Inpatient management protocols to reduce health care costs

A group of 12 internists, members of a university-affiliated hospital, designed and implemented protocols for the general inpatient management of four medical problems (chest pain, stroke, pneumonia, and upper gastrointestinal hemorrhage). Hospital charges for the 63 cases were compared with charges generated by 64 controls who had been patients admitted to the same physicians with the same diagnoses during the same period of the preceding year, before the project was begun. A group of nonparticipating internists was similarly evaluated during the two time periods to control for changes in practice patterns extraneous to the intervention. Adjustment was made for inflation (6%) and differences in case mix. The program resulted in a 15% reduction in total average charge generated by the cases. Sizeable reductions were achieved in utilization of EKGs (34.8%), x-rays (15.4%), laboratory testing (20.4%), and drugs (11.4%). Given the prevailing attitude that health care costs are too high and that many services are unnecessary, the benefit of altering physician behavior by using standards established by them for themselves could be substantial, especially with the threat of more restrictive and less sympathetic modes of controlling costs.     

Stability of skeletal Class III malocclusion after combined maxillary and mandibular procedures: titanium versus resorbable plates and screws for maxillary fixation.

PURPOSE: The aim of this study was to evaluate skeletal stability after double jaw surgery for correction of skeletal Class III malocclusion to assess if there were any differences between resorbable plate and screws and titanium rigid fixation of the maxilla. PATIENTS AND METHODS: Twenty-two Class III patients had bilateral sagittal split osteotomy for mandibular setback stabilized with rigid internal fixation. Low level Le Fort I osteotomy for maxillary advancement was stabilized with conventional titanium plate and screws in 12 patients (group 1) and with resorbable plate and screws in 10 patients (group 2). Lateral cephalograms were taken before surgery, immediately postoperatively, 8 weeks after surgery, and 1 year postoperatively. RESULTS: Before surgery both groups were balanced with respect to linear and angular measurements of craniofacial morphology. One year after surgery, maxillary stability was excellent in both groups. In group 1 no significant correlations were found between maxillary advancement and relapse. In group 2, significant correlations were found between maxillary advancement and relapse at A point and posterior nasal spine. No significant differences in postoperative skeletal and dental stability between groups were observed. CONCLUSION: Surgical correction of Class III malocclusion after combined maxillary and mandibular procedures appears to be a fairly stable procedure for maxillary advancements up to 5 mm independently from the type of fixation used to stabilize the maxilla. Resorbable devices should be used with caution for bony movements of greater magnitude until their usefulness is evaluated in studies with large maxillary advancements.     

Association of myopathy with large-scale mitochondrial dna duplications and deletions: Which is pathogenic?

We identified large-scale heteroplasmic mitochondrial DNA (mtDNA) rearrangements in a 50–year-old woman with an adult-onset progressive myopathy. The predominant mtDNA abnormality was a 21.2–kb duplicated molecule. In addition, a small population of the corresponding partially deleted 4.6–kb molecule was detected. Skeletal muscle histology revealed fibers that were negative for cytochrome c oxidase (COX) activity and had reduced mtDNA-encoded COX subunits. By single-fiber polymerase chain reaction analysis, COX-negative fibers contained a low number of wild-type or duplicated mtDNA molecules (ie, nondeleted). In situ hybridization demonstrated that the abnormal fibers contained increased amounts of mtDNA compared with normal fibers and that most of the genomes were deleted. We concluded that deleted mtDNA molecules were primarily responsible for the phenotype in this patient.     

Interphase fluorescence in situ hybridization analysis of del(11)(q23) and del(17)(p13) in chronic lymphocytic leukemia. a study of 40 early-onset patients

Although B-cell chronic lymphocytic leukemia (B-CLL) is the most common form of leukemia in Western countries, little is known about its underlying molecular abnormalities and their prognostic significance, particularly for use in early therapeutic interventions in young patients. As TP53 tumor suppressor gene abnormalities and 11q23 deletions are reported to be prognostically adverse in hematologic malignancies, we used interphase fluorescence in situ hybridization to analyze their incidence and prognostic significance in young B-CLL patients. Bone marrow samples from 40 untreated B-CLL patients at diagnosis were studied using five yeast artificial chromosome clones from the 11q23.1 approximately q23.3 chromosomal region and a probe specific for the 17p13.1 locus. Twenty-three patients (58%) carried 11q deletions. Interestingly, 16 of 17 patients (94%) who showed early disease progression exhibited this chromosomal abnormality, suggesting that 11q deletions may help to identify more aggressive disease in early stage patients. In contrast, monoallelic TP53 deletions were found in all of the patients. The TP53 and 11q deletions were only present in a proportion of the clonal B-cells, which suggests that they are secondary events in B-CLL.     

Vascular modulation through exercise improves chemotherapy efficacy in Ewing sarcoma

Recent studies in mouse models of cancer have shown that exercise improves tumor vascular function, thereby improving chemotherapy delivery and efficacy. However, the mechanisms underlying this improvement remain unclear and the effect of exercise on Ewing sarcoma (ES), a pediatric bone and soft tissue cancer, is unknown. The effect of exercise on tumor vascular hyperpermeability, which inversely correlates with drug delivery to the tumor, has also not been evaluated. We hypothesized that exercise improves chemotherapy efficacy by enhancing its delivery through improving tumor vascular permeability. We treated ES‐bearing mice with doxorubicin with or without moderate treadmill exercise. Exercise did not significantly alter ES tumor vessel morphology. However, compared to control mice, tumors of exercised mice had significantly reduced hyperpermeability, significantly decreased hypoxia, and higher doxorubicin penetration. Compared to doxorubicin alone, doxorubicin plus exercise inhibited tumor growth more efficiently. We evaluated endothelial cell sphingosine‐1‐phosphate receptors 1 and 2 (S1PR1 and S1PR2) as potential mediators of the improved vascular permeability and increased function afforded by exercise. Relative to tumors from control mice, vessels in tumors from exercised mice had increased S1PR1 and decreased S1PR2 expression. Our results support a model in which exercise remodels ES vasculature to reduce vessel hyperpermeability, potentially via modulation of S1PR1 and S1PR2, thereby improving doxorubicin delivery and inhibiting tumor growth more than doxorubicin alone does. Our data suggest moderate aerobic exercise should be tested in clinical trials as a potentially useful adjuvant to standard chemotherapy for patients with ES.     

Prognostic role of the recepteur d'origine nantais (RON) expression in ovarian cancer patients

ObjectiveThe aim of the study was to investigate the potential clinical relevance of immunohistochemically assessed RON expression in a large, single institution series of primary untreated advanced ovarian cancer patients.MethodsImmunohistochemical analysis was performed by using the polyclonal rabbit anti-RON-β antibody (C-20, clone sc-322, Santa Cruz, California). Results were expressed as the total proportion of immunostained tumor cells (RON positivity), or the percentage of cells showing strong staining of RON expression (H-RON positivity).ResultsIn the overall series RON positive immunoreaction was observed in 103/141 cases, while H-Ron positivity was detected in 577141 (40.4%) cases. No association between RON and H-RON expression with response to first-line treatment was documented. During the follow up period, progression and death of disease were observed in 111 (78.7%) and 76 (53.9%) cases, respectively. Cases with strong H-RON expression has a shorter overall survival (median = 35 months) than cases with low RON levels (median = 59 months) (X² = ? 2.1, p value = 0.032). In multivariate analysis, only platinum resistance, and extent of residual tumor retained an independent negative prognostic role for OS, with the percentages of H-RON positively immunostained cells showing a borderline statistical significance (p value = 0.0643). The unfavourable role of elevated percentages of H-RON expression was maintained only in the subgroup of platinum resistant recurrent ovarian cancer patients (X² = 3.89, p value = 0.048) compared to the platinum sensitive ones (X² = 1.98, p value = 0.16).ConclusionsThe assessment of RON expression deserves further attention as a parameter helpful to identify poor prognosis ovarian cancer patients potentially candidates to investigational agents.     

Performance of cervicovaginal fetal fibronectin in a community hospital setting

Objective To assess the accuracy of vaginal fetal fibronectin (FFN) as a screening test for preterm delivery in a community hospital. Study design A prospective cohort of patients at high risk for preterm delivery at a community hospital underwent testing with FFN over a 15 month-period (March 2004–May 2005). Indications for testing were preterm labor, multiple pregnancies, cervical shortening, and cerclage. Pregnancy characteristics were retrieved on all women with positive FFN results and controls in a 1:2 ratio. Outcome variables included interval to delivery; length of hospital stay; and rates of preterm delivery <37 weeks. In the presence of serial FFN testing, only the initial result was used for calculation of diagnostic indices. Statistical analysis utilized t-test, Fisher’s exact test and logistic regression analyis to control for gestational age at testing, with P < 0.05 or odds ratio (OR) with 95% confidence interval (CI) not inclusive of the unity considered significant. Results Two hundred and fifty seven FFN tests were performed in 230 women, of which 33 (14.3%) had positive FFN results. Duration of hospital stay was significantly shorter for patients with negative than positive results (8 h vs. 2.1 days, P = 0.011). Women with positive FFN were more likely to deliver within 14 days (OR = 6.5, 95% CI 1.4; 30.7), within 21 days (OR = 4.8; 95% CI 1.4; 16.6), before 34 weeks (OR = 5.0, 95% CI 1.7; 14.8) and before 37 weeks (OR = 3.1; 95% CI 1.3; 7.1) than women with negative results. Conclusion A negative FFN result provides enough reassurance to allow shorter hospital stay. In a real-world setting (a community hospital with a population heterogenous for risk factors for preterm delivery, and in a non-protocol setting) the performance of FFN testing closely mirrors that obtained in academic institutions, where the test was studied in more uniform populations under strict protocols. Summary The performance of vaginal fibronectin in patients with heterogeneous risk factors for preterm delivery closely mirrors that obtained in studies conducted in populations with homogeneous risk factors.     

Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant

BackgroundDiffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although GD2-CAR T-cells demonstrated significant anti-tumor activity against DMG H3K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. We investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.MethodsImmunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models, and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.ResultsGD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual IGF1R/IR antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo, and in vivo.ConclusionOur study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for treating patients affected by DMG/DIPG and, potentially, by pHGG.     

Selective targeted delivery of TNFalpha to tumor blood vessels

We sought to enhance the selective toxicity of tumor necrosis factor alpha (TNFalpha) to permit its systemic use in cancer therapy. Because ligand-targeted therapeutics have proven successful in improving the selective toxicity of drugs, we prepared a fusion protein (L19mTNFalpha) composed of mouse TNFalpha and a high-affinity antibody fragment (L19 scFv) to the extradomain B (ED-B) domain of fibronectin, a marker of angiogenesis. L19mTNFalpha was expressed in mammalian cells, purified, and characterized. L19mTNFalpha was an immunoreactive and biologically active homotrimer. Radiolabeled L19mTNFalpha selectively targeted tumor neovasculature in tumor-bearing mice, where it accumulated selectively and persistently (tumor-to-blood ratio of the percentage of injected dose per gram [%ID/g] of 700, 48 hours from injection). L19mTNFalpha showed a greater anticancer therapeutic activity than both mTNFalpha and TN11mTNFalpha, a control fusion protein in which an antibody fragment, irrelevant in the tumor model used, substituted for L19. This activity was further dramatically enhanced by its combination with melphalan or the recently reported fusion protein L19-IL2. In conclusion, L19mTNFalpha allows concentrating therapeutically active doses of TNFalpha at the tumor level, thus opening new possibilities for the systemic use of TNFalpha in cancer therapy.