Abstract
Background
The increasing incidence of pediatric inflammatory bowel disease (IBD), along with more extensive and severe disease in children, raises concern for related health care ...expenditures.
Aim
The aim of this study was to quantify and characterize costs of pediatric IBD in the year following diagnosis.
Methods
We identified all patients diagnosed with IBD at Connecticut Children’s Medical Center in 2016 with a minimum of 1 year follow-up. Clinical and demographic factors were recorded at diagnosis. We examined paid service and professional costs related to outpatient medications and infusions, outpatient procedures and radiology imaging, inpatient services, and outpatient visits. Actual dollar reimbursements were from private and public payers. Data is reported as mean ± SD and median (IQR).
Results
First-year cost data were collected on 67 patients (43 Crohn’s disease CD, 24 ulcerative colitis UC, mean age 13 years SD 3.22) revealing a mean cost of $45,753 (SD $37,938), with $43,095 (SD $30,828) for CD and $50,516 (SD $48,557) for UC. Severe CD (n = 11) had a mean cost of $71,176 (SD $43,817) and severe UC (n = 5) $134,178 (SD $40,920). Patients receiving infusion therapy had a mean cost of $59,376 (SD $38,724) compared with $27,903 (SD $28,795) for those not receiving infusions. Overall cost distribution showed 37% from infusion costs, 25% hospital costs, 18% outpatient procedures, 10% outpatient oral medications, 7% outpatient imaging, and 3% outpatient visits.
Conclusions
Infusion therapy is a key driver of first-year costs for children newly diagnosed with IBD. Understanding cost distribution in relation to disease presentation can be helpful to anticipate future related costs.
Pediatric inflammatory bowel disease is increasing in incidence and severity, which raises concern for related health care expenditures. Severity of disease at time of diagnosis and use of biologic infusion therapy dramatically increase costs in the first year after diagnosis.
Mechanisms of drug resistance other than P-glycoprotein are of increasing interest as the list of newly identified members of the ABC transport family has grown. We sought to characterize the ...phenotype of the newly discovered ABC transporter encoded by the mitoxantrone resistance gene, MXR, also known as ABCP1 or BCRP. The pharmacodynamics of mitoxantrone and 12 other fluorescent drugs were evaluated by confocal microscopy in four multidrug-resistant human colon (S1) and breast (MCF-7) cancer cell lines. We utilized two sublines, MCF-7 AdVp3000 and S1-M1-80, and detected overexpression of MXR by PCR, immunoblot assay and immunohistochemistry. These MXR overexpressing sublines were compared to cell lines with P-glycoprotein- and MRP-mediated resistance. High levels of cross-resistance were observed for mitoxantrone, the anthracyclines, bisantrene and topotecan. Reduced levels of mitoxantrone, daunorubicin, bisantrene, topotecan, rhodamine 123 and prazosin were observed in the two sublines with high MXR expression. Neither the P-glycoprotein substrates vinblastine, paclitaxel, verapamil and calcein-AM, nor the MRP substrate calcein, were extruded from MCF-7 AdVp3000 and S1-M1-80 cells. Thus, the multidrug-resistant phenotype due to MXR expression is overlapping with, but distinct from, that due to P-glycoprotein. Further, cells that overexpress the MXR protein seem to be more resistant to mitoxantrone and topotecan than cells with P-glycoprotein-mediated multidrug resistance. Our studies suggest that the ABC half-transporter, MXR, is a potent, new mechanism for conferring multiple drug resistance. Definition of its mechanism of transport and its role in clinical oncology is required.
Reports of multiple distinct mitoxantrone-resistant sublines without overexpression of P-glycoprotein or the multidrug-resistance associated protein have raised the possibility of the existence of ...another major transporter conferring drug resistance. In the present study, a cDNA library from mitoxantrone-resistant S1-M1-80 human colon carcinoma cells was screened by differential hybridization. Two cDNAs of different lengths were isolated and designated MXR1 and MXR2. Sequencing revealed a high degree of homology for the cDNAs with Expressed Sequence Tag sequences previously identified as belonging to an ATP binding cassette transporter. Homology to the Drosophila white gene and its homologues was found for the predicted amino acid sequence. Using either cDNA as a probe in a Northern analysis demonstrated high levels of expression in the S1-M1-80 cells and in the human breast cancer subline, MCF-7 AdVp3000. Levels were lower in earlier steps of selection, and in partial revertants. The gene is amplified 10-12-fold in the MCF-7 AdVp3000 cells, but not in the S1-M1-80 cells These studies are consistent with the identification of a new ATP binding cassette transporter, which is overexpressed in mitoxantrone-resistant cells.
The mitoxantrone resistance (MXR) gene encodes a recently characterized ATP-binding cassette half-transporter that confers multidrug resistance. We studied resistance to the camptothecins in two ...sublines expressing high levels of MXR: S1-M1-80 cells derived from parental S1 colon cancer cells and MCF-7 AdVp3,000 isolated from parental MCF-7 breast cancer cells. Both cell lines were 400- to 1,000-fold more resistant to topotecan, 9-amino-20(S)-camptothecin, and the active metabolite of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), than their parental cell lines. The cell lines demonstrated much less resistance to camptothecin and to several camptothecin analogues. Reduced accumulation and energy-dependent efflux of topotecan was demonstrated by confocal microscopy. A significant reduction in cleavable complexes in the resistant cells could be observed after SN-38 treatment but not after camptothecin treatment. In addition to topotecan and SN-38, MXR-overexpressing cells are highly resistant to mitoxantrone and epirubicin. Because these compounds are susceptible to glucuronidation, we examined UDP-glucurono-syltransferase (UGT) activity in parental and resistant cells by TLC. Glucuronides were found at equal levels in both parental and resistant colon cancer cell lines for epirubicin and to a lesser extent for SN-38 and mitoxantrone. Low levels of glucuronidation could also be detected in the resistant breast cancer cells. These results were confirmed by analysis of the UGT1A family mRNAs. We thus conclude that colon and breast cancer cells have a capacity for glucuronidation that could contribute to intrinsic drug resistance in colon cancer cells and may be acquired in breast cancer cells. The lack of selection for higher levels of UGT capacity in the colon cells suggests that high levels of expression of MXR alone are sufficient to confer resistance to the camptothecins.
7-Ethyl-10-hydroxycamptothecin (SN-38) is a very promising anticancer drug used for the treatment of metastatic colonrectal cancer. SN-38 is the active metabolite of irinotecan, a semisynthetic ...anticancer drug derived from 20(S)camptothecin. In this study, we examined the potential for each of the UGT1-encoded isoforms (UGT1A1 and UGT1A3 through UGT1A10) to glucuronidate SN-38. The amount of specific protein for each isoform was determined by Western blot analysis. Although UGT1A1 was previously shown to metabolize this drug, the results of this study show that UGT1A7 glucuronidates this chemical at a 9- to 21-fold higher level at pH 6.4 and pH 7.6, respectively, than that by UGT1A1. The activity of UGT1A7 is from 8.4- to 19-fold higher at pH 6.4 and 12- to 40-fold higher at pH 7.6 than that by the other 7 UGT1 encoded isoforms. UGT1A7 glucuronidates SN-38 with an apparent Km of 5 μM. Hence, the distribution of this isoform in the gastrointestinal tract has the potential to impact the effectiveness of this chemotherapeutic agent.
IntroductionItaly produced and imported a large amount of raw asbestos, up to the ban in 1992, with a peak in the period between 1976 and 1980 at about 160 000 tons/year. The National Register of ...Mesotheliomas (ReNaM, “Registro Nazionale dei Mesoteliomi” in Italian), a surveillance system of mesothelioma incidence, has been active since 2002, operating through a regional structure.MethodsThe Operating Regional Center (COR) actively researches cases and defines asbestos exposure on the basis of national guidelines. Diagnostic, demographic and exposure characteristics of non-occupationally exposed cases are analysed and described with respect to occupationally exposed cases.ResultsStandardised incidence rates for pleural mesothelioma in 2008 were 3.84 (per 100 000) for men and 1.45 for women, respectively. Among the 15 845 mesothelioma cases registered between 1993 and 2008, exposure to asbestos fibres was investigated for 12 065 individuals (76.1%), identifying 530 (4.4%) with familial exposure (they lived with an occupationally exposed cohabitant), 514 (4.3%) with environmental exposure to asbestos (they lived near sources of asbestos pollution and were never occupationally exposed) and 188 (1.6%) exposed through hobby-related or other leisure activities. Clusters of cases due to environmental exposure are mainly related to the presence of asbestos-cement industry plants (Casale Monferrato, Broni, Bari), to shipbuilding and repair activities (Monfalcone, Trieste, La Spezia, Genova) and soil contamination (Biancavilla in Sicily).ConclusionsAsbestos pollution outside the workplace contributes significantly to the burden of asbestos-related diseases, suggesting the need to prevent exposures and to discuss how to deal with compensation rights for malignant mesothelioma cases induced by non-occupational exposure to asbestos.
Previous ecological spatial studies of malignant mesothelioma cases, mostly based on mortality data, lack reliable data on individual exposure to asbestos, thus failing to assess the contribution of ...different occupational and environmental sources in the determination of risk excess in specific areas. This study aims to identify territorial clusters of malignant mesothelioma through a Bayesian spatial analysis and to characterize them by the integrated use of asbestos exposure information retrieved from the Italian national mesothelioma registry (ReNaM).
In the period 1993 to 2008, 15,322 incident cases of all-site malignant mesothelioma were recorded and 11,852 occupational, residential and familial histories were obtained by individual interviews. Observed cases were assigned to the municipality of residence at the time of diagnosis and compared to those expected based on the age-specific rates of the respective geographical area. A spatial cluster analysis was performed for each area applying a Bayesian hierarchical model. Information about modalities and economic sectors of asbestos exposure was analyzed for each cluster.
Thirty-two clusters of malignant mesothelioma were identified and characterized using the exposure data. Asbestos cement manufacturing industries and shipbuilding and repair facilities represented the main sources of asbestos exposure, but a major contribution to asbestos exposure was also provided by sectors with no direct use of asbestos, such as non-asbestos textile industries, metal engineering and construction. A high proportion of cases with environmental exposure was found in clusters where asbestos cement plants were located or a natural source of asbestos (or asbestos-like) fibers was identifiable. Differences in type and sources of exposure can also explain the varying percentage of cases occurring in women among clusters.
Our study demonstrates shared exposure patterns in territorial clusters of malignant mesothelioma due to single or multiple industrial sources, with major implications for public health policies, health surveillance, compensation procedures and site remediation programs.
The grey partridge became extinct in the province of Siena (central Italy) in the late seventies, whereas the red-legged partridge had already disappeared by the beginning of the twentieth century. ...Some reintroduction attempts of both species carried out in the 1980s gave encouraging but not definitive results, and failed after an initial success. This was probably due to the low number of birds released, the small size of the re-introduction areas, their isolation, the farm-bred origin of the partridges, and hunting. In the province of Siena, for the first time in Italy, a large-scale reintroduction program of grey and red-legged partridges was experimented. The project started up in 1995 with seven reintroduction areas for grey and four for red-legged partridge, and was extended to 19 areas (22,562 ha) for grey and 7 (6858 ha) for red-legged partridge in 2002. Population viability analyses for both species showed that if reintroduced populations were isolated they would be extinct in a few years. Therefore, a metapopulation approach was adopted (contemporary releases in reintroduction areas close to each other). In each area, 100-1000 partridges per year were released for a minimum of 3 years, from different farms in order to achieve the maximum initial genetic diversity. Releases were effected in late summer (August-September) in acclimatization pens containing 10-20 aviaries. The reintroduced population showed marked variability of some demographic parameters, such as pair density and brood production rate; instead, average brood size was relatively constant across the study areas, but with annual variations. Reintroduction success was limited to a few areas only, mainly depending on the habitat characteristics of the areas, their surface area and isolation, and on the degree of care for the birds during the acclimatization period.
A radio-tracking study was carried out on a re-introduced population of grey partridges in a 10.6-km
2
study area located in central Italy, in order to assess mortality rate and to evaluate the ...feasibility of carrying out large scale re-introductions of the species. Thirty-nine grey partridges were caught by live-traps during winter 2000 and equipped with backpack radio-transmitter. All released birds were offspring of partridges re-introduced previously on the study area and no significant differences were found in survival probabilities between sexes, age classes (juveniles or adults), and weight classes (<400 g or ≥400 g), with the exception of the juveniles-adult comparison with the weight class ≥400 g. Kaplan-Meier estimates give an average survival of 734 days (SE = 15.5). GLM analysis showed an overall interaction effect of the sex, age, and weight (P = 0.03). Mortality increased during the covey break up, if compared to other periods, although the differences were not significant; the same was for males, for adults, and for both weight classes, while significant differences resulted for female and juvenile survival rate among periods. Predation was the main mortality source for radio-tagged grey partridges (71.0%), followed by disease (25.8%). The high mortality rate found in our study could be explained in part with the origin of the population that was originally re-introduced using hand-reared grey partridges. Some important negative characters of reared birds, such as the poor anti-predator behaviour and the low diseases resistance, could carry over during the first and following wild generations.
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