Cost-effectiveness of alternative strategies for integrating MRI into breast cancer screening for women at high risk.

BACKGROUND: Magnetic resonance imaging (MRI) is recommended for women at high risk for breast cancer. We evaluated the cost-effectiveness of alternative screening strategies involving MRI. METHODS: Using a microsimulation model, we generated life histories under different risk profiles, and assessed the impact of screening on quality-adjusted life-years, and lifetime costs, both discounted at 3%. We compared 12 screening strategies combining annual or biennial MRI with mammography and clinical breast examination (CBE) in intervals of 0.5, 1, or 2 years vs without, and reported incremental cost-effectiveness ratios (ICERs). RESULTS: Based on an ICER threshold of $100,000/QALY, the most cost-effective strategy for women at 25% lifetime risk was to stagger MRI and mammography plus CBE every year from age 30 to 74, yielding ICER $58,400 (compared to biennial MRI alone). At 50% lifetime risk and with 70% reduction in MRI cost, the recommended strategy was to stagger MRI and mammography plus CBE every 6 months (ICER=$84,400). At 75% lifetime risk, the recommended strategy is biennial MRI combined with mammography plus CBE every 6 months (ICER=$62,800). CONCLUSIONS: The high costs of MRI and its lower specificity are limiting factors for annual screening schedule of MRI, except for women at sufficiently high risk.

A systematic review of care delivery models and economic analyses in lymphedema: health policy impact (2004-2011).

A project of the American Lymphedema Framework Project (ALFP), this review seeks to examine the policy and economic impact of caring for patients with lymphedema, a common side effect of cancer treatment. This review is the first of its kind undertaken to investigate, coordinate, and streamline lymphedema policy initiatives in the United States with potential applicability worldwide. As part of a large scale literature review aiming to systematically evaluate the level of evidence of contemporary peer-reviewed lymphedema literature (2004 to 2011), publications on care delivery models, health policy, and economic impact were retrieved, summarized, and evaluated by a team of investigators and clinical experts. The review substantiates lymphedema education models and clinical models implemented at the community, health care provider, and individual level that improve delivery of care. The review exposes the lack of economic analysis related to lymphedema. Despite a dearth of evidence, efforts towards policy initiatives at the federal and state level are underway. These initiatives and the evidence to support them are examined and recommendations for translating these findings into clinical practice are made. Medical and community-based disease management interventions, taking on a public approach, are effective delivery models for lymphedema care and demonstrate great potential to improve cancer survivorship care. Efforts to create policy at the federal, state, and local level should target implementation of these models. More research is needed to identify costs associated with the treatment of lymphedema and to model the cost outlays and potential cost savings associated with comprehensive management of chronic lymphedema.

Risk factors and incidence of thromboembolic events (TEEs) in older men and women with breast cancer.

BACKGROUND: The purpose of this study is to evaluate the risk factors and the prevalence of thromboembolic events (TEEs) in breast cancer patients. PATIENTS AND METHODS: This is a retrospective cohort study using the Surveillance, Epidemiology, and End Results-Medicare database. Breast cancer patients diagnosed from 1992 to 2005 ≥66 years old were identified. International Classification of Diseases, Ninth Revision, and Healthcare Common Procedure Coding System codes were used to identify TEEs within 1 year of the breast cancer diagnosis. Analyses were conducted using descriptive statistics and logistic regression. RESULTS: A total of 89 841 patients were included, of them 2658 (2.96%) developed a TEE. In the multivariable analysis, males had higher risk of a TEE than women [odd ratio (OR) = 1.57; confidence interval (CI) 1.10-2.25] and blacks had higher risk than whites (OR = 1.20; CI 1.04-1.40). Compared with stage I patients, patients with stage II, III and IV had 22%, 39% and 98% increase, respectively, in risk. Placement of central catheters (OR = 2.71; CI 2.43-3.02), chemotherapy treatment (OR = 1.66; CI 1.48-1.86) or treatment with erythropoiesis-stimulating agents (ESAs) (OR = 1.33; CI 1.33-1.52) increase the risk. Other significant predictors included comorbidities, age, receptor status, marital status and year of diagnosis. Similar estimates were seen for pulmonary embolism, deep vein thromboembolism and other TEEs. CONCLUSIONS: In total, 2.96% of patients in this cohort developed a TEE within 1 year from breast cancer diagnosis. Stage, gender, race, use of chemotherapy and ESAs, comorbidities, receptor status and catheter placement were associated with the development of TEEs.

Schwannoma mimicking liver tumor.

Thoracic neurogenic tumors typically originate from the posterior mediastinum and the intercostal nerves. No report of a chest wall schwannoma extending toward the subphrenic areas and making a significant indentation into liver parenchyma exists to date. We present a liver tumor-mimicking schwannoma of the intercostal nerves. A 58-year-old woman presented with a painful lesion in the right subphrenic area and abdominal pain in the right upper quadrant for two months. Abdominal ultrasonography and magnetic resonance imaging revealed a tumor, 9.1 x 7.1 x 8.9 cm in size, with an inner cystic change in segment V and VI of the liver. The tumor was completely resected together with part of the 9th rib. Pathology confirmed a schwannoma and showed a tumor composed of spindle cells with oval to wavy nuclei. The patient was still asymptomatic at follow-up after 36 months, with no sign of recurrence.

Regulation of acetylcholine release by extracellular matrix proteins at developing motoneurons in Xenopus cell cultures.

Integrins mediate cell-extracellular matrix connections and are particularly important during neuronal development. We here investigated the regulatory role of extracellular matrix (ECM) proteins on the synaptic transmission at developing motoneurons. Synaptic currents were recorded from innervated myocytes of 1-day-old Xenopus cultures by whole-cell recordings. Soluble fibronectin and laminin had no significant effect on the frequency of spontaneous synaptic currents (SSCs) by themselves and markedly increased SSC frequency in the presence of low concentration of protein kinase C (PKC) activators. Pretreatment with Gly-Arg-Gly-Asp-Ser peptide inhibited the SSC increasing action of 12-o-tetradecanoyl-phorbol-13-acetate (TPA, 0.5 microM) plus fibronectin, but not that of TPA plus laminin. Genistein but not cytochalasin D inhibited the SSC increasing action of TPA plus fibronectin or laminin. High concentration of TPA (5 microM) markedly increased the SSC frequency by itself and occluded the SSC increasing action of fibronectin. Very low concentration of TPA (0.05 microM) markedly enhanced the SSC frequency when the cells were plated onto fibronectin- or laminin-coated substratum for 1 day. The SSC frequency increased markedly right after a train stimulation, which was defined as post-train potentiation (PTrP), when the cultures were plated onto fibronectin substratum and chronically treated with brain-derived neurotrophic factor (BDNF). The PTrP phenomenon is not observed upon chronic treatment with neurotrophin-3, glial cell line-derived neurotrophic factor, or ciliary neurotrophic factor. Our results suggest that the activation of PKC and tyrosine kinase but not actin reorganization plays a role in the SSC potentiating action of fibronectin. BDNF exerts synergistic effects in increasing synaptic transmission in neurons grown on fibronectin substratum. ECMs in concert with neurotrophic factor may play a role in regulating synaptic function at developing motoneurons.

Cytotoxic constituents of Polyalthia longifolia var. pendula.

A new halimane diterpene, 3beta,5beta, 16alpha-trihydroxyhalima-13(14)-en-15,16-olide (1), and a new oxoprotoberberine alkaloid, (-)-8-oxopolyalthiaine (2), along with 20 known compounds, were isolated from a methanolic extract of Polyalthia longifolia var. pendula. The structures of compounds 1 and 2 were established by spectroscopic analysis. Several of these compounds were evaluated for cytotoxicity toward a small panel of human cell lines.

No evidence for microsatellite instability from allelotype analysis of benign and low malignant potential ovarian neoplasms.

UNLABELLED: The genetic events that lead to the development of benign and low malignant potential (LMP) tumors from normal ovarian surface epithelium are not well understood. In contrast to invasive ovarian neoplasms, loss of heterozygosity (LOH) is not common in these tumors except on the X chromosome, but one report has suggested that an alternative genetic mechanism, microsatellite instability (MSI), might be an important pathogenic mechanism for LMP ovarian tumors. OBJECTIVE: To determine the frequency of MSI in LMP tumors and to detect novel regions of LOH in benign and LMP ovarian tumors. METHODS: Sixty-nine microsatellite markers were analyzed in 23 benign and 31 LMP ovarian tumors. RESULTS: No evidence of MSI was found in any of the tumors studied, nor were any novel regions of LOH identified. CONCLUSIONS: This suggests that new approaches may be necessary to understand the genetic basis of benign and LMP ovarian neoplasms since neither LOH nor MSI appears to play a major role.

Rare mutations and no hypermethylation at the CDKN2A locus in epithelial ovarian tumours.

The tumour-suppressor gene CDKN2A (p16, MTS1, CDK4I) encodes a cell cycle-regulatory protein and is located on chromosome 9p21, a region deleted in a wide variety of human cancers. To determine the role of the CDKN2A gene in the development of ovarian adenocarcinomas, we examined a large series of benign, low malignant potential (LMP) and invasive ovarian neoplasms for evidence of loss of heterozygosity (LOH), homozygous deletions, point mutations and hypermethylation of the CDKN2A locus. We have previously reported LOH on 9p in 45% of malignant ovarian neoplasms and a smaller percentage of benign and LMP tumours. In the current study, 6 malignant tumours were identified with partial deletions of 9p21. In 5 of these, the CDKN2A gene lays within the minimal deleted region. Homozygous deletions of CDKN2A were observed in only 2/88 invasive ovarian tumours and in 5/11 ovarian cancer cell lines. Of 15 primary ovarian tumours analyzed, one nonsense mutation was identified in a mucinous LMP tumour. No evidence of hypermethylation of the CDKN2A gene was found in 50 primary ovarian adenocarcinomas nor in 3 ovarian cancer cell lines. In conclusion, homozygous deletions, mutations and the de novo methylation of 5' CpG island are not frequent modes of inactivation of the CDKN2A gene in ovarian cancer. The target of 9p LOH in ovarian adenocarcinomas is therefore unknown.

Analysis of loss of heterozygosity and KRAS2 mutations in ovarian neoplasms: clinicopathological correlations.

The molecular events that give rise to ovarian epithelial neoplasms are not well understood. In particular, it is not known whether adenocarcinomas arise from benign or low malignant potential (LMP) precursors. We have examined a large series of benign (25) and LMP (31) ovarian tumors for loss of heterozygosity (LOH) at multiple loci on 17 chromosomes. LOH was observed in benign tumors on chromosomes 6 (14%) and 9 (5%) and on the X chromosome (33%) only. LOH on these chromosomes was also detected in a small number of LMP neoplasms, suggesting that these may derive sometimes from benign precursors. In addition, we examined LOH in 93 adenocarcinomas. Analysis of associations between LOH events showed that LOH on chromosomes 5 and 17 (P = 0.0002) and on chromosomes 17 and 18 (P = 0.00007) were associated significantly with each other, which suggests that these may represent cooperative, progressive events. No novel significant associations were identified between LOH events and stage, grade, or histology, which would indicate the existence of genetic heterogeneity in ovarian neoplasms. KRAS2 mutations were detected more often in LMP neoplasms than in malignant tumors (P = 0.004) and were detected more often in Stage I/II malignant tumors than in Stage III/IV malignant tumors (P = 0.033), suggesting that LMP tumors with KRAS2 mutations are unlikely to progress to frank malignancy. Univariate (but not multivariate) survival analysis showed that LOH of chromosomes 11 (P = 0.039) and 17 (P = 0.04) was associated with a significantly worse prognosis. Replication of these novel findings is necessary, and the identification, isolation, and characterization of the critical genes affected by LOH will determine their importance in the pathogenesis of ovarian malignancies.

Allelic loss on chromosome 7q in ovarian adenocarcinomas: two critical regions and a rearrangement of the PLANH1 locus.

The presence of a tumour suppressor gene on chromosome 7q is indicated by cytogenetic, loss of heterozygosity (LOH) and chromosome transfer studies. One candidate gene in this region is Plasminogen Activator Inhibitor-1 (PAI-1). The PAI-1 gene product is involved in proteolysis and may therefore influence tumour spread and invasion. We have analysed a series of 139 ovarian epithelial tumours at four loci in the region 7q21-q31 which includes the PAI-1 gene. The highest rates of loss were found in malignant tumours (FIGO stages I-IV) at markers D7S471 (38%, 20/52 informative cases) and D7S522 (34%, 15/44). No loss was seen in benign tumours and only one out of 27 (4%) informative LMP tumours demonstrated LOH. The smallest region of overlap (SRO) lies between D7S471 and PAI-1. We also identified a rearrangement in one tumour in the PAI-1 gene, suggesting that this may be the inactivated gene in this region. In addition LOH at the more distal marker, D7S522, which lies outside the SRO, shows significant association with stage (P=0.0343) and with LOH on chromosome 13 (P=0.0024). This is in contrast to all other markers examined. These data suggest the presence of two critical regions on 7q which may be important in subsets of epithelial ovarian tumours.