severe that most of the cases required 2 to 5 times wound debridements. The initial aggressive debridement / open stump amputation saved the limb and life of all patients.

Conclusion

A mine blast causes extensive injuries and psychological trauma. Management is needed urgently, surgery is difficult, and amputation is often inevitable. Maximum lives and limbs can be saved with aggressive debridement, repeated inspections and dressings under anaesthesia and definitive closure at optimum time.Key Words: Amputation, Antipersonnel mine, Crush syndrome, Debridements, Mine blast injury, Secondary missiles, Shrapenels     

Prekallikrein-Kallikrein conversion rate as a predictor of contrast material catastrophies

An in vitro is described that attempts to detect patients with a potential for adverse systemic reactions to contrast material. This test involves measuring the rate of conversion of prekallikrein to kallikrein under certain standard conditions. In a preliminary retrospective study, the test could be used to identify such patients with a sensitivity of 88%, a specificity of 82%, and a predictive value of 79%.     

Disordered salivary immunoglobulin secretion and sodium transport in human chronic graft-versus-host disease

Whole saliva samples and lip biopsies were collected from 12 allogeneic bone marrow transplant recipients who developed extensive chronic graft-versus-host disease (GVHD) and from 10 healthy allogeneic and syngeneic recipients without GVHD. Six of ten biopsies from patients with chronic GVHD had lichenoid stomatitis or sialadenitis, or both, with sialodochitis. Seven of nine biopsies from patients free of chronic GVHD were entirely normal, and two had either mild glandular or mucosal changes. Salivary gland involvement in chronic GVHD was associated with decreased or absent levels of salivary IgA and inorganic phosphate, decreased salivary flow rates, and increased concentrations of salivary sodium, albumin, and IgG. The most striking abnormalities were found in patients with histologic evidence of sialadenitis. In contrast, marrow transplant recipients without chronic GVHD had normal salivary immunoglobulin and electrolyte levels. Secretory IgA deficiency may contribute to the frequent sinobronchial infections observed in patients with chronic GVHD.     

Histopathology of hepatic acute graft-versus-host disease in the dog. A double blind study confirms the specificity of small bile duct lesions.

To test the association of small bile duct destructive lesions in the liver with acute graft-versus-host disease, a blind (coded) histological study was done comparing liver tissue from three groups of dogs given 1,200 R of total-body irradiation: one not given marrow infusions after irradiation, another given autologous hemopoietic grafts, and a third given marrow grafts from DLA-nonidentical unrelated donors. The dogs with unrelated grafts all developed graft-versus-host disease, and their liver histology was distinguished from that of the dogs in the other two groups by three findings: (1) extensive small bile ductule necrosis and atypia; (2) infiltrates of mononuclear cells around and in ductules; and (3) individual hepatocyte necrosis scattered throughout the lobules. Thus, bile duct lesions appear to be a good marker for assessing the presence and severity of hepatic graft-versus-host disease in dogs.     

Multiple tumors after androgen therapy.

A case of multiple small well-differentiated hepatomas with early peliosis hepatis, multiple pancreatic islet cell tumors, and a renal medullary interstitial cell tumor following five years of androgen and prednisone therapy for idiopathic aplastic anemia is reported in a patient who died shortly after allogeneic bone marrow transplantation. The hepatic tumors were well differentiated, and the pancreatic tumors were of mixed ribbon and islet cell pattern. Therapeutic and experimental implications and the relevant literature are briefly summarized.     

Does the addition of information on genotype improve prediction of the risk of melanoma and nonmelanoma skin cancer beyond that obtained from skin phenotype?

The authors quantified improvement in predicting cutaneous malignant melanoma, basal cell carcinoma, and squamous cell carcinoma of the skin made possible by information on common variants of the melanocortin-1 receptor gene (MC1R) in a 1998-1999 population-based case-control study of subjects aged 20-59 years of northern European ancestry in Tasmania, Australia. Melanin density at the upper inner arm was estimated by spectrophotometry. DNA samples were genotyped for five MC1R variants: Val60Leu, Asp84Glu, Arg151Cys, Arg160Trp, and Asp294His. Among controls (n = 267), variant carriers, versus noncarriers, had lower (p < 0.01) mean melanin concentrations. Increased risk conferred by genotype was restricted mainly to those with the darkest skins: for subjects with at least 2% melanin, the odds of carrying each additional variant were higher for cutaneous malignant melanoma (n = 39; odds ratio = 1.45, 95% confidence interval: 0.87, 2.44), basal cell carcinoma (n = 35; odds ratio = 1.86, 95% confidence interval: 1.14, 3.02), and squamous cell carcinoma (n = 42; odds ratio = 2.67, 95% confidence interval: 1.50, 4.74) cases than for controls (n = 135). Adding MC1R information to prediction based on age, sex, and cutaneous melanin increased the area under the receiver operating characteristic curve by 1.4% (cutaneous malignant melanoma), 3.2% (basal cell carcinoma), or 2.0% (squamous cell carcinoma). The improvement in prediction was probably too small to be valuable in a clinical setting.     

Enriched environment and acceleration of visual system development

Rearing mice from birth in an enriched environment leads to a conspicuous acceleration of visual system development appreciable at behavioral, electrophysiological and molecular level. Little is known about the possible mechanisms of action through which enriched environment affects visual system development. It has been suggested that differences in maternal behavior between enriched and non-enriched conditions could contribute to the earliest effects of enriched environment on visual development and that neurotrophins, BDNF in particular, might be involved. Here, we examined Brain Derived Neurotrophic Factor (BDNF) levels in the visual cortex during development and showed that an increase occurs in the first week of life in enriched pups compared to standard reared pups; BDNF levels at birth were equal in the two groups. This suggests a postnatal rather than a prenatal effect of environment on BDNF. A detailed analysis of maternal care behavior showed that pups raised in a condition of social and physical enrichment experienced higher levels of licking behavior and physical contact compared to standard reared pups and that enhanced levels of licking were also provided to pups in an enriched environment where no adult females other than the mother were present. Thus, different levels of maternal care in different environmental conditions could act as indirect mediator for the earliest effects of enrichment on visual system development. Some of the effects of different levels of maternal care on the offspring behavior are long lasting. We measured the visual acuity of differentially reared mice at the end of the period of visual acuity development (postnatal day 45) and at 12 months of age, using a behavioral discrimination task. We found better learning abilities and higher visual acuity in enriched compared to standard reared mice at both ages.     

Broad phenotypic variability in a single pedigree with a novel 1410delC mutation in the PST domain of the PAX6 gene

The PAX6 mutation present in an individual with aniridia was determined and phenotypic features of immediate relatives carrying the same mutation investigated. Mutation analysis revealed a novel single base deletion 1410delC in the PAX6 gene in ten affected individuals. Clinical features ranged from total aniridia to very mild anterior segment findings. Other findings included partial aniridia, iris stromal hypoplasia, keratitis, cataract, glaucoma, optic disc anomalies and foveal hypoplasia. It appears that independent modifying factors may underlie the variability of the different phenotypic features of the PAX6 mutation.     

Using Standardized Oral Examinations to Evaluate General Competencies

Emergency medicine residency programs are required by the Accreditation Council for Graduate Medical Education (ACGME) to formally evaluate each resident with oral and written examinations. The Michigan State University Emergency Medicine Residency Program in Lansing conducts monthly standardized oral examinations (SOEs) as part of each resident's evaluation. Recently, the ACGME has advanced six areas, termed "general competencies," that should be acquired during graduate medical education. According to the ACGME, these competencies should be included in the educational process of all residency programs. In promulgating these competencies, the ACGME did not provide examples of core content, strategies for implementation, or methods of evaluation; rather, individual residency programs are required to develop their own methods. The authors describe a modification of an existing SOE strategy that assesses residents' knowledge, skills, experiences, and attitudes as reflected in the general competencies.