Breast cancer and cytomegalovirus.

PURPOSE: To determine whether cytomegalovirus is causally associated with breast cancer and whether cytomegalovirus should be categorised as an oncogenic virus. METHODS: We undertook a review of published epidemiological and laboratory studies, using established causal criteria: Bradford Hill criteria to determine whether cytomegalovirus is associated with breast cancer; and Evans/Mueller criteria to determine whether cytomegalovirus should be categorised as an oncogenic virus. RESULTS: Although there are inconsistencies in the findings of published epidemiological and laboratory studies, these may be explained by factors such as: differences in timing of blood samples, differences in selection of cases and controls, or high cytomegalovirus seroprevalence among participants in the epidemiological studies; and, in the laboratory studies, differences in sample preparations, age of sample, whether or not paired breast cancer and normal breast tissue samples were used, differences in the tests, primers and/or antibodies used, differences in histological types of breast cancer studied, and/or features of the virus. CONCLUSIONS: Overall, the results of published studies of cytomegalovirus and breast cancer suggest cytomegalovirus is a causal factor for at least some types of breast cancer. If the evidence for a link between cytomegalovirus and breast cancer continues to strengthen, further research could lead to: targeted screening; therapy using antiviral drugs; and, perhaps, primary prevention of a significant proportion of breast cancer. Vaccination against viruses has already been shown to be effective in preventing cervix and liver cancer; cytomegalovirus vaccines are already under development.

Bevacizumab is equally effective and no more toxic in elderly patients with advanced colorectal cancer: a subgroup analysis from the AGITG MAX trial: an international randomised controlled trial of Capecitabine, Bevacizumab and Mitomycin C.

BACKGROUND: In an ageing population, a greater proportion of geriatric patients will be considered for systemic chemotherapy. Colorectal cancer (CRC) is a common malignancy and will be a major health issue in geriatrics. We used the MAX population to investigate whether age affected the improved outcome found in CRC when bevacizumab is added to capecitabine chemotherapy. PATIENTS AND METHODS: MAX, a three arm study of Capecitabine (C) versus CBevacizumab (CB) versus CBMitomycin C (CBM), found an improvement in progression-free survival (PFS), with addition of B [+/- mitomycin C (MMC)] to C. This analysis assesses the effect of adding B (+/- MMC) to C on PFS, overall survival (OS), response rate (RR), toxicity and dose intensity in geriatric patients (age ≥ 75 years). RESULTS: Ninety-nine patients (21%) were aged 75-86 years. Baseline characteristics were well balanced. Eighty-eight per cent commenced C at the lower optional dose of 2000 mg/m(2)/day; days 1-14, q21 (61% for <75 years) and 88% were Eastern Cooperative Oncology Group 0-1. Co-morbidities were as expected in this population. The addition of B significantly improved PFS in geriatric patients(C 5.8 months versus CB 8.8 months, Hazard ratio (HR) 0.65 and C versus CBM 10.4 months HR 0.38). The interaction test for OS, RR and PFS revealed no impact of age. Dose intensity was maintained >90% in all patients. There were no major differences in toxicity patterns between age cohorts. CONCLUSIONS: Addition of B to C significantly improved PFS in this geriatric population, with similar benefits to those aged <75 years. Treatment was well tolerated with no signal of increased toxicity (including thromboembolism) when compared with those aged <75 years.

Association of angiopoietin-2, C-reactive protein and markers of obesity and insulin resistance with survival outcome in colorectal cancer.

BACKGROUND: This study investigated the relationship of obesity, insulin resistance, inflammation and angiogenesis with cancer progression and survival in a colorectal cancer cohort. METHODS: Clinical and pathological data, along with anthropometric and follow-up data, were collected from 344 consecutive colorectal cancer patients. Serum samples at diagnosis were analysed by immunoassay for adiponectin, C-reactive protein (CRP), vascular endothelial growth factor-A (VEGF-A), angiopoietin-2 (Ang-2), insulin-like growth factor-1 (IGF-1), insulin and C-peptide. RESULTS: Serum Ang-2 and VEGF-A levels increased with tumour T stage (P=0.007 and P=0.025, respectively) and N stage (P=0.02 and P=0.03, respectively), and correlated with CRP levels (r=0.43, P<0.001 and r=0.23, P<0.001, respectively). Angiopoietin-2 correlated with C-peptide (r=0.14, P=0.007) and VEGF-A with IGF-1 in males (r=0.25, P=0.001). Kaplan-Meier analysis showed that patients with high serum levels of CRP and Ang-2 had significantly reduced survival (both P≤0.001). After adjusting for tumour stage and age, Ang-2 remained a significant predictor of survival. The CRP levels were inversely associated with survival in American Joint Committee on Cancer stage II patients (P=0.038), suggesting that CRP could be used to support treatment decisions in this subgroup. Serum markers and anthropometric measures of obesity correlated with each other, but not with survival. CONCLUSION: Our study supports the concept that obesity-related inflammation, rather than obesity itself, is associated with colorectal cancer progression and survival. The study confirms serum Ang-2 as a predictive marker for outcome of colorectal cancer.

Audit of anticoagulant thromboprophylaxis in hospitalized oncology patients.

BACKGROUND: Venous thromboembolism (VTE) is a significant problem in oncology patients. VTE prophylaxis is underutilized in hospitalized medical patients, but there are few data for the appropriateness and frequency of its use in the oncology subgroup. We aimed to document local practice. METHODS: A cross-sectional chart review of all hospitalized patients cared for by the Christchurch Hospital Oncology Service was carried out during two defined 4-week periods. Assessment for indications and contraindications to prophylactic anticoagulation was based on the 2004 American College of Chest Physicians evidence-based consensus guidelines. RESULTS: Of 113 admissions to the oncology service, 38 (33.6%) had indications for prophylactic anticoagulation. However, 23 of these also had contraindications, leaving only 15 (13%) admissions where prophylactic anticoagulation was deemed appropriate. Only one was appropriately given prophylactic anticoagulation. CONCLUSION: Only a minority of hospitalized oncology patients are appropriate for prophylactic anticoagulation. Where it is suitable, however, it is poorly utilized locally. Local promotion of VTE prophylaxis and further study of this subgroup of hospitalized medical patients may improve uptake of this practice and attenuate morbidity from VTE.

The angiogenic factor thymidine phosphorylase up-regulates the cell adhesion molecule P-selectin in human vascular endothelial cells and is associated with P-selectin expression in breast cancers.

Thymidine phosphorylase (TP) is an angiogenic enzyme, catalysing the reversible phosphorylation of thymidine to thymine and 2-deoxyribose. TP is up-regulated in neoplasia, being associated with advanced tumour stage, microvessel density and prognosis in several tumour types. Although TP is a non-mitogenic migratory factor for endothelium, the mechanism by which TP mediates these effects is still unclear. We compared the gene expression profile of endothelial cells grown in vitro in the presence or absence of TP by cDNA microarray analysis. To determine the time-course of TP angiogenic induction, endothelial cells were stimulated with TP (10 ng/ml) for 5 and 18 h. Gene expression levels of Tie2, angiopoietin (Ang)1 and Ang2, measured by RNase protection assay (RPA), showed maximal alteration at 18 h. cDNA from human umbilical vein endothelial cells (HUVEC) grown for 18 h in the presence or absence of TP (10 ng/ml) was hybridized to a human cDNA cytokine array representing 375 angiogenic genes. Significantly altered expression occurred in 89 human angiogenic genes (72 genes were up-regulated and 17 down-regulated). Changes in five genes relevant to vascular remodelling biology (Tie2, nNos, P-selectin, ephrin-B1 and TP) were validated in triplicate experiments by real-time RT-PCR. But only P-selectin gene expression remained significant. Correlation between P-selectin and TP was assessed by immunohistochemistry on 161 human breast cancers, using human tissue microarray. Tumour cell TP correlated with tumour cell P-selectin but not with endothelial cell P-selectin. These data show that TP stimulates changes in mRNA expression maximally after 18 h culture in vitro. It confirms a role for TP in vascular remodelling involving several classes of genes, including the cell adhesion molecule, P-selectin. Although confirmation of the role of TP-mediated cell adhesion molecule (CAM) induction is required; however, this pathway may provide an attractive therapeutic target, since it is likely to affect several important tumour processes, including angiogenesis and metastasis.

Inhibition of NF-kappa B activity and cFLIP expression contribute to viral-induced apoptosis.

Virus-induced activation of nuclear factor-kappa B (NF-kappaB) is required for Type 3 (T3) reovirus-induced apoptosis. We now show that NF-kappaB is also activated by the prototypic Type 1 reovirus strain Lang (T1L), which induces significantly less apoptosis than T3 viruses, indicating that NF-kappaB activation alone is not sufficient for apoptosis in reovirus-infected cells. A second phase of virus-induced NF-kappaB regulation, where NF-kappaB activation is inhibited at later times following infection with T3 Abney (T3A), is absent in T1L-infected cells. This suggests that inhibition of NF-kappaB activation at later times post infection also contributes to reovirus-induced apoptosis. Reovirus-induced inhibition of stimulus-induced activation of NF-kappaB is significantly associated with apoptosis following infection of HEK293 cells with reassortant reoviruses and is determined by the T3 S1 gene segment, which is also the primary determinant of reovirus-induced apoptosis. Inhibition of stimulus-induced activation of NF-kappaB also occurs following infection of primary cardiac myocytes with apoptotic (8B) but not non-apoptotic (T1L) reoviruses. Expression levels of the NF-kappaB-regulated cellular FLICE inhibitory protein (cFLIP) reflect NF-kappaB activation in reovirus-infected cells. Further, inhibition of NF-kappaB activity and cFLIP expression promote T1L-induced apoptosis. These results demonstrate that inhibition of stimulus-induced activation of NF-kappaB and the resulting decrease in cFLIP expression promote reovirus-induced apoptosis.

Expression of vascular endothelial growth factor D is associated with hypoxia inducible factor (HIF-1alpha) and the HIF-1alpha target gene DEC1, but not lymph node metastasis in primary human breast carcinomas.

BACKGROUND: Vascular endothelial growth factor D (VEGF-D) induces angiogenesis and lymphangiogenesis. Nodal metastasis is recognised as a powerful prognostic marker in breast carcinoma, but the molecular mechanisms underlying this process are unknown. Although it has been suggested that VEGF-D may regulate nodal metastasis, this is based largely on animal models, its role in human disease being unclear. AIMS: To measure the pattern and degree of VEGF-D protein expression in normal and neoplastic human breast tissues. METHODS: The pattern and degree of VEGF-D expression was measured in normal tissue and invasive carcinomas, and expression was correlated with clinicopathological parameters, hypoxia markers, and survival. Because other VEGF family members are affected by oestrogen, whether VEGF-D is regulated by oestrogen in breast cancer cell lines was also assessed. RESULTS: VEGF-D was significantly positively associated with hypoxia inducible factor (HIF-1alpha) (p = 0.03) and the HIF-1alpha regulated gene DEC1 (p = 0.001), but not lymph node status, the number of involved lymph nodes, patient age, tumour size, tumour grade, lymphovascular invasion, oestrogen receptor, progesterone receptor, c-erb-B2, or tumour histology (all p>0.05). There was no significant relation between tumour VEGF-D expression and relapse free (p = 0.78) or overall (p = 0.94) survival. VEGF-D expression was enhanced by oestrogen in MCF-7 and T47D breast cancer cells, and was blocked by hydroxytamoxifen. CONCLUSION: These findings support a role for hypoxia and oestrogen induced VEGF-D in human breast cancer and also suggest that tamoxifen and related oestrogen antagonists may exert some of their antitumour effects through the abrogation of VEGF-D induced function.

Radionuclide transport simulation and uncertainty analyses with the saturated-zone site-scale model at Yucca Mountain, Nevada.

Evaluation of radionuclide transport in the saturated zone (SZ) to the accessible environment is an important component of performance assessment for the proposed radioactive waste repository at Yucca Mountain. Simulations of radionuclide migration in the SZ have been performed using the calibrated three-dimensional (3-D) SZ site-scale flow and transport model. An innovative particle-tracking method was used to simulate transport that includes the processes of advection, dispersion, matrix diffusion, and sorption. The uncertainties in groundwater flow and radionuclide transport were quantitatively evaluated to develop uncertainty distributions for key model parameters, and multiple realizations of the SZ system were simulated using the SZ site-scale model. The results of multiple realizations of radionuclide transport indicate significant aggregate uncertainty in transport times through the SZ. The simulated radionuclide mass breakthrough curves in the SZ have been coupled with other components of the repository system in Total System Performance Assessment (TSPA) analyses and constitute the means by which uncertainty in the SZ is incorporated into regulatory analyses. Regression analysis has been used to determine the sensitivity of radionuclide transport simulation results to the uncertainty of individual model input parameters. Results of the sensitivity analysis indicate that median radionuclide transport times were dominantly controlled by uncertainty in the specific discharge in the SZ, with sorption and retardation in the alluvium playing important roles for some radionuclides.

The saturated zone at Yucca Mountain: an overview of the characterization and assessment of the saturated zone as a barrier to potential radionuclide migration.

The US Department of Energy is pursuing Yucca Mountain, Nevada, for the development of a geologic repository for the disposal of spent nuclear fuel and high-level radioactive waste, if the repository is able to meet applicable radiation protection standards established by the US Nuclear Regulatory Commission and the US Environmental Protection Agency (EPA). Effective performance of such a repository would rely on a number of natural and engineered barriers to isolate radioactive waste from the accessible environment. Groundwater beneath Yucca Mountain is the primary medium through which most radionuclides might move away from the potential repository. The saturated zone (SZ) system is expected to act as a natural barrier to this possible movement of radionuclides both by delaying their transport and by reducing their concentration before they reach the accessible environment. Information obtained from Yucca Mountain Site Characterization Project activities is used to estimate groundwater flow rates through the site-scale SZ flow and transport model area and to constrain general conceptual models of groundwater flow in the site-scale area. The site-scale conceptual model is a synthesis of what is known about flow and transport processes at the scale required for total system performance assessment of the site. This knowledge builds on and is consistent with knowledge that has accumulated at the regional scale but is more detailed because more data are available at the site-scale level. The mathematical basis of the site-scale model and the associated numerical approaches are designed to assist in quantifying the uncertainty in the permeability of rocks in the geologic framework model and to represent accurately the flow and transport processes included in the site-scale conceptual model. Confidence in the results of the mathematical model was obtained by comparing calculated to observed hydraulic heads, estimated to measured permeabilities, and lateral flow rates calculated by the site-scale model to those calculated by the regional-scale flow model. In addition, it was confirmed that the flow paths leaving the region of the potential repository are consistent with those inferred from gradients of measured head and those independently inferred from water-chemistry data. The general approach of the site-scale SZ flow and transport model analysis is to calculate unit breakthrough curves for radionuclides at the interface between the SZ and the biosphere using the three-dimensional site-scale SZ flow and transport model. Uncertainties are explicitly incorporated into the site-scale SZ flow and transport abstractions through key parameters and conceptual models.

Vascular endothelial growth factor-B and vascular endothelial growth factor-C expression in renal cell carcinomas: regulation by the von Hippel-Lindau gene and hypoxia.

Angiogenesis is essential for tumor growth and metastasis. It is regulated by numerous angiogenic factors, one of the most important being vascular endothelial growth factor (VEGF). Recently VEGF-B and VEGF-C, two new VEGF family members, have been identified that bind to the tyrosine kinase receptors flt-1 (VEGFR1), KDR (VEGFR2), and flt-4 (VEGFR3). Although the importance of VEGF-A has been shown in renal carcinomas, the contribution of these new ligands in kidney tumors is not clear. We have, therefore, measured the mRNA level of VEGF-B and VEGF-C together with their receptors by RNase protection assay (RPA) in 26 normal kidney samples and 45 renal cell cancers. We observed a significant up-regulation of VEGF-B (P = 0.002) but not VEGF-C (P = 0.3) in neoplastic kidney compared with normal tissues. In addition, although VEGF receptors were higher in tumors than normal kidney, there was a significant up-regulation of only flt-1 (P = 0.003) but not KDR (P = 0.12) or flt-4 (P = 0.09). There was also a significant correlation between VEGF-C and both of its receptors flt-4 (P = 0.006) and KDR (P = 0.03) but no association between VEGF-B and its receptor flt-1 (P = 0.23). A significant increase was observed in flt-1 (P < 0.001), KDR (P = 0.02), and flt-4 (P = 0.01) but not VEGF-B (P = 0.82) or VEGF-C (P = 0.52) expression in clear cell compared with chromophil (papillary) carcinomas. No significant association was demonstrated between VEGF-B, VEGF-C, flt-1, KDR, and flt-4 with patient sex, patient age, or tumor size (P > 0.05). The effect of von Hippel-Lindau (VHL) gene and hypoxia on VEGF-B and VEGF-C expression in the renal carcinoma cell line 786-0 transfected with wild-type and mutant VHL was determined by growing cells under 21% O2- and 0.1% O2. In wild-type VHL cells, whereas VEGF-A was significantly up-regulated under hypoxic compared with normoxic conditions (P < 0.001), expression of VEGF-C was reduced (P < 0.002). Nevertheless, the repression of VEGF-C was lost in mutant VHL cell lines under hypoxia. In contrast VEGF-B was not regulated by VHL despite clear up-regulation in vivo. These findings strongly support an enhanced role for this pathway in clear cell carcinomas by regulating angiogenesis and/or lymphangiogenesis. The study shows that clear cell tumors are able to up-regulate angiogenic growth factor receptors more efficiently than chromophil (papillary), that clear cell tumors can use pathways independent of VHL to regulate angiogenesis, and that this combined regulation may account for their more aggressive phenotype, which suggests that targeting VEGFR1 (flt-l) may be particularly effective in these tumor types.

Angiopoietin-1 is inversely related to thymidine phosphorylase expression in human breast cancer, indicating a role in vascular remodeling.

PURPOSE: Angiogenesis is essential for tumor growth and metastasis. It is a complex, dynamic process that is coordinated by several classes of angiogenic factors. One candidate family is the Tie2 tyrosine kinase, whose expression is restricted largely to endothelial cells. Tie2 has three known ligands, angiopoietin (Ang)-1, Ang-2, and Ang-4, that have different functional effects but play a requisite role in embryonic vessel remodeling. Because there are only limited data on the Tie2 pathway in human breast cancer, and our previous data have suggested that breast tumors establish a blood supply by vascular remodeling, we have investigated the expression of Ang-1, Ang-2, Ang-4, and Tie2 in a series of normal and neoplastic human breast tissues. EXPERIMENTAL DESIGN: We examined mRNA expression by reverse transcription-PCR in 6 normal and 52 malignant breast tissues and correlated expression with clinicopathological and angiogenic variables. We also examined the effect of physiological levels of estrogen on Ang expression. RESULTS: Ang-1, Ang-2, Ang-4, and Tie2 were detected in 19%, 52%, 35%, and 65%, respectively, of tumor samples. There was a significant reduction in expression of tumor Ang-1 (P = 0.04), Ang-2 (P = 0.01), Ang-4 (P = 0.004), and Tie2 (P = 0.02) compared with that in normal breast tissues. There was a significant relationship in tumors between all Angs and between each ligand and Tie2. In a multivariate analysis, there were significant positive correlations between Ang-4 and estrogen receptor (P = 0.016) and a significant inverse correlation between Ang-1 and thymidine phosphorylase expression (P = 0.01). No significant associations were observed between the other members of the Ang/Tie2 gene family and patient age, tumor size, lymph node status, tumor grade, vascular invasion, tumor vascularity, vascular maturation, thymidine phosphorylase, or vascular endothelial growth factor A expression (P > 0.05 for all). The potential regulation of Ang-4 by estrogen was further investigated in vitro. Addition of physiological concentrations of 17beta-estradiol (1 nM) to hormone-free media caused no significant change in Ang-4 mRNA abundance (P = 0.75) in the estrogen receptor-positive cell line MCF-7 after either 2 or 18 h, despite demonstrating induction for the estrogen response gene pS2. CONCLUSIONS: These findings suggest that the Ang/Tie2 pathway plays a significant role in human breast tumor angiogenesis but provide no initial evidence for direct regulation of the pathway by estrogen.

VEGF-B expression in human primary breast cancers is associated with lymph node metastasis but not angiogenesis.

Angiogenesis is essential for tumour growth and metastasis. It is regulated by numerous angiogenic factors, one of the most important being vascular endothelial growth factor (VEGF). Recently VEGF-B, a new VEGF family member that binds to the tyrosine kinase receptor flt-1, has been identified. Although the importance of VEGF has been shown in many human tumour types, the contribution of VEGF-B to tumour neovascularization is unknown in any tumour type. This study therefore measured the mRNA level of VEGF-B and its receptor flt-1 by ribonuclease protection assay and the pattern of VEGF-B expression by immunohistochemistry in 13 normal breast samples and 68 invasive breast cancers. Flt-1 expression was significantly higher in tumours than in normal breast (p=0.02) but no significant difference was seen in VEGF-B between normal and neoplastic breast (p=0.3). There was a significant association between VEGF-B and node status (p=0.02) and the number of involved nodes (p=0.01), but not with age (p=0.7), size (p=0.6), oestrogen receptor (ER) (p=0.2), grade (p=0.5) or vascular invasion (p=0.16). No significant relationship was present between VEGF-B and flt-1 (p=0.2) or tumour vascularity (p=0.4). VEGF-B was expressed mostly in the cytoplasm of tumour cells, although occasional stromal components including fibroblasts and endothelial cells were also positive. No difference in VEGF-B expression was observed adjacent to regions of necrosis, in keeping with this VEGF family member not being hypoxically regulated. These findings suggest that VEGF-B may contribute to tumour progression by a non-angiogenic mechanism, possibly by increasing plasminogen activators and hence metastasis, as has been described in vitro. Measurement of VEGF-B together with other angiogenic factors may identify a poor prognostic patient group, which may benefit from anti-VEGF receptor therapy targeted to flt-1 (VEGFR1) as well as kdr (VEGFR2).

The short form of the alternatively spliced flt-4 but not its ligand vascular endothelial growth factor C is related to lymph node metastasis in human breast cancers.

Angiogenesis is essential for tumor growth and metastasis. It is regulated by numerous angiogenic factors, one of the most important being vascular endothelial growth factor (VEGF). Recently, VEGF-C, a new VEGF family member, has been identified that binds to the tyrosine kinase receptors flt-4 [VEGF receptor (VEGFR) 3] and KDR (VEGFR2). Although the importance of VEGF has been shown in many human tumor types, the contribution of VEGF-C and its primary receptor flt-4 to tumor progression is less well understood. We have therefore measured the level of VEGF-C, flt-4, and KDR mRNA by RNase protection assay and the pattern of VEGF-C expression by immunohistochemistry in 11 normal breast tissue samples and 61 invasive breast cancers. No significant difference in VEGF-C expression was observed between normal and neoplastic breast tissues (P = 0.11). There was a significant correlation between VEGF-C and both flt-4 (P = 0.02) and KDR (P = 0.0002), but no association was seen between VEGF-C and either lymph node status (P = 0.66) or number of involved nodes (P = 0.88), patient age (P = 0.83), tumor size (P = 0.20), estrogen receptor status (P = 0.67), or tumor grade (P = 0.35). No significant relationship was present between VEGF-C and vascular invasion (P = 0.30), tumor vascularity (P = 0.21), VEGF-A (P = 0.62), or thymidine phosphorylase expression (P = 1.00). VEGF-C was expressed predominantly in the cytoplasm of tumor cells, although occasional stromal components including fibroblasts were also positive. We could demonstrate no association between lymph node metastasis and either VEGF-C (P = 0.66) or flt-4 (P = 0.4). However, we did observe a significant loss of the long but not the short isoform of flt-4 in tumors compared with normal tissues (P = 0.02 and P = 0.25, respectively), and this difference was largely accounted for by the reduction of long flt-4 in node-positive tumors. These findings strongly support a role for VEGF-C/flt-4 signaling in tumor growth by enhancement of angiogenesis and/or lymphangiogenesis and suggest that differential regulation of these processes may be controlled via flt-4 isoform transcription. They further suggest that the measurement of flt-4 isoform expression may identify a patient group that is likely to have node-positive disease and therefore benefit from additional treatment and also emphasize an additional ligand interaction that could be exploited by anti-VEGFR therapy.

Hemorrhagic lymphadenopathy as a presenting feature of primary al amyloidosis.

Lymphadenopathy associated with hemorrhage as a presenting feature of primary (AL) amyloidosis has not previously been described. We report two such cases one of whom had an acquired factor X and IX deficiency. The clinical presentations were characterized by sudden spontaneous enlargement of lymph nodes followed by partial regression. In both cases significant delay in diagnosis, and hence treatment, occurred due to the mode of presentation. One patient died with rapidly progressive disease but the other has had an excellent response to therapy with high-dose melphalan (HDM, 200 mg/m2) and peripheral blood stem cell rescue. AL amyloid should be considered in all patients presenting with hemorrhagic lymphadenopathy.

Monte Carlo methods for the in vivo analysis of cisplatin using X-ray fluorescence.

A Monte Carlo method has been used to model the measurement of cisplatin uptake with in vivo X-ray fluorescence. A user-code has been written for the EGS4 Monte Carlo system that incorporates linear polarisation and multiple element fluorescence extensions. The yield of fluorescent photons to the mainly Compton scattered background is computed for our detector arrangement. The detector consists of a mutually orthogonal arrangement of X-ray tube, aluminium polariser and high purity germanium scintillation detector. The influence of tube voltage on the minimum detectable concentration is modelled for 100 through 150 kVp X-radiation. The code is able to predict absorbed dose to the patient which will influence the optimal choice of tube voltage. The influence of alterations to collimator design and scatterer construction can also be examined. A minimum detectable concentration of 50 ppm is determined from measurements with a 115 kVp X-ray source and a 615 ppm cisplatin sample in a water phantom.

Identification of a novel PTEN mutation (L139X) in a patient with Cowden disease and Sjögren's syndrome.

Cowden disease is an autosomal dominant disorder associated with an increased risk of breast, thyroid, and skin cancer in which germline mutations in a candidate tumour suppressor gene (PTEN) have been identified previously. Sjögren's syndrome is a chronic inflammatory and autoimmune disorder of exocrine glands for which the genetic basis is unknown. This report describes a novel PTEN mutation (L139X) in a patient with Cowden disease and Sjögren's syndrome. This observation raises the possibility of a link between mutations in the PTEN gene and Sjögren's syndrome.

Clinical pharmacokinetics and dose optimisation of carboplatin.

Carboplatin shares some of the therapeutic advantages of cisplatin, but without a significant incidence of the dose-limiting neurotoxicity and nephrotoxicity which is experienced with cisplatin. However, its use is associated with dose-limiting bone marrow suppression. Carboplatin is present in the blood as 3 distinct species. These are total platinum and 2 unbound species, carboplatin itself and a decarboxylated platinum-containing degradation product. The 2 main methods used to assay the unbound species are flameless atomic absorption spectrophotometry and high performance liquid chromatography. The first of these methods assays both unbound platinum species, the second is specific for carboplatin. Both unbound species have similar pharmacokinetic profiles for the first 12 hours post-dose. Carboplatin appears to have a linear pharmacokinetic profile over the doses used clinically and does not interact significantly with drugs that are used commonly in combination chemotherapy. The pharmacokinetics of carboplatin are adequately described by an open 2-compartment model with elimination from the central compartment. Its clearance is proportional to the glomerular filtration rate and the volume of distribution of the central compartment appears to correlate with extracellular fluid volume. The elimination half-life varies with renal function and is typically between 2 and 6 hours in patients with a normal glomerular filtration rate and may be as long as 18 hours in patients with impaired renal function. Relationships between systemic exposure to carboplatin, described as the area under the concentration-time curve (AUC), and both toxicity and response have been described. For toxicity the strongest evidence exists for a relationship between AUC and thrombocytopenia. To a lesser extent the relationship between AUC and neutropenia has also been described. Patients already treated with platinum analogues have been shown to develop a greater degree of myelosuppression from any given AUC. In addition, some evidence suggests a relationship between the shape of the concentration-time curve and myelotoxicity, where constant infusions appear less likely to cause myelosuppression on a mg/m2 dose administration basis. The relationship between AUC and response rate is not as clear, this may be related to the lack of studies describing both the dose and AUC of carboplatin. There appears to be a more clearly defined AUC-response relationship for ovarian cancer than for other malignancies, with an AUC of between 5 and 7 mg/ml.min being associated with the maximal response rate [located at the plateau on an AUC-response curve]. However, new data suggest that higher AUCs may lead to greater response rates. Data from testicular cancer also strongly supports an AUC-response relationship with an increased number of treatment failures with carboplatin AUCs < 5 to 6 mg/ml.min. Given the AUC-effect relationships described above a number of studies have been performed to develop models to describe the relationship between both dose and AUC and dose and platelet nadir. In adults, perhaps the most common method is that of Calvert which describes the relationship between dose and AUC. Paediatric formulas have also been described. More recently a number of limited sampling strategies have been proposed as well as Bayesian dose individualisation techniques.