Management of fever and neutropenia in paediatric cancer patients: room for improvement?

PURPOSE OF REVIEW Fever and neutropenia is the most common complication in the treatment of childhood cancer. This review will summarize recent publications that focus on improving the management of this condition as well as those that seek to optimize translational research efforts. RECENT FINDINGS A number of clinical decision rules are available to assist in the identification of low-risk fever and neutropenia however few have undergone external validation and formal impact analysis. Emerging evidence suggests acute fever and neutropenia management strategies should include time to antibiotic recommendations, and quality improvement initiatives have focused on eliminating barriers to early antibiotic administration. Despite reported increases in antimicrobial resistance, few studies have focused on the prediction, prevention, and optimal treatment of these infections and the effect on risk stratification remains unknown. A consensus guideline for paediatric fever and neutropenia research is now available and may help reduce some of the heterogeneity between studies that have previously limited the translation of evidence into clinical practice. SUMMARY Risk stratification is recommended for children with cancer and fever and neutropenia. Further research is required to quantify the overall impact of this approach and to refine exactly which children will benefit from early antibiotic administration as well as modifications to empiric regimens to cover antibiotic-resistant organisms.

Core outcomes and definitions for pediatric fever and neutropenia research: a consensus statement from an international panel.

BACKGROUND There are no specific recommendations for the design and reporting of studies of children with fever and neutropenia (FN). As a result, there is marked heterogeneity in the variables and outcomes that are reported and new definitions continue to emerge. These inconsistencies hinder the ability of researchers and clinicians to compare, contrast and combine results. The objective was to achieve expert consensus on a core set of variables and outcomes that should be measured and reported, as a minimum, in pediatric FN studies. PROCEDURE The Delphi method was used to achieve consensus among an international group of clinicians, pharmacists, researchers, and patient representatives. Four surveys focusing on (i) the identification of a core set of variables and outcomes; and (ii) definitions of these variables and outcomes, were administered electronically. Consensus was predefined as more than 80% agreement on any statement. RESULTS There were forty-five survey participants and the response rate ranged between 84 and 96%. There was consensus on eight core variables and 10 core outcomes that should be collected and reported in all studies of children with FN. Consensus definitions were identified for all of the core outcomes. CONCLUSION Using the Delphi method, expert consensus on a set of core variables and outcomes, and their corresponding definitions, was achieved. These core sets represent the minimum that should be collected and reported in all studies of children with FN. This will promote collaboration and ensure consistency and comparability between studies.

Mechanisms of Ad-p53 induced apoptosis in human malignant glioma

Malignant brain tumors are one of the most challenging cancers affecting society today. In a recent survey, an estimated 17,000 annual cases were recorded with a staggering total of 13,300 deaths. A unique degree of heterogeneity typifies glial tumors and presents a challenge for solitary anti-neoplastic treatments. Tumors subsist as heterogeneous masses that progress through dysplasia to astrocytomas, mixed glioma and glioblastoma multiforme. Although traditional therapeutic approaches have provided increments of success, the median survival time remains 12 months. The urgency to improve upon current clinical protocols has encouraged alternative experimental strategies such as p53 adenoviral gene therapy (Ad-p53). This study addresses the efficacy of Ad-p53 for the treatment of glioma. Our model presents a tumor response that is unique among human cancers. Ad-p53 effectively induces apoptosis in mutant p53 expressing cells yet fails to do so in those with wildtype p53. In order to adopt Adp53 as a standard anti-cancer modality, we characterized the role of the tumor suppressor gene p53 in mediating apoptosis. We demonstrate that altering cellular p53 status through the introduction of a dominant negative mutant p53 (175H, 248W, 273H) sensitized cells to Ad-p53. We discovered that wild-type p53 expressing glioma cells retain the apoptotic machinery necessary to accomplish cell death, but have developed mechanisms that interfere with p53 signaling. Earlier studies have not addressed the mechanisms of Ad-p53 apoptosis nor the resistance exhibited by wild-type p53 glioma. To explain the divergent phenotypes, we identified apoptotic pathways activated and effectors of the response. We illustrated that modulation of the death receptor Fas/APO-1 is a principal means of Ad-p53 signaling that is impaired in wild-type p53 glioma. Moreover, the apoptotic response was found to be a multi-faceted process that engaged several caspases, most notably caspases -1, -3 and -8. Lastly, we assessed the ability of anti-apoptotic molecules Bcl-2 and CrmA to inhibit Ad-p53 apoptosis. These studies revealed that Ad-p53 is a powerful tool for inducing apoptosis that can be delayed but not inhibited by anti-apoptotic means. This work is critical for understanding the development of glioma and the phenotypic and genotypic alterations that account for tumor resistance. ^

Molecular alterations in nucleotide excision repair genes in malignant glioma and their relevance to malignant progression and drug resistance

Recently, it has become apparent that DNA repair mechanisms are involved in the malignant progression and resistance to therapy of gliomas. Many investigators have shown that increased levels of O6-methyl guanine DNA alkyltransferase, a DNA monoalkyl adduct repair enzyme, are correlated with resistance of malignant glioma cell lines to nitrosourea-based chemotherapy. Three important DNA excision repair genes ERCC1 (excision repair cross complementation group 1), ERCC2 (excision repair cross complementation group 2), and ERCC6 (excision repair cross complementation group 6) have been studied in human tumors. Gene copy number variation of ERCC1 and ERCC2 has been observed in primary glioma tissues. A number of reports describing a relationship between ERCC1 gene alterations and resistance to anti-cancer drugs have been also described. The levels of ERCC1 gene expression, however, have not been correlated with drug resistance in gliomas. The expression of ERCC6 gene transcribes has been shown to vary with tissue types and to be highest in the brain. There have been no comprehensive studies so far, however, of ERCC6 gene expression and molecular alterations in malignant glioma. This project examined the ERCC1 expression levels and correlated them with cisplatin resistance in malignant glioma cell lines. We also examined the molecular alterations of ERCC6 gene in primary glioma tissues and cells and analyzed whether these alterations are related to tumor progression and chemotherapy resistance. Our results indicate the presence of mutations and/or deletions in exons II and V of the ERCC6 gene, and these alterations are more frequent in exon II. Furthermore, the mutations and/or deletions in exon II were shown to be associated with increased malignant grade of gliomas. The results on the Levels of ERCC1 gene transcripts showed that expression levels correlate with cisplatin resistance. The increase in ERCC1 mRNA induced by cisplatin could be down-regulated by cyclosporin A and herbimycin A. The results of this study are likely to provide useful information for clinical treatment of human gliomas. ^

Cutaneous malignant melanoma: A study of skin cancer in the United States from 1973--1997

Cutaneous malignant melanoma (CMM) is the cancer of the melanocytes, the cells that produce the pigment melanin, and is an aggressive skin cancer that is most prevalent in the white population. Although most cases of malignant melanoma are white, black and other non-white populations also develop this disease. However, the etiologic factors involved in the development of melanoma in these lower-risk populations are not well known. Generally, survival rates of malignant melanoma have been found to be lower in blacks than for whites with similar stage of disease at diagnosis. ^ This study presents an analysis of the differences in survival between black and white cases with malignant melanoma of the skin as the only or first primary cancer, found in the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) cancer registry from 1973 to 1997. A total of 54,193 cases of CMM were diagnosed in black and white patients between 1973 and 1997. Black patients tended to be older, with a mean age of 64.46 years, compared to 53.14 years for white patients. Eighty-nine percent of patients were diagnosed with CMM as the only cancer. (Abstract shortened by UMI.)^

Loss of activator protein-2alpha results in overexpression of the thrombin receptor and correlates with the malignant phenotype of human melanoma

Increasing evidence demonstrates that the thrombin receptor (protease activated receptor-1, PAR-1) plays a major role in tumor invasion and contributes to the metastatic phenotype of human melanoma. We demonstrate that the metastatic potential of human melanoma cells correlates with overexpression of PAR-1. The promoter of the PAR-1 gene contains multiple putative AP-2 and Sp1 consensus elements. We provide evidence that an inverse correlation exists between the expression of AP-2 and the expression of PAR-1 in human melanoma cells. Re-expression of AP-2 in WM266-4 melanoma cells (AP-2 negative) resulted in decreased mRNA and protein expression of PAR-1 and significantly reduced the tumor potential in nude mice. ChIP analysis of the PAR-1 promoter regions bp −365 to −329 (complex 1) and bp −206 to −180 (complex 2) demonstrates that in metastatic cells Sp1 is predominantly binding to the PAR-1 promoter, while in nonmetastatic cells AP-2 is bound. In vitro analysis of complex 1 demonstrates that AP-2 and Sp1 bind to this region in a mutually exclusive manner. Transfection experiments with full-length and progressive deletions of the PAR-1 promoter luciferase constructs demonstrated that metastatic cells had increased promoter activity compared to low and nonmetastatic melanoma cells. Our data shows that exogenous AP-2 expression decreased promoter activity, while transient expression of Sp1 further activated expression of the reporter gene. Mutational analysis of complex 1 within PAR-1 luciferase constructs further demonstrates that the regulation of PAR-1 is mediated through interactions with AP-2 and Sp1. Moreover, loss of AP-2 in metastatic cells alters the AP-2 to Sp1 ratio and DNA-binding activity resulting in overexpression of PAR-1. In addition, we evaluated the expression of AP-2 and PAR-1 utilizing a tissue microarray of 93 melanocytic lesions spanning from benign nevi to melanoma metastasis. We report loss of AP-2 expression in malignant tumors compared to benign tissue while PAR-1 was expressed more often in metastatic melanoma cells than in benign melanocytes. We propose that loss of AP-2 results in increased expression of PAR-1, which in turn results in upregulation of gene products that contribute to the metastatic phenotype of melanoma. ^

Health in Africa : a medical handbook for European travellers and residents, embracing a study of malarial fever as it is found in British Central Africa

by David Kerr Cross

Ligand-directed targeting of malignant gliomas

The dramatic poor survival of patients diagnosed with glioblastoma multiforme (GBM) is a reflection of the struggles that accompany traditional treatments. Thus, the development of molecular-based targeted therapies represents new windows for intervention. In this study, we hypothesized that we could select peptide-ligands that selectively target GBM based on the idea that the glioma microenvironment may induce or modify the expression of cell surface receptors that could be accessed by circulating peptides. To select the peptides we employed two distinct in vivo screenings. First, a random phage-displayed peptide library was injected into mice bearing intracranial tumors. Phage that bound to tumor were recovered and sequenced. We found that the tumor-derived phage CLSYKGRC, CNKVSTKC and CQSSREKC were recovered with the highest frequencies and used for subsequent targeting experiments. Second, the phage peptide library was injected into mice without tumors and phage were recovered from brain and sequenced. A phage-displayed peptide (CRTIGPSVC) with homology to transferrin (Tf) was selected and injected into brain tumor-bearing mice. Results showed that after 6 hours of circulation, the CLSYKGRC, CNKVSTKC and CQSSREKC-phage selectively targeted GBM vasculature. In contrast, Tf-like phage accumulated outside the tumor blood vessels in the cytoplasm of cells located within GBM, suggesting it was internalized in vivo. However, after short periods of circulation this phage was restricted to the tumor vasculature. Importantly, none of the selected phage targeted normal brain cells in animals bearing intracranial tumors. An affinity column coupled to the CNKVSTKC zpeptide was used to identify receptors from GBM. Using mass-spectrometry Vimentin, a marker of glial malignancy, was identified as a potential receptor. Other studies showed that the Tf-like phage bound selectively to Apo-Tf (iron free), with no binding to Holo-Tf (iron loaded) or to Tf receptor (TfR). However, the binding of Tf-like phage to glioma cells that express TfR increased in the presence of Apo-Tf. Thus, the Tf-like phage could indirectly target TfR using the endogenous Tf pathway. We propose that the novel peptides identified in this study could be conjugated to therapeutic or imaging agents for use GBM. ^

The diagnostic value of a 12-lead electrocardiogram in patients with cardiac tamponade due to a malignant pericardial effusion

Background. Cardiac tamponade can occur when a large amount of fluid, gas, singly or in combination, accumulating within the pericardium, compresses the heart causing circulatory compromise. Although previous investigators have found the 12-lead ECG to have a poor predictive value in diagnosing cardiac tamponade, very few studies have evaluated it as a follow up tool for ruling in or ruling out tamponade in patients with previously diagnosed malignant pericardial effusions. ^ Methods. 127 patients with malignant pericardial effusions at the MD Anderson Cancer Center were included in this retrospective study. While 83 of these patients had a cardiac tamponade diagnosed by echocardiographic criteria (Gold standard), 44 did not. We computed the sensitivity (Se), specificity (Sp), positive (PPV) and negative predictive values (NPV) for individual and combinations of ECG abnormalities. Individual ECG abnormalities were also entered singly into a univariate logistic regression model to predict tamponade. ^ Results. For patients with effusions of all sizes, electrical alternans had a Se, Sp, PPV and NPV of 22.61%, 97.61%, 95% and 39.25% respectively. These parameters for low voltage complexes were 55.95%, 74.44%, 81.03%, 46.37% respectively. The presence of all three ECG abnormalities had a Se = 8.33%, Sp = 100%, PPV = 100% and NPV = 35.83% while the presence of at least one of the three ECG abnormalities had a Se = 89.28%, Sp = 46.51%, PPV = 76.53%, NPV = 68.96%. For patients with effusions of all sizes electrical alternans had an OR of 12.28 (1.58–95.17, p = 0.016), while the presence of at least one ECG abnormality had an OR of 7.25 (2.9–18.1, p = 0.000) in predicting tamponade. ^ Conclusions. Although individual ECG abnormalities had low sensitivities, specificities, NPVs and PPVs with the exception of electrical alternans, the presence of at least one of the three ECG abnormalities had a high sensitivity in diagnosing cardiac tamponade. This could point to its potential use as a screening test with a correspondingly high NPV to rule out a diagnosis of tamponade in patients with malignant pericardial effusions. This could save expensive echocardiographic assessments in patients with previously diagnosed pericardial effusions. ^

The seroprevalence of Rocky Mountain spotted fever in shelter dogs in Harris County

Rocky Mountain spotted fever (RMSF) is a tick-borne illness caused by the bacteria Rickettsia rickettsii, with infections occurring in humans and dogs. The prominent tick vector of RMSF, Dermacantor variabilis, and another potential vector, Rhipacephalus sanguineus, are prevalent in Texas. The goal of this study was to determine the prevalence of past infections by testing for IgG antibodies to R. rickettsii in dogs in an animal shelter in Harris County using an immunofluorescence assay (IFA) test. We found that 12.6% (24) of 191 dogs tested had a positive IFA test at 1:64 serum dilution, indicating infection at some time in the past. We also sampled the ticks present on dogs in the animal shelter to understand the prevalence of potential vector species. Of a total of 58 ticks, 86% were D. variabilis and the remaining 14% were R. sanguineus. The results of this study demonstrate that RMSF has the potential to be, and may already be, endemic to the Harris County area. Public health actions such as heightened surveillance and education that RMSF is present would be appropriate in the Harris County area.^

Matrix metalloproteinase-1 as a prognosticator in malignant glioma

The overall purpose of this study was to assess the relationship between the promoter region polymorphism (-2607 1G/2G) of matrix metalloproteinase-1 (MMP-1) polymorphism and outcome in brain tumor patients diagnosed with a primary brain tumor between 1994 and 2000 at The University of Texas M. D. Anderson Cancer Center. The MMP-1 polymorphism was genotyped for all brain tumor patients who participated in the Family Brain Tumor Study and for whom blood samples were available. Relevant covariates were abstracted from medical records for all cases from the original protocol, including information on demographics, tumor histology, therapy and outcome was obtained. The hypothesis was that brain tumor patients with the 2G allele have a poorer prognosis and shorter survival than brain tumor patients with the 1G allele. ^ Experimental Design: Genetic variants for the MMP-1 enzyme were determined by a polymerase chain reaction-restriction fragment length polymorphism assay. Comparison was made between the overall survival for cases with the 2G polymorphism and overall survival for cases with the 1G polymorphism using multivariable Cox Proportional-Hazard analysis, controlling for age, sex, Karnofsky Performance Scale (KPS), extent of surgery, tumor histology and treatment received. Kaplan-Meier and Cox Proportional-Hazard analyses were utilized to assess if the MMP-1 polymorphisms were related to overall survival. Results: Overall survival was not statistically significantly different between the 2G allele brain tumor patients and the 1G allele patients and there was no statistically significant difference between tumor types. ^ Conclusions: No association was found between MMP-1 polymorphisms and survival in patients with malignant gliomas. ^

Suspected outbreak of dengue fever in Houston: Clinical characteristics and determination of autochthonous transmission between 2003 and 2005

Houston, Texas maintains the appropriate climate and mosquito populations to support the circulation of dengue viruses. The city is susceptible to the introduction and subsequent local transmission of dengue virus with its proximity to dengue-endemic Mexico and the high degree of international travel routed through its airports. In 2008, a study at the University of Texas School of Public Health identified 58 suspected dengue fever cases that presented at hospitals and clinics in the Houston area. Serum or CSF samples of the 58 samples tested positive or equivocal for the presence of anti-dengue IgM antibodies (Rodriguez, 2008). Here, we present the results of an investigation aimed to describe the clinical characteristics of the 58 suspected dengue fever cases and to determine if local transmission had occurred. Data from medical record abstractions and personal telephone interviews were used to describe clinical characteristics and travel history of the suspected cases. Our analysis classified six probable dengue fever cases based on the case definition from the World Health Organization. Three of the probable cases for which we were able to obtain travel history had not recently traveled to an endemic area prior to onset of symptoms suggesting the illnesses were locally acquired in Houston. Further analysis led us to hypothesize that additional cases of dengue fever are present in our study population. Fifty-one percent of the study population was diagnosed with meningitis and/or encephalitis. Sixty percent of the individuals who received a lumbar puncture had abnormal CSF. Together these findings indicate viral infection with neurological involvement, which has been reported to occur with dengue fever. Among the individuals who received liver enzyme analysis, 54% had evidence of abnormal liver enzyme levels, a clinical sign commonly observed with dengue. Our results indicate that a suspected outbreak of dengue fever with autochthonous transmission occurred in the Houston area between 2003 and 2005. ^