Targeting microparticles to select tissue via radiation-induced upregulation of endothelial cell adhesion molecules

Purpose. Certain endothelial cell adhesion molecules are up regulated in tissue that has been irradiated for therapeutic purposes. This up-regulation of adhesion molecules provides a potential avenue for targeting drugs to select tissues. Methods. Microspheres were coated with a mAb to ICAM-1 and the level of adhesion of the anti-ICAM-1 microspheres to irradiated tissue in vitro and in vivo was quantified. Results. Under in vitro flow conditions, the number of adherent microspheres on irradiated HUVEC was 4.8 ± 0.9 times that of control; the adhesion of anti-ICAM-1 microspheres on irradiated HUVEC could be enhanced by more than 170% in the presence of RBC (20% hematocrit) in the medium. In vivo in a rat cranial window model, the number of adherent anti-ICAM-1 microspheres in locally irradiated cerebral tissue was 8 and 13 times that of IgG microspheres at 24 h and 48 h post-irradiation, respectively and returned to baseline 7 days post-irradiation. In locally irradiated animals, the number of adhering microspheres in unirradiated tissue remained at the basal level. Conclusions. Radiation-induced up-regulation of endothelial cell adhesion molecules may be exploited to target drugs and/or genes to select segments of the endothelium.     

Effect of oral ketoconazole on first-pass effect of nifedipine after oral administration in dogs

The long-term oral ketoconazole (KTZ) treatment extensively inhibits hepatic CYP3A activity. We investigated the effect of the KTZ treatment on hepatic and intestinal extraction of nifedipine (NIF) using beagle dogs. Four dogs were given orally KTZ for 20 days (200 mg, bid). NIF was administered either intravenously (0.5 mg/kg) or orally (20 mg) 10 and 20 days before the KTZ treatment and 10 and 20 days after start of KTZ treatment. CLtot of NIF after intravenous administration decreased to about 50% during the KTZ treatment. C(max) and AUC after oral administration increased to 2.5-fold and fourfold, respectively, by the KTZ treatment. The hepatic extraction ratio of NIF decreased to about a half by KTZ. A significant decrease in intestinal extraction ratio was not observed. In conclusion, the KTZ treatment inhibits hepatic extraction more profoundly than intestinal extraction of NIF. Therefore, inhibition of hepatic extraction of NIF by the KTZ treatment mainly results in substantial increase in systemic bioavailability in dogs. Because KTZ inhibits human CYP3A activities similar to canine CYP3A activities, the long-term oral KTZ treatment may dramatically increase bioavailability of NIF or other CYP3A substrates in humans.     

Atypical benign epilepsy of childhood with rolandic spikes: features of a subset requiring more than one medication for seizure control

The objective of this study was to compare the clinical and electroencephalographic features of two groups of children with benign epilepsy of childhood with rolandic spikes: those in whom seizure control was attained either without the use of medication or with a single medication (group 1) and those requiring two medications for seizure control (group 2). A consecutive series of children with benign epilepsy of childhood with rolandic spikes was identified in a single pediatric neurology practice. Medical charts were then systematically retrospectively reviewed. A total of 66 children with benign epilepsy of childhood with rolandic spikes was identified; 52 (78.8%) required either no medication (n = 7) or a single medication (n = 45) for seizure control, whereas 14 (21.2%) required two medications. The two groups did not differ with respect to gender, age of onset, type (generalized or partial) of initial seizure, or whether EEG abnormalities were unilateral or bilateral. They did differ significantly with respect to the mean number of seizures experienced prior to initiating treatment (group 1, 2.06, versus group 2, 4.36; t = 3.40, P = .005). In those treated (n = 59), the initial medication selected (carbamazepine versus noncarbamazepine) in the two groups was significantly different: group 1, 40 (carbamazepine)/45, versus group 2, 9 (carbamazepine)/14; chi2 = 4.59; P = .03. The difference in frequency between the two groups of associated comorbid conditions (tics, attention-deficit hyperactivity disorder [ADHD], learning disability) almost reached the threshold of statistical significance: group 1, 7/52, versus group 2, 5/14 (chi2 = 3.67, P = .06). A subset of children with benign epilepsy of childhood with rolandic spikes may require more than one medication for effective seizure control. This subset experiences more seizures prior to the initiation of treatment, is more likely to be treated initially with a noncarbamazepine medication, and tends to have a higher frequency of associated conditions.     

A novel chronic childhood sensory predominant neuropathy

Chronic childhood neuropathies are predominantly hereditary in origin. Specific distinct clinical entities have been described, however, occasionally children with an unusual clinical phenotype are encountered in practice. We describe four children (3 males, 1 female) of Lebanese Moslem descent all sharing a common great-great-grandparent pairing with such a novel clinical spectrum. The three males were first cousins, each the product of a different parental consanguineous (i.e., parents second cousins) mating, whereas the female was a third cousin to each of the males whose parents were also second cousins. Each child presented early in life with developmental delay with associated hypotonia and areflexia. All had a sensorineural hearing loss documented and two of the patients were dysmorphic in facial appearance. Nerve conduction studies highlighted a sensory axonal neuropathy and sural nerve biopsy undertaken in two patients confirmed an axonal neuropathy. Detailed genetic and metabolic testing was negative. Followed into later childhood, each child continued to manifest motoric impairment, unsteadiness, areflexia, and cognitive disability. These children appear to provide evidence for a novel autosomal recessive inherited chronic predominantly sensory neuropathy that shares core clinical features with observed variability in associated symptoms.     

Large-Scale pathology-based cancer data - a reflection of population-based cancer data

Pathology-based cancer data is a high quality reflection of the patterns of cancer in the population it represents, provided the demographic details of the patients are carefully recorded. Relative frequency data is neither a replacement for population-based data nor a suggested alternative; it simply enhances the quality of population data and in very large data sets reflects the cancer patterns observed in the representative populations. Aware of the standard shortfalls of pathology-based data, the department of pathology, The Aga Khan University Hospital (AKUH) standardized its data, representing 53.4% of the cancer data of Karachi Division (Pakistan) and also reflecting the cancer pattern of other provinces of Pakistan. This data was compared with 4 different population and institutional-based data sets. The findings substantiate the observation that despite the problems of interpretation of data from pathology laboratories, they are an invaluable source of information on cancer patterns in much of the world where incidence data are unavailable . If developing countries, unable to organize National Population- Based Registry should as an alternate develop National Pathology-based Registers a well targeted and monitored, a Cancer Control Program would be possible. A good quality, large-scale pathology data with demographic details of the patient recorded can also be extended to give coverage to the population.     

Prospects for herpes-simplex-virus thymidine-kinase and cytokine gene transduction as immunomodulatory gene therapy for prostate cancer

In completed and ongoing clinical trials, adenovirus-mediated (Ad.) expression of herpes-simplex-virus thymidine-kinase (HSV-tk) gene transduction followed by ganciclovir (GCV) therapy has produced limited toxicity and evidence of antitumor activity following injection of the prostate. Furthermore, this system has been shown to direct systemic antitumor activity in several experimental cancer models, including that of prostate cancer, which may serve as the basis for in-situ immunomodulatory gene therapy. In a mouse model of prostate cancer, natural killer (NK) cells have been identified as the mediator of antimetastatic activity following Ad.HSV-tk + GCV, resulting in the combination of Ad.HSV-tk and adenovirus-mediated expression of interleukin 12 (Ad.IL-12) to exploit this cytokine's ability to enhance NK proliferation and cytotoxicity. Combination therapy demonstrated superior local and systemic growth suppression over that obtained with either therapy alone. Importantly, when the metastatic tumor burden was increased to an extent that negated the growth-suppressive activity directed by Ad.HSV-tk + GCV or Ad.IL-12 alone, combination therapy continued to demonstrate significant growth suppression. Examination of tumor-infiltrating lymphocytes documented enhanced NK lytic activity following combination therapy. Therefore, it appears that the combination of Ad.HSV-tk and Ad.IL-12 should be validated in a clinical trial for the treatment of prostate cancer.     

Quality improvement in laparoscopic radical prostatectomy for pT2 prostate cancer: impact of video documentation review on positive surgical margin

PURPOSE: We correlated intraoperative video documentation and pathology findings to understand the mechanisms by which positive surgical margins occur and improve the surgical technique. MATERIALS AND METHODS: Between January 2003 and May 2004, 240 consecutive patients underwent laparoscopic radical prostatectomy, of whom 180 had pT2 prostate cancer and represent the population of this study. After the first 90 patients (group 1) we started a quality assurance study, analyzing intraoperative video recordings and correlating them with pathology findings in patients with a positive margin. The cancer characteristics and positive margin rate were compared between the first 90 patients and the subsequent 90 after the study was initiated (group 2). RESULTS: Of the 12 cases of positive surgical margins studied the video review helped identify 8 with a technical error. In all 4 cases in which a technical error could not be identified the positive margin site was at the distal apex. The most frequent identifiable mechanism by which positive margins occurred was a capsular tear during neurovascular bundle dissection. The 2 groups were comparable in regard to preoperative cancer characteristics and total tumor volume. In patients who underwent bilateral nerve sparing the positive margin rate was 10.6% in group 1 and 5.4% in group 2 (p = 0.18). All positive margins in group 2 involved the prostatic apex. CONCLUSIONS: Quality assurance efforts through pathological and intraoperative documentation review can help decrease the positive margin rate, particularly in organ confined disease. However, eradicating positive margins at the distal prostatic apex remains a challenge.     

Chronic perforation of the sigmoid colon by foreign body

Colorectal foreign bodies (FBs) may be ingested or introduced transanally and then migrate proximally. Without a reliable history, it may be impossible to determine which way a certain colorectal FB gained access. We present a case of a nonverbal mentally retarded boy with a flat piece of plastic impacted in the sigmoid colon, the colonoscopic extraction of which failed. He underwent laparotomy more than a year later to remove the FB, where chronic perforation of the sigmoid colon was discovered. The perforation was sealed with extensive adhesions to the pelvic wall, and histologically, the colon showed a chronic granulomatous reaction. We discuss the types, presentations, and diagnosis of intestinal perforation with FBs. Chronic perforation may present with radiologic and pathologic features that suggest inflammatory bowel disease.