Double β-lactam regimen compared to an aminoglycoside/β-lactam regimen as empiric antibiotic therapy for febrile granulocytopenic cancer patients

In a prospective, randomized trial, 205 febrile episodes in granulocytopenic cancer patients were treated with ceftazidime with or without tobramycin (C±T), both agents being administered only if the initial granulocyte count was below 200/l, or ceftazidime plus piperacillin (C+P). The overall response rate was 71% (39 of 60 for C±T and 45 of 58 for C+P). Logistic regression analyses documented no evidence of a significant difference between the two regimens in overall treatment effect after accounting for the linear effects of potentially important variables, such as infection type and granulocyte count. Although the response rates for the subgroup of patients with bacteremias was better with the C+P regimen (P=0.06), there was no difference in response for patients with bacteremia and profound (<100/gml) sustained granulocytopenia. The double -lactam combination demonstrated in vitro synergism in 73%; antagonism was not seen. Both regimens produced execllent serum bactericidal levels (C±T geometric mean peak 1:170; C+P peak 1:137) against gram-negative but not gram-positive pathogens (1:4; 1:7 respectively) that had caused bacteremia. Emergence of resistance and significant coagulopathy and/or bleeding did not occur during therapy. Antibiotic-related nephrotoxicity was noted in 7 of 95 trials in the C+P and in 6 of 89 trials in the C±T group (P=0.19). The incidence of secondary infections in patients with profound (<100/l) sustained granulocytopenia was lower in the C±T group (P=0.04). Alimentary canal anaerobic flora preservation with C±T, and suppression with C+P, was demonstrated. These results suggest that these regimens are of similar effectiveness and neigher is associated with major toxicity.     

Chemical allergy: considerations for the practical application of cytokine profiling.

Chemical respiratory allergy is an important occupational health problem, but there are currently available no validated methods for hazard identification. This is due in part to the fact that the relevant cellular and molecular mechanisms of sensitization of the respiratory tract have been unclear, with particular controversy regarding the role of IgE. There is now increasing evidence that respiratory sensitization is associated with the preferential activation of type 2 T lymphocytes and the expression of type 2 cytokines interleukin (IL)-4, IL-5, IL-10, and IL-13. Type 2 cell products favor immediate type hypersensitivity reactions, serving as growth and differentiation factors for mast cells and eosinophils, the cellular effectors of the clinical manifestations of the allergic responses, and promoting IgE antibody production. There has been considerable interest in the application of cytokine profiling for the characterization of chemical allergens, with cytokine phenotypes analyzed in freshly isolated tissue, or following culture in the presence or absence of mitogen at the level of protein secretion or mRNA expression. Experience to date suggests that the measurement of induced cytokine secretion profiles shows promise for the hazard identification and characterization of chemical respiratory allergens. The purpose of this brief review article is to consider the approaches available and to highlight key procedural issues.     

Antitumor vaccination of patients with glioblastoma multiforme: a pilot study to assess feasibility, safety, and clinical benefit.

PURPOSE: Prognosis of patients with glioblastoma is poor. Therefore, in glioblastoma patients, we analyzed whether antitumor vaccination with a virus-modified autologous tumor cell vaccine is feasible and safe. Also, we determined the influence on progression-free survival and overall survival and on vaccination-induced antitumor reactivity. PATIENTS AND METHODS: In a nonrandomized study, 23 patients were vaccinated and compared with nonvaccinated controls (n = 87). Vaccine was prepared from patient's tumor cell cultures by infection of the cells with Newcastle Disease Virus, followed by gamma-irradiation, and applied up to eight times. Antitumor immune reactivity was determined in skin, blood, and relapsed tumor by delayed-type hypersensitivity skin reaction, ELISPOT assay, and immunohistochemistry, respectively. RESULTS: Establishment of tumor cell cultures was successful in approximately 90% of patients. After vaccination, we observed no severe side effects. The median progression-free survival of vaccinated patients was 40 weeks (v 26 weeks in controls; log-rank test, P = .024), and the median overall survival of vaccinated patients was 100 weeks (v 49 weeks in controls; log-rank test, P < .001). Forty-five percent of the controls survived 1 year, 11% survived 2 years, and there were no long-term survivors (> or = 3 years). Ninety-one percent of vaccinated patients survived 1 year, 39% survived 2 years, and 4% were long-term survivors. In the vaccinated group, immune monitoring revealed significant increases of delayed-type hypersensitivity reactivity, numbers of tumor-reactive memory T cells, and numbers of CD8(+) tumor-infiltrating T-lymphocytes in secondary tumors. CONCLUSION: Postoperative vaccination with virus-modified autologous tumor cells seems to be feasible and safe and to improve the prognosis of patients with glioblastomas. This could be substantiated by the observed antitumor immune 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.     

Computed tomography (CT) evaluation of breast cancer patients with osteolytic bone metastases undergoing palliative radiotherapy—a feasibility study

Twenty-five patients with osteolytic metastases had computed tomography (CT) scans before and 3 months after palliative radiotherapy. The median % density change following single 8 Gy, 20 Gy/5#, 30 Gy/10# were: 128 (range 98–255), 141 (79–342), and 145 (65–235), respectively. It is feasible to evaluate remineralization of osteolytic lesions with palliative radiotherapy.     

Correlation of serum hormone concentrations in maternal and umbilical cord samples.

Evidence suggests that adult cancer risk of hormonally related tumors may be influenced by the in utero environment, and most speculation on the biological mechanism has focused on the hormonal component. Epidemiological studies investigating the biological nature of pregnancy and maternal factors associated with offspring's cancer risk have relied on maternal hormone measurements. The degree to which maternal hormone levels represent the fetal environment, however, is not widely known. Pregnancy estrogen, androstenedione, testosterone, dehydroepiandrosterone (DHEA), and DHEA-sulfate concentrations were measured in maternal and mixed umbilical cord sera from 86 singleton pregnancies. Spearman correlations between maternal and cord hormone levels generally ranged between 0.2 and 0.3. The correlation was 0.26 for estriol, the estrogen of highest concentration in pregnancy, and 0.27 for estradiol, the most biologically active estrogen. The correlations between mother and offspring for the estrogens and DHEA appeared similar for males and females, whereas there was a suggestion that the maternal-umbilical cord correlations for other androgens varied in magnitude by fetal sex, and all correlations appeared higher in pregnancies lasting <38 weeks compared with longer gestational lengths, although these stratified findings may have been attributable to chance. These data show a moderate degree of correlation in hormone concentrations between the maternal and fetal circulation. Studies using maternal hormone concentrations as a proxy for the fetal environment should consider the misclassification resulting with the use of this marker.     

Confocal microscopy for real-time detection of oral cavity neoplasia.

PURPOSE: The goal of this study was to characterize features of normal and neoplastic oral mucosa using reflectance confocal microscopy. EXPERIMENTAL DESIGN: Oral cavity biopsies were acquired from 17 patients at the Head and Neck Clinic of The University of Texas M. D. Anderson Cancer Center who were undergoing surgery for squamous cell carcinoma within the oral cavity. Reflectance confocal images were obtained at multiple image plane depths from biopsies within 6 h of excision. After imaging, biopsies were fixed in 10% formalin and submitted for routine histological examination. Reflectance confocal images were compared with histological images from the same sample to determine which tissue features contribute to image contrast and can be potentially imaged using in vivo confocal microscopy. RESULTS: Confocal images were successfully acquired from 15 biopsy pairs from 17 patients. Depth-related changes in cell diameter and nuclear density were observed at multiple anatomical sites within the oral cavity. In squamous cell carcinomas, densely packed, pleomorphic tumor nuclei could be visualized with distinct differences in nuclear density and morphology distinguishable between confocal images of neoplastic and nonneoplastic oral cavity. Other features of noncancerous and cancerous oral tissue that could be identified in the confocal images included areas of inflammation, fibrosis, muscle fibers, and salivary glands. CONCLUSIONS: Our results support the potential for this tool to play a significant role in the clinical evaluation of oral lesions, real-time identification of tumor margins, and monitoring of response to therapeutic treatment.     

Overly Literal Interpretations of Speech in Autism: Understanding That Messages Arise from Minds

Children with autism and children with Down's syndrome watched the following enactment. A protagonist put one item in location A and another in location B and then left the scene. Subsequently, the items were swapped the other way round. Finally, the protagonist (who remained ignorant of the swap) requested the item in A. The observing child participant was asked to judge (1) which item the protagonist wanted and (2) which item the protagonist put in A. Unlike children with Down's syndrome, those with autism made more errors in judging that the speaker wanted the item in B than in judging that the item the speaker put in A is now in B; children with autism wrongly tended to interpret utterances literally, and they did this significantly more frequently than children with Down's syndrome. We conclude that children with autism have a difficulty making non literal interpretations that cannot be explained as (1) a realist bias, (2) an inability to inhibit a prepotent response, and (3) a failure to keep track of the exchange of items.     

An Investigation of Adolescents' Substance Use Behaviors, Depressed Affect, and Suicidal Behaviors

Data from a four-wave panel design of 975 adolescents were used to study inter-relationships among suicidal behaviors, depressive symptoms, and substance use behaviors. Persistently high levels of problem drinking and depressive symptoms were associated with higher levels of suicidal thoughts and attempts. Higher levels of depressive symptoms and greater cigarette and illicit drug use distinguished suicidal ideators from attempters. Adolescents attempting suicide reported lower levels of family social support, a greater use of substances to cope with stressors, and a higher density of substance-using peers. Implications of the findings for preventive interventions with high-risk teens are discussed.