Phase II trial of high-dose cisplatin with sodium thiosulfate nephroprotection in patients with advanced carcinoma of the uterine cervix previously untreated with chemotherapy.

Cisplatin is one of the most active single agents in the treatment of advanced cancer of the cervix. The concurrent administration of the nephroprotective agent, sodium thiosulfate, has enabled exploitation of the therapeutic potential of cisplatin. To explore the role of cisplatin dose intensity in the treatment of patients with cancer of the uterine cervix, patients with persistent/recurrent measurable disease were treated with cisplatin at 200 mg/m2 as a 2-hr infusion with sodium thiosulfate given at 3.3 g/m2 1 hr prior to cisplatin and 6.6 g/m2 during the cisplatin infusion. Treatment was repeated monthly. Due to the known cumulative toxicity of cisplatin, treatment beyond two cycles (400 mg/m2) was given only to those patients who had at least demonstrated a PR. Audiologic evaluation was done prior to each cycle of treatment. Eleven patients were entered with a median age of 43 years (range, 25-57), a median KPS of 80% (range, 60-90%), and nine epidermoid and two adenocarcinoma, and all patients had received previous pelvic irradiation. Twenty-eight cycles of treatment were given: 1, five cycles; 3, three cycles; 7, two cycles. No greater than or equal to 3+ hematologic, neurologic, or renal toxicity was demonstrated. Ototoxicity was demonstrated in the mild to moderate hearing loss range (3000-8000 Hz). The greatest threshold shift occurred after the first course of cisplatin. There were three PRs with a maximum duration of 4 months. Due to the significant toxicities encountered, the low response rate, and the limited duration of responses, this trial was closed early to accrual.     

Demonstration of low frequency of human papillomavirus DNA in cervical adenocarcinoma and adenocarcinoma in situ by the polymerase chain reaction and in situ hybridization.

There is evidence that cervical adenocarcinoma is increasing in incidence, particularly in young women. In order to assess the possible role of human papillomaviruses in cervical glandular oncogenesis, 16 cases of invasive adenocarcinoma and eight cases of adenocarcinoma in situ have been examined by in situ DNA hybridization using biotinylated probes to human papillomavirus types 6, 11, 16, 18, and 31, and assessed by polymerase chain reaction analysis for human papillomavirus types 11, 16, and 18 sequences. Of the invasive adenocarcinomas, four of 16 contained human papillomavirus type 16 sequences and one of 16 contained type 18 sequences as assessed by polymerase chain reaction analysis. Five of eight cases of adenocarcinoma in situ contained human papillomavirus type 16 sequences by polymerase chain reaction analysis. Only one invasive adenocarcinoma and one case of adenocarcinoma in situ showed a positive in situ hybridization signal. The low rate of carriage of the human papillomavirus sequences examined suggests that these viral types may not play a major role in cervical glandular neoplasia.     

The clearance of a single i.v. bolus of recombinant human erythropoietin from the serum of patients with myelodysplastic syndromes and its effects on erythropoiesis.

The serum erythropoietin (EPO) concentration in patients with myelodysplasia (MDS) varies widely at similar hemoglobin concentrations, although the reasons for this variation are unclear. We have studied the pharmacokinetics of an i.v. bolus of recombinant human EPO in ten subjects with myelodysplasia. Basal serum EPO concentration varied from 210 to 5984 mU/ml. Plasma half-time clearance (t1/2) varied from 3.9 to 20.0 h. A significant positive correlation was found between t1/2 and basal EPO concentration. An increase in immature peripheral blood reticulocytes was found on days 1 and 2 after EPO treatment; this may represent either an effect on hemopoiesis or on reticulocyte release from the bone marrow.     

The use of albumin microspheres in the treatment of carrageenan-induced inflammation in the rat.

Free hydrocortisone, hydrocortisone incorporated into microspheres and empty microspheres have been administered orally to rats with carrageenan-induced hindpaw inflammation. Hydrocortisone administered in particles was effective at a lower dose than free steroid in reducing inflammation. Inflammatory exudates were able to release steroid from the microspheres by proteolytic degradation.     

The effects of baclofen and pertussis toxin on epileptiform activity induced in the hippocampal slice by magnesium depletion

Bathing hippocampal slices in artificial cerebrospinal fluid without magnesium elicits repetitive, long ictal-like discharges termed ictaform events. The ictaform events are separated by interictal periods that are initially silent with no interictal bursts. Interictal bursts appear in the later part of the interictal periods and intensify just before the next ictaform event. The GABAB agonist, baclofen, entirely suppressed interictal bursts during the interictal periods and produced a dose-dependent prolongation of the interictal period. Conversely, in slices pretreated with pertussis toxin to reduce the GABAB neurotransmission, interictal bursts were greatly increased, often occupying the entire interictal period, although the total duration of the interictal periods was not affected. Pertussis toxin pretreatment also lengthened the ictaform events. These opposing effects of baclofen and pertussis toxin suggest that GABAB neuro-transmission is important in regulating both the occurrence of interictal bursts in the interictal period, as well as the duration of ictaform events in the low magnesium model of epileptiform activity.     

The allergens of Epicoccum nigrum Link. I. Identification of the allergens by immunoblotting.

Two atmospheric isolates of Epicoccum nigrum (EN) were grown under sporulation conditions. Dialyzed extracts of spores, (greater than 95% pure) and pure mycelia were used for skin testing, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and immunoblotting. By skin testing, 49 of the 126 atopic patients were found to be sensitive to EN in St. Louis, Mo., and Corpus Christi, Texas, combined. On immunoblotting, which was performed on 17 sera, 44 bands (12.3 to 119.0 kd) were detected; six were unique to spore, four were unique to mycelium, and 34 were common to both. No single band bound IgE from all sera. The most frequent band corresponding to 42 kd occurred in 11 sera. Five other bands were recognized by more than one half, whereas the remainder bound fewer sera. All skin test-positive patients had positive immunoblots; the number of bands recognized varied from three to 25. Spore or mycelium-specific, as well as common bands were recognized by 13 of 17 sera. Two sera recognized only spore and mycelium-specific bands. Only spore-specific bands were bound by two sera. No strain differences were detected. The binding patterns were comparable in the sera from both St. Louis, Mo., and Corpus Christi, Texas. These data suggest that EN is a significant allergen in urban communities. Allergenic proteins occur in both spore and mycelium, suggesting that both must be included in the reagents for skin testing and immunotherapy.     

Neuronal vacuole formation in the rat posterior cingulate/retrosplenial cortex after treatment with the N-methyl-d-aspartate (NMDA) antagonist MK-801 (dizocilpine maleate)

Cytoplasmic vacuoles appear in neurons of the posterior cingulate/retrosplenial cortex (PC/RS) of rats after treatment with N-methyl-d-aspartate (NMDA) receptor antagonists. Prominent dilatation of mitochondria and endoplasmic reticulum has been described within 2 h; however, the ultrastructural features of vacuole formation are unknown. To investigate this, the present study examined the PC/RS cortex of male rats (age 60–70 days) at 15, 30, 45, 60, 90, and 120 min after subcutaneous treatment with 1 mg/kg of the noncompetitive NMDA antagonist MK-801 (dizocilpine maleate, 5-methyl-10, 11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine). Subtle mitochondrial dilatation was identified in a few neurons as early as 15 min postdose (MPD). By 30 MPD, dilatation was more pronounced in mitochondria and also involved the endoplasmic reticulum and perinuclear space. Ribosomal disaggregation and degranulation were also evident by 30 MPD. At all subsequent time points, dilatation of mitochondria and endoplasmic reticulum progressed in severity. Although the relative involvement of mitochondria and endoplasmic reticulum varied, glia were not involved. These ultrastructural data suggest that after treatment with MK-801, mitochondrial dilatation precedes involvement of endoplasmic reticulum in vacuolization of susceptible PC/RS cortical neurons. The early mitochondrial effects identified in this study suggest an initial metabolic insult that rapidly progresses to affect endoplasmic reticulum and ribosomes. This strengthens the relationship between the ability of certain NMDA antagonists to induce energy perturbations and neuronal vacuoles in the same region of the rat cerebral cortex.