Cost-comparison analysis of a multiplatform tumour profiling service to guide advanced cancer treatment.

BACKGROUND: Tumor profiling is increasingly used in advanced cancer patients to define treatment options, especially in refractory cases where no standard treatment is available. Caris Molecular Intelligence (CMI) is a multiplatform tumor profiling service that is comprehensive of next-generation sequencing (NGS) of DNA and RNA, immunohistochemistry (IHC) and in situ hybridisation (FISH). The aim of this study is to compare costs of CMI-guided treatment with prior or planned treatment options in correlation with outcome results. METHODS: Retrospective data from five clinical trials were collected to define the treatment decision prior to the receipt of the CMI report (n = 137 patients). A systematic review of treatment data from 11 clinical studies of CMI (n = 385 patients) allowed a comparison of planned vs actual (n = 137) and prior vs actual (n = 229) treatment costs. RESULTS: Treatment plan was changed in 88% of CMI-profiled cases. The actual CMI guided treatment cost per cycle was £995 in 385 treated patients. Planned treatment costs were comparable to actual treatment costs (£979 vs £945; p = 0.7123) and prior treatment costs were not significantly different to profiling-guided treatments (£892 vs £850; p = 0.631). CONCLUSIONS: Caris Molecular Intelligence guided treatment cost per cycle was in the range of prior or planned treatment cost/cycle. Due to beneficial overall survival the additional cost of performing CMI's multiplatform testing to the treatment costs seems to be cost-effective.

Does the primary site really matter? Profiling mucinous ovarian cancers of uncertain primary origin (MO-CUP) to personalise treatment and inform the design of clinical trials.

OBJECTIVE: Advanced stage mucinous ovarian cancers are diagnostically and therapeutically challenging. Histotype specific trials have failed due to low recruitment after excluding non-ovarian primaries. Mucinous ovarian cancers are commonly metastatic from other sites however lack definitive diagnostic markers. We suggest a classification of mucinous ovarian cancers of uncertain primary origin 'MO-CUPs' in clinical trials. This study aims to identify drug targets to guide treatment and future trials. METHODS: We analyzed a large de-identified, multi-platform tumor profiling dataset of MO-CUPs enriched for advanced stage and recurrent cases submitted to Caris Life Sciences. Available data included a 45-gene next-generation sequencing (NGS) panel, gene amplification of HER2 and cMET and 18 immunohistochemical (IHC) markers of drug sensitivity/resistance. RESULTS: Mucinous tumors from 333 patients were analyzed, including 38 borderline tumors and 295 invasive cancers. The most common mutations in a subset (n = 128) of invasive cancers were KRAS (60%), TP53 (38%), PIK3CA (13%) and PTEN (9%). Borderline tumors had higher rates of BRAF mutations, and PGP and TOP2A overexpression than invasive cases. KRAS mutant invasive cancers had lower expression of thymidylate synthase (p = 0.01) and higher expression of TUBB3 (p = 0.01) than KRAS wildtype tumors. CONCLUSIONS: To our knowledge, this is the largest series profiling mucinous ovarian cancers and almost certainly includes cases of ovarian and non-ovarian origin. Given the difficulty recruiting patients to histotype-specific trials in rare subsets of ovarian cancer, it may be more important to focus on identifying potential treatment targets and to personalise treatment and design clinical trials in MO-CUPS agnostic of primary site to overcome these issues.

Preventive, predictive, and personalized medicine for effective and affordable cancer care.

Preventive, predictive, and personalized medicine (PPPM) has created a wealth of new opportunities but added also new complexities and challenges. The European Cancer Prevention Organization already embraced unanimously molecular biology for primary and secondary prevention. The rapidly exploding genomic language and complexity of methods face oncologists with exponentially growing knowledge they need to assess and apply. Tissue specimen quality becomes one major concern. Some new innovative medicines cost beyond any reasonable threshold of financial support from patients, health care providers, and governments and risk sustainability for the health care system. In this review, we evaluate the path for genomic guidance to become the standard for diagnostics in cancer care and formulate potential solutions to simplify its implementation. Basically, introduction of molecular biology to guide therapeutic decisions can be facilitated through supporting the oncologist, the pathologist, the molecular laboratory, and the interventionist. Oncologists need to know the exact indication, utility, and limitations of each genomic service. Minimal requirements on the label must be addressed by the service provider. The interventionist is there to bring the most optimal tissue sample to pathology where the tissue is expanded to a variety of appropriate liquid-based samples. The large body of results then should be translated into meaningful clinical guidance for the individual patient. Surveillance, with the appropriate application of health economic indicators, can make this system long lasting. For governments and health care providers, optimal cancer care must result in a cost-effective, resource-sustainable, and patient-focused outcome.

The tamoxifen-induced suppression of telomerase activity in the human hepatoblastoma cell line HepG2: a result of post-translational regulation.

PURPOSE: Patients with advanced hepatocellular carcinoma (HCC) have shown to benefit from tamoxifen treatment. The mechanisms of tamoxifen action in HCC, however, are not yet clearly understood. Results from studies on the human hepatoblastoma cell line HepG2 provide evidence that estrogen-receptor-alpha-independent antiproliferative actions of tamoxifen in HCC are mediated by the suppression of telomerase activity [5]. MATERIALS AND METHODS: We investigate the pathway of the tamoxifen-induced down-regulation of telomerase activity, using HepG2 cells incubated over 24 h or 48 h in the presence of 20 microM tamoxifen. RESULTS: The transcriptional levels of the three telomerase core components-human telomerase RNA (hTR), human telomerase reverse transcriptase (hTERT) (all variants), and telomerase-associated protein (TP1)-did not change during tamoxifen treatment, as revealed by RT-PCR analysis. Furthermore, the hTERT splice pattern was not shifted from the active full-length variant (+alpha/+beta) to the inactive deletion variants (-alpha; -beta; -alpha/-beta) and the level of the 120 kDa hTERT full-length protein remained constant, as shown by Western blot analysis. Protein kinase C (PKC) activity has been suggested to be crucial for post-translational up-regulation of telomerase activity. In HepG2 cells, we observed a tamoxifen-induced suppression of the total protein kinase C (PKC) activity (cytosolic and membrane-bound). Inhibition of PKC with bisindolylmaleimide I resulted in a reduction of telomerase activity, as revealed by TRAP-assay. Alpha-tocopherol (vitamin E) diminished the effects of tamoxifen on PKC-activity as well as on telomerase activity. CONCLUSIONS: We conclude that the tamoxifen-induced decrease of telomerase activity in HepG2 cells is mediated post-translationally via suppression of PKC-activity.

Temporal nitric oxide dynamics in the paranasal sinuses during humming.

In this study, the temporal shape of voice-induced nitric oxide (NO) signals in exhaled air has been investigated in eight healthy individuals by means of laser magnetic resonance spectroscopy. The results of the experimental part have been compared with calculated signals obtained by using a simple one-compartment model of the paranasal sinuses. In the experimental part, a rapidly increasing NO concentration has been found when the subjects started humming. After reaching a maximum, the emission starts to decrease with the shape of an exponential decay and finally reaches a constant level. The time constant of this decay (NO washout) is 3.0 +/- 1.2 s. The peak height of the NO emission during humming increases when the time between two humming processes increases. When no voice-induced NO emission takes place, the NO concentration in the paranasal sinuses rebuilds again to a maximum concentration. The typical time constant for the NO recovery is 4.5 +/- 3.2 min. A three-compartment model defining exactly the geometry and anatomy of the paranasal sinuses has been developed that is based on three main assumptions of the NO dynamics: 1) constant NO production of the epithelium in the sinuses; 2) the rate of the chemical reaction of NO with the epithelium of the paranasal sinuses is proportional to the NO concentration; and 3) the emission of NO from the sinuses (volume/s) is proportional to the NO concentration. It is shown that the three-compartment model under the experimental conditions can be reduced to a one-compartment model, which describes the complete temporal behavior of the NO exchange.

Initial body mass indexes have contrary effects on change in body weight and mortality of patients on maintenance hemodialysis treatment.

Malnutrition is a relevant risk factor for mortality for patients on maintenance hemodialysis treatment. In a retrospective study including 377 patients who began hemodialysis treatment between 1986 and 2001, we assessed the prevalence of different statuses of nutrition and the impact of the initial status of nutrition on the change in body weight and patient survival. We found an inverse relationship between body mass index (BMI, kg/m2) and the gain in body weight and BMI within 12 months of hemodialysis treatment. Underweight and normal weight patients had a substantial increase in these parameters, greatest in underweight subjects, whereas overweight and obese patients showed only a moderate increase or none (P =.0019, P =.00036). Adjusted mortality rates showed an inverse correlation with the initial BMI (P <.0001). There was a statistically significant difference in the mortality between patients with normal weight and overweight or obesity, respectively, showing a more favorable prognosis in overweight and obese patients (P =.0007; P =.022; log-rank, normal versus overweight, P =.012). Weight loss was the greatest independent risk factor for mortality in general. Adjusted hazard ratio of death was highest in underweight patients (3.999; CI, 2.708 to 5.905; P <.0001) and decreased to 2.251 (CI, 1.795 to 2.822; P <.0001) in normal weight, 1.927 (CI, 1.390 to 2.670; P <.0001) in overweight, and 1.651 (CI, 0.841 to 3.236; P =.1439) in obese subjects when patients with weight loss were compared with patients who preserved their initial weight or gained weight. Overall, the initial BMI has an influence on the change in body weight as well as on patient survival in general and in the case of weight loss in particular.

Socioeconomic status and physical stature in 19th-century Bavaria.

We present analyses of 19th-century Bavarian conscript records, which cover the whole male population at age 21 and which are unusually rich in content. They include not only occupations of the conscripts, but that of the parents alike, and also the wealth of the conscripts, other family characteristics and their diseases at the time of the conscription. This enables us to investigate the relationship between the conscripts' and the parents' socioeconomic status as well as their effects on the height of the conscripts. Overall, the conscripts' occupations match that of their parents rather well, and deviations can mainly be attributed to their young age. However, we also find significant height differences between the occupational groups of the conscripts even after controlling for the parents' occupations. This could be caused by a reverse effect of height on occupational advancements, but as conscripts doing manual work are generally shorter than those with non-manual occupations irrespective of their rank, we assume that the working conditions of the adolescents and young men actually influenced their growth.

Pulmonary NO and C18O2 uptake during pressure-induced lung expansion in rabbits.

In artificially ventilated animals we investigated the dependence of the pulmonary diffusing capacities of nitric oxide (NO) and doubly 18O-labeled carbon dioxide (DLNO, DLC18O2) on lung expansion with respect to ventilator-driven increases in intrapulmonary pressure. For this purpose we applied computerized single-breath experiments to 11 anesthetized paralyzed rabbits (weight 2.8-3.8 kg) at various alveolar volumes (45-72 ml) by studying the almost entire inspiratory limb of the respective pressure/volume curves (intrapulmonary pressure: 6-27 cmH2O). The animals were ventilated with room air, employing a computerized ventilatory servo-system that we designed to maintain mechanical ventilation and to execute the particular lung function tests automatically. Each single-breath maneuver was started from residual volume (13.5+/-2 ml, mean+/-SD) by inflating the rabbit lungs with 35-55 ml indicator gas mixture containing 0.05% NO in N2 or 0.9% C18O2 in N2. Alveolar partial pressures of NO and C18O2 were measured by respiratory mass spectrometry. Values of DLNO and DLC18O2 ranged between 1.55 and 2.49 ml/(mmHg min) and 11.7 and 16.6 ml/(mmHg min), respectively. Linear regression analyses yielded a significant increase in DLNO with simultaneous increase in alveolar volume (P<0.005) and intrapulmonary pressure (P<0.023) whereas DLC18O2 was not improved. Our results suggest that the ventilator-driven lung expansion impaired the C18O2 blood uptake conductance, finally compensating for the beneficial effect of the increase in alveolar volume on DLC18O2 values.

Tamoxifen induces suppression of cell viability and apoptosis in the human hepatoblastoma cell line HepG2 via down-regulation of telomerase activity.

BACKGROUND/AIMS: Antiproliferative action of tamoxifen in the estrogen receptor-alpha-negative human hepatoblastoma cell line HepG2 was investigated. METHODS: HepG2 cells, seeded at different densities (4000-36 000 cells/cm(2)), were incubated with tamoxifen (1, 10, or 20 microM) or the telomerase inhibitor 3'-azido-3'-deoxythymidine (AZT) (0.6-3.0 mM) up to 72 h. Cell viability was assessed (MTT-test), flow cytometric analysis was performed, and telomerase activity was measured (telomeric repeat amplification protocol assay). RESULTS: Ten or 20 microM tamoxifen induced a reduction of cell viability. Basically reduction of viability was related to an increase in the fraction of G0/1-phase. When tamoxifen was present at higher concentration (20 microM) or at low cell density (4000/cm(2)) an additional increase of the rate of apoptotic cells occurred with a delay, aggravating the effect of tamoxifen on cell viability substantially. When apoptosis was induced a significant suppression of telomerase activity preceded regularly. Direct inhibition of telomerase activity with AZT resulted in a decrease of cell viability and apoptosis. CONCLUSION: The tamoxifen-induced reduction of cell viability in HepG2 cells depends on drug concentration and cell density and is due to cytostatic and cytocide effects. The latter may be mediated by a down-regulation of telomerase activity.