Non-solid Tumors Research Articles

Biological characterization of ETP-46321 a selective and efficacious inhibitor of phosphoinositide-3-kinases

Inhibitors of PI3K signaling are of great therapeutic interest in oncology. The phosphoinositide-3-kinase signaling pathway is activated in a variety of solid and non-solid tumors. We have identified an imidazopyrazine derivative, ETP-46321, as a potent inhibitor of PI3Kα [Formula: see text]. The compound was 6 times less potent towards PI3Kδ and more than 200 and 60 times less potent at inhibiting PI3Kβ and PI3Kγ and did not significantly inhibit the related phosphoinositide-3-kinase-related protein kinase family kinases mTOR or DNA PK (IC(50)'s > 5μM), or an additional 287 protein kinases that were screened. ETP-46321 inhibited PI3K signaling in treated tumor cell lines, induced cell cycle arrest and inhibited VEGF-dependent sprouting of HUVEC cells. The compound was anti-proliferative and synergized with both cytotoxic and targeted therapeutics. The compound induced a reduction in the phosphorylation of Akt in U87 MG xenografts after a single treatment. The growth of colon and lung cancinoma HT-29 and A549 xenografts was delayed by once a day treatment with ETP-46321. The compound synergized with Doxotaxel in a model of ovarian cancer.

Multifunctional hybrid materials for combined photo and chemotherapy of cancer

Combined chemo and photothermal therapy in in vitro testing has been achieved by means of multifunctional nanoparticles formed by plasmonic gold nanoclusters with a protecting shell of porous silica that contains an antitumor drug. We propose a therapeutic nanoplatform that associates the optical activity of small gold nanoparticles aggregates with the cytotoxic activity of 20(S)-camptothecin simultaneously released for the efficient destruction of cancer cells. For this purpose, a method was used for the controlled assembly of gold nanoparticles into stable clusters with a tailored absorption cross-section in the vis/NIR spectrum, which involves aggregation in alkaline medium of 15 nm diameter gold colloids protected with a thin silica layer. Clusters were further encapsulated in an ordered homogeneous mesoporous silica coating that provides biocompatibility and stability in physiological fluids. After internalization in 42-MG-BA human glioma cells, these protected gold nanoclusters were able to produce effective photothermolysis under femtosecond pulse laser irradiation of 790 nm. Cell death occurred by combination of a thermal mechanism and mechanical disruption of the membrane cell due to induced generation of micrometer-scale bubbles by vaporizing the water inside the channels of the mesoporous silica coating. Moreover, the incorporation of 20(S)-camptothecin within the pores of the external shell, which was released during the process, provoked significant cell death increase. This therapeutic model could be of interest for application in the treatment and suppression of non-solid tumors.

Histologic patterns and molecular characteristics of lung adenocarcinoma associated with clinical outcome

Lung adenocarcinoma is histologically heterogeneous and has 5 distinct histologic growth patterns: lepidic, acinar, papillary, micropapillary, and solid. To date, there is no consensus regarding the clinical utility of these patterns. The authors performed a detailed semiquantitative assessment of histologic patterns of 240 lung adenocarcinomas and determined the association with patients' clinicopathologic features, including recurrence-free survival (RFS) and overall survival (OS) rates. In a subset of tumors, expression levels of 2 prognostic molecular markers were evaluated: thyroid transcription factor-1 (TTF-1) (n = 218) and a panel of 5 proteins (referred as the FILM signature index) (n = 185). Four mutually exclusive tumor histology pattern groups were identified: 1) any solid (38%), 2) any papillary but no solid (14%), 3) lepidic and acinar but no solid or papillary (30%), and 4) acinar only (18%). Patients in group 3 had a higher RFS rate than patients in group 1 (hazard ratio [HR], 0.4510; P = .0165) and group 2 (HR, 0.4253; P = .0425). Solid pattern tumors (group 1) were associated with a lower OS rate than nonsolid pattern tumors (all stages: HR; 1.665; P = .0144; stages I and II: HR, 2.157; P = .008). In the patients who had tumors with a nonsolid pattern, high TTF-1 expression was associated significantly with higher RFS (HR, 0.994; P = .0017) and OS (HR, 0.996; P = .0276) rates in all stages, and a high FILM signature index score was associated with lower RFS and OS rates in all stages (RFS: HR, 1.343; P = .0192; OS: HR, 1.371; P = .0156) and in stages I and II (RFS: HR, 1.419; P = .0095; OS: HR, 1.315; P = .0422). The presence of a solid histologic pattern was identified as a marker of unfavorable prognosis in patients with primary lung adenocarcinoma. High TTF-1 expression and low FILM signature index scores were associated with a better prognosis for patients who had tumors with a nonsolid pattern.

ImMucin: A novel therapeutic vaccine with promiscuous MHC binding for the treatment of MUC1-expressing tumors

An optimal cancer vaccine should be able to induce highly potent, long-lasting, tumor-specific responses in the majority of the cancer patient population. One approach for achieving this is to use synthetic peptide vaccines derived from widely expressed tumor-associated antigens, that promiscuously bind multiple MHC class I and class II alleles. MUC1-SP-L (ImMucin, VXL100) is a 21mer peptide encoding the complete signal peptide domain of MUC1, a tumor-associated antigen expressed by over 90% of solid and non-solid tumors. MUC1-SP-L was predicted in silico to bind various MHC class I and MHC class II alleles, covering the majority of the Caucasian population. PBLs obtained from 13 naïve donors all proliferated, with a Stimulation Index (SI≥2), to the MUC1-SP-L peptide, producing mixed CD4+ and CD8+ responses. Similar results were manifested by MUC1-SP-L in PBLs derived from 9 of 10 cancer patients with MUC1 positive tumors. CD4+ and CD8+ T cell populations exhibited CD45RO memory markers and secreted IFN-gamma and IL-2 following stimulation with MUC1-SP-L. These T cells also exhibited proliferation to the MUC1-SP-L inner 9mer epitopes and cytotoxicity against tumor cell lines expressing MUC1 and a concordant MHC class I allele. Cytotoxicity to MUC1-expressing human and murine tumors was shown also in T cells obtained from HLA-A2 transgenic mice and BALB/c syngeneic mice immunized with the MUC1-SP-L and GM-CSF. In an immunotherapy model, BALB/c mice inoculated with metastatic MUC1 transfected murine DA3 mammary tumor cells, exhibited significantly prolonged survival following vaccination with MUC1-SP-L. Our results indicate superior immunological and anti-tumor properties of MUC1-SP-L compared to previously published MUC1-derived epitopes.

Abstract 627: Etp-47187 a novel potent and efficacious dual inhibitor of phosphoinositide-3-kinases and mTOR

Abstract The phosphoinositide-3-kinase (PI3K) signaling pathway is activated in a variety of solid and non-solid tumors. In many instances this is due to either activating mutations in the catalytic subunit of PI3Kα, p110α, or inactivating mutations or deletions of the tumor suppressor PTEN. In addition, the PI3K pathway is activated by mutations in certain receptor tyrosine kinases as well as by mutation of the oncogene KRAS. All of these lesions lead to enhanced activity of both PI3K and mTOR. Hence there is great interest to discover inhibitors of PI3K and mTOR for the treatment for cancer. Following a rational design strategy, we identified the fused thiadiazole derivative ETP-47187 as a potent dual inhibitor of PI3Kα and mTOR Kis = 0.18 nM and 1.2 nM, respectively. ETP-47187 also inhibits three oncogenc mutants of p110α: p110α E542K Ki = 0.38 nM, p110α E545K Ki = 0.2 nM and p110α H1047R Ki = 0.29 nM as well as PI3Kβ, PI3KΔ and PI3Kγ Kis 2.7, 0.26 and 1.5 nM, respectively. The compound inhibits PI3K signaling in treated tumor cell lines; the EC50 for inhibition of the phosphorylation of Akt was 5 nM. ETP-47187 has a pharmacokinetic profile suitable for oral dosing in mice (%F = 73%, Cl = 0.11 L/hr/kg; Vds = 0.38 L/h/kg). Treatment of tumor bearing mice with the compound causes a dose dependent reduction in P-Akt levels in the tumor. Once a day treatment of mice bearing human tumor xenografts with ETP-47187 results in significant tumor growth delay and is well tolerated. In a mouse model of lung cancer induced by expression of an oncogenic mutant KRAS, treatment with ETP-47187 blocked tumor growth and lead to a significant PET response. These and combination data will be discussed. We believe ETP-47187 and compounds like it are suitable to propose for clinical development in cancer patients with activated PI3K signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 627. doi:10.1158/1538-7445.AM2011-627

Abstract 3325: Phenotypic heterogeneity and distribution of human glioblastoma tumour-initiating cells

Abstract In the last years the idea that tumours arise from a sub-population of cells endowed with “stem cell” features completely revolutionized the field of Oncology. This hypothesis found its initial confirmation by studies on non-solid tumours and then has been extended also to solid tumours. It is a common believe that the so called “cancer stem cells” concept could also provide new insights into the cellular and molecular mechanism of tumour growth and to the development of new therapeutic strategies for the treatment of incurable cancers. The most lethal tumour of the Central Nervous System is Glioblastoma Multiforme (GBM) which accounts for over 60% of brain tumours. Median life expectancy in optimally managed patients is only 12-14 months with only 25% surviving 24 months. The current clinical management of patients diagnosed with a GBM involves a combination of surgery, radiotherapy and chemotherapy. Radiotherapy has been the principle therapeutic modality since the late seventies and additional targeted chemotherapy is of only modest benefit. Thus the need for new treatments is an unmet clinical need. It is hypothesized that “cancer stem cells” are a significant factor in gliomagenesis and in the emergence of treatment resistant clones in GBM. However, it is not known how these cells contribute to the heterogeneity of this process. Here we report the isolation and genetic characterization of distinct “cancer stem cell” populations from different areas of the same GBM specimens: margin, necrotic and core mass. Our results demonstrated that only the cells derived from the core mass retain stem cell features, such as clonogenicity and multipotency, and possess long-term self-renewal and tumour-initiating capacity, therefore can be considered as bona fide “cancer stem cells”. On the contrary, cancer stem cells are rarely found in the other areas. Most importantly, cells derived from margin areas are not endowed with migratory ability and are genetically aberrant, displaying patterns of karyotypic alterations that overlap only partially with those present in core mass cells. This approach could help us in increasing our understanding of the heterogeneity of cell populations in human GBM in relation to the concept of a stem cell hierarchy in tumours. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3325. doi:10.1158/1538-7445.AM2011-3325

Preoperative MRI Evaluation of Pituitary Macroadenoma: Imaging Features Predictive of Successful Transsphenoidal Surgery

The purpose of this study was to determine whether the preoperative MRI findings of enhanced diffusivity, macrocyst content, and internal hemorrhage in pituitary macroadenomas are predictive of successful transsphenoidal hypophysectomy. We retrospectively reviewed the preoperative and postoperative sella protocol MR images of 28 patients who underwent transsphenoidal hypophysectomy for chiasm-compressing macroadenoma. Chiasmatic decompression defined surgical success. Two neuroradiologists differentiated nonsolid (macrocystic and macrohemorrhagic) from solid tumors, computed apparent diffusion coefficient (ADC) and T2-weighted signal intensity normalized to pons in solid tumors, and measured change in tumor height. A neuropathologist graded reticulin content in tumor specimens. Categorical and dichotomous variables were examined with the chi-square or Fisher's exact test; continuous-scale data were analyzed with the Student's t test, analysis of variance, or linear regression. Transsphenoidal hypophysectomy succeeded in the management of 10 of 11 nonsolid tumors and nine of 17 solid tumors (p = 0.049). The ratios of tumor to brainstem ADC in the nine successfully resected solid tumors were higher than in the eight cases of failed treatment (p = 0.008) with no significant difference in ratio of tumor to brainstem T2-weighted signal intensity (p = 0.76). All six solid tumors with enhanced diffusivity (ratio of tumor to brainstem ADC > 1.1) were successfully managed with transsphenoidal hypophysectomy, compared with three of 11 with an ADC ratio less than 1.1 (p = 0.009). There was a significant main effect of ADC ratio groupings on change in tumor height (p = 0.02), and a linear relation was found between ADC ratio and change in tumor height (p = 0.04). Taken together, tumors with nonsolid features or an ADC ratio greater than 1.1 were highly resectable (p < 0.001; sensitivity, 0.84; specificity, 0.89). ADC ratios in reticulin-poor solid tumors were higher than those in reticulin-rich tumors (p = 0.024). Macrocystic and macrohemorrhagic adenomas and solid tumors with enhanced diffusivity are more likely to be successfully managed with transsphenoidal hypophysectomy. Transsphenoidal hypophysectomy of solid, enhancing tumors with restricted diffusion is more likely to fail, possibly because of the greater reticulin content of the tumor; initial transcranial surgery may be appropriate in these cases.

Pulmonary Nodules: Preliminary Experience with Semiautomated Volumetric Evaluation by CT Stratum

To evaluate the performance of custom-made software designed to quantify volume and weight of focal portions of lung tumors in regions of interest (ROI) and volume of interest on thin-section computed tomography (CT) images by stratum of CT values. Volume and weight of lung portions were measured three-dimensionally and semiautomatically by CT stratum and compared with standard manual measurements. One each of a partly solid tumor (including initial and follow-up high-resolution CT scans), partly solid tumor with most parts showing solid density, and nonsolid tumors in the mid-zone of the lung were analyzed. The doubling time (DT) of tumor volume and mass were calculated by stratum of CT values. The software-measured tumor weight in lung periphery was reproducible, with and without trimming of intervening lung structures between borders of ROIs and tumor. For the lesion in the midlung zone, the fairly thick nearby pulmonary vessels degraded the measurements, with a higher measurement error, indicating the need to trim these structures off the ROI. Software measurements allowed quantification of tumor progress based on increase in tumor mass, without significant increase in tumor volume. The DTs for both tumor volume and mass were different among the four strata of CT values in the partly solid nodule. Our semiautomated volumetric method involving measurement by CT stratum is promising for evaluation of lung tumor progress and aggressiveness.

Brain cancer stem cells

Cancers comprise heterogeneous cells, ranging from highly proliferative immature precursors to more differentiated cell lineages. In the last decade, several groups have demonstrated the existence of cancer stem cells in both nonsolid solid tumors, including some of the brain: glioblastoma multiforme (GBM), medulloblastoma, and ependymoma. These cells, like their normal counterpart in homologous tissues, are multipotent, undifferentiated, self-sustaining, yet transformed cells. In particular, glioblastoma-stem like cells (GBSCs) self-renew under clonal conditions and differentiate into neuron- and glia-like cells, with aberrant, mixed neuronal/astroglial phenotypes. Remarkably, upon subcutaneous and intracerebral transplantation in immunosuppressed mice, GBSCs are able to form secondary tumors that closely resemble the human pathology, a property retained also throughout serial transplantation. The search is up for the identification of the markers and the molecular mechanisms that underpin the tumorigenic potential of these cells. This is critical if we aim at defining new therapeutic approaches for the treatment of malignant brain tumors. Lately, it has been shown that some key regulatory system that plays pivotal roles in neural stem cell physiology can also regulate the tumorigenic ability of cancer stem cells in GBMs. This suggests that the study of cancer stem cells in brain tumors might help to identify new and more specific therapeutic molecular effectors, with the cancer stem cells themselves representing one of the main targets, in fact the Holy Grail, in cancer cell therapy. This review includes a summary review on brain cancer cells and their usefulness as emerging targets in cancer cell therapy.

Semi-automatic Volumetric Measurement of Lung Cancer Using Multi-detector CT: Effects of Nodule Characteristics

The aims of this study were to determine interobserver variability in volume measurements of lung tumors (including part-solid and nonsolid types) using novel computer-aided diagnosis (CAD) tools and a machine learning approach and to determine the potential reasons for variability. In 60 consecutive patients with peripheral lung cancer, the three-dimensional volumes of nodules were measured using the perimeter method by an experienced chest radiologist. In addition, for the same patients, maximal diameters and three-dimensional volumes were measured with and without a novel CAD tool by six observers. The coefficient of variance (CV) as index of interobserver variability was calculated. For the measurement of volume, the results of the perimeter method were compared to those of the CAD method. Furthermore, the CV was calculated for the following subgroups: nodule diameter, internal opacity, margin, spiculation, and adherence to vessels and the chest wall. There was significant interobserver variability among the six observers for manual, but not CAD, measurements of maximal diameter (P < .001 and P = .207, respectively). Volume measured with the perimeter method by a chest radiologist was well correlated with volume measured with the aid of the CAD system by six radiologists (r = 0.98-0.99). There was no significant difference in the CV for size, internal opacity, spiculation of nodules, or adherence to pulmonary vessels and the chest wall. The CV was significantly higher for obscure marginal nodules than for clear marginal nodules (P < .01). The novel CAD tool could be used to measure the volume of not only solid but also part-solid and nonsolid lung tumors.

Molekylær diagnostikk av maligne lymfomer

Malignant lymphomas comprise a heterogeneous group of non-solid tumors originating in lymphocytes at different maturation stages. The diagnosis is based on a traditional histopathological diagnostic procedure supplemented with immunophenotyping, cytogenetics, molecular genetic analyses and clinical information. This article describes experimental molecular diagnostics, mainly based on microarray-based gene expression technology. Results achieved through an international multicentre project (headed by the National Cancer Institute in the USA), in which the Norwegian Radium Hospital has taken part as the only Nordic institution, are summarized. The findings are discussed in light of other relevant studies identified through a non-systematic search in PubMed. New clinically relevant subgroups of malignant B-cell lymphomas have been characterized. Retrospective survival analyses have shown correlations between gene expression profiles and patient outcome and have provided important biological knowledge, which has led to new targeted treatments (currently being tested in clinical studies). As a supplement to today's diagnostics, molecular diagnostics yields an improved diagnostic precision and opens up for new treatment possibilities for patients with malignant lymphomas.

Data quality at the Cancer Registry of Norway: An overview of comparability, completeness, validity and timeliness

AimTo provide a comprehensive evaluation of the quality of the data collected on both solid and non-solid tumours at the Cancer Registry of Norway (CRN). MethodsEstablished quantitative and semi-quantitative methods were used to assess comparability, completeness, accuracy and timeliness of data for the period 1953–2005, with special attention to the registration period 2001–2005. ResultsThe CRN coding and classification system by and large follows international standards, with some further subdivisions of morphology groupings performed in-house. The overall completeness was estimated at 98.8% for the registration period 2001–2005. There remains a variable degree of under-reporting particularly for haematological malignancies (C90–95) and tumours of the central nervous system (C70–72). For the same period, 93.8% of the cases were morphologically verified (site-specific range: 60.0–99.8%). The under-reporting in 2005 due to timely publication is estimated at 2.2% overall, based on the number of cases received at the registry during the following year. ConclusionThis review suggests the routines in place at the CRN yields comparable data that can be considered reasonably accurate, close-to-complete and timely, thereby justifying our policy of the reporting of annual incidence one year after the year of diagnosis.

Hypermethylation of the ABCB1 downstream gene promoter accompanies ABCB1 gene amplification and increased expression in docetaxel-resistant MCF-7 breast tumor cells

Drug transporters have been implicated in resistance of solid and non-solid tumors to a variety of chemotherapeutic agents. Higher expression of the ABCB1 drug transporter is often observed in drug-resistant tumor cells, although the precise mechanism remains unclear. During selection of MCF-7 cells for survival in increasing concentrations of docetaxel (MCF-7TXT cells), we observed in this study a temporal correlation between the acquisition of docetaxel resistance at selection dose 9 and the increased expression of ABCB1. Both the magnitude of docetaxel resistance and the level of ABCB1 expression then rose as the selection dose was further elevated. We also observed through bisulfite sequencing experiments that the ABCB1 downstream promoter became increasingly methylated following the acquisition of drug resistance (selection doses 10-12). Transcription was solely attributed to the upstream ABCB1 promoter within MCF-7TXT cells at the highest selection dose suggesting that hypermethylation caused a shift in promoter usage. The hypermethylation was also accompanied by regional amplification of chromosome 7 containing the ABCB1 gene and its neighbor ABCB4 but not DBF-4. The amplification of the ABCB1 gene correlated positively both with the hypermethylation of the ABCB1 downstream promoter (r=0.90) and the increased expression of ABCB1 (r=0.78). Moreover demethylation of the ABCB1 downstream promoter induced by 5-aza-2Â’deoxycytidine treatment decreased the expression of ABCB1 mRNA in MCF-7TXT cells. Taken together, our findings suggest that the increased expression of ABCB1 upon acquisition of docetaxel resistance in breast tumor cells can be multifactorial, involving both epigenetic changes in promoter usage and regional chromosome amplification.

Comment on “Impact of recent intravenous chemotherapy on outcome in severe sepsis and septic shock patients with haematological malignancies” by Vandijck et al.

Dear Sir: We read with great interest the study by Vandijck et al., which demonstrated promising survival rates in adult cancer patients referred to the ICU with severe sepsis and septic shock [1]. Interestingly, in their study the administration of recent chemotherapy was not associated with an increased risk of death. This is contrast to ours and previous studies in pediatric oncology patients who required admission to a PICU [2, 3]. The most common indications for intensive care treatment in pediatric oncology patients are severe sepsis, septic shock, respiratory and cardiocirculatory failure, and neurologic complications [2, 4]. In our study in children with malignancies admitted to our PICU, six risk factors were significantly associated with non-survival: non-solid tumours (leukemia/lymphoma), failure of three or more organ systems, neutropenia, septic shock, mechanical ventilation, and inotropic medication [2]. The occurrence of neutropenia in our study was related to recent administration of chemotherapy. In contrast to the study by Vandijck et al. these data point to an increased susceptibility to severe complications in children with hematologic malignancies secondary to chemotherapyrelated toxicity. So, where do the differences between adult and pediatric oncology populations come from? Notwithstanding many differences between the two cohorts (age, physiology, variations in chemotherapeutic regimens, pharmacokinetics, tumor biology etc.), the results presented by Vandijck et al. are quite surprising, and are difficult to interpret from a pediatric oncology perspective. It is our understanding that hematologic malignancies are treated with highdose frontline chemotherapies, resulting in profound bone marrow suppression, rendering the individual child highly susceptible to invasive, systemic infections (bacterial, fungal, viral, etc.). This cascade may result in severe sepsis, septic shock, and catecholamine-refractory shock which in turn are associated with multiple organ dysfunctions. It has been demonstrated in numerous studies that the number of organ dysfunctions is directly related to outcome in children with cancer [2–5]. This finding seems applicable to adult cohorts as well, and it is reflected by a significant correlation between the SOFA score and 28-day mortality in the study by Vandijck et al. [1]. One possible factor contributing to differences between pediatric and adult cancer patients may be related to the use of high doses of corticosteroids for induction therapy in children with leukemia and lymphoma. However, irrespective of the differences between children and adults, the data presented in their study should encourage us to offer intensive care treatment to these high-risk patients based upon individual clinical assessment. To initiate effective treatment strategies, early consultation with the intensivist and prompt referral to the ICU/PICU if indicated is of paramount importance.

A novel thioredoxin reductase inhibitor inhibits cell growth and induces apoptosis in HL-60 and K562 cells

Human thioredoxin reductase (TrxR) system is associated with cancer cell growth and anti-apoptosis process. Effects of 1,2-[bis(1,2-benzisoselenazolone-3(2H)-ketone)]ethane (BBSKE), a novel TrxR inhibitor, were investigated on human leukemia cell lines HL-60 and K562. BBSKE treatment induced cell growth inhibition and apoptosis in both cell lines. Apoptosis induced by BBSKE is through Bcl-2/Bax and caspase-3 pathways. Ehrlich's ascites carcinoma-bearing mice were used to investigate the anti-tumor effect of BBSKE in vivo. Tumor-bearing mice treated with BBSKE showed an increase of life span with a comparable effect to cyclophosphamide (CTX). These results suggest a potential usage of BBSKE as a therapeutic agent against non-solid tumors.

Long-term follow-up study of a population-based 1996–1998 mass screening programme for lung cancer using mobile low-dose spiral computed tomography

Early diagnosis and treatment are important for improvement of the low survival rate of patients with lung cancer. The objective of this study was to evaluate the long-term survival rate of patients identified to have lung cancer by our population-based baseline and annual repeat low-radiation dose computed tomography (low-dose CT) screenings, conducted in 1996-1998. A total of 13,037 CT scans were obtained from 5480 subjects (2969 men, 2511 women) aged 40-74 years at the initial CT screening. Lung cancer was detected in 63 subjects (57 were detected by CT scans and underwent surgery; 1 was detected by sputum cytology and underwent surgery; 3 rejected treatment; and 2 were interval cases that developed symptoms prior to the next annual repeat CT screening). Follow-up study included review of medical records. Death certificates were examined to check for any deceased interval case among participants. Postoperative follow-up of the 50 survived patients ranged from 70 to 117 (median, 101) months. Eight patients died during follow-up (6 due to lung cancer from 20 to 67 months after surgery and 2 deaths unrelated to lung cancer, each 7 and 60 months following surgery). Three patients who rejected treatment died 14 months to 6 years after positive screening CT scans, and the 2 interval cases died at each 17 and 30 months, respectively, following negative screening CT scans. Survival was analysed in 59 patients with lung cancer detected by low-dose CT screening (excluding two patients; one was detected by sputum cytology and the other had mass lesion already noted on the chest radiograph of the previous year). The 10-year survival calculated by the Kaplan-Meier method was 83.1% (95% CI: 0.735-0.927) for death from all causes and 86.2% (95% CI: 0.773-0.951) for death from lung cancer. The survival rate was excellent for never-smokers, patients with BAC and adenocarcinoma/mixed types with non-solid CT density pattern, associated with Noguchi's type A or B and pathologic stage IA. A poorer prognosis was noted in smokers with adenocarcinomas/mixed types, associated with part-solid or solid CT density pattern and Noguchi's type C or D. All patients with non-solid tumours measuring 6-13.5mm at presentation are alive, patients with part-solid tumours, measuring 17mm or more, or solid tumours, measuring 13mm or more at presentation were associated with increased risk of lung cancer-related morbidity or mortality. The estimated rate of possible over-diagnosis was 13% in total and we failed to cure 17% of patients encountered in the programme. Low-dose CT screening substantially improves the 10-year survival for lung cancer with minimal use of invasive treatment procedures.

Brain tumour stem cells: possibilities of new therapeutic strategies

Cancers are composed of heterogeneous cell populations, including highly proliferative immature precursors and differentiated cells, which may belong to different lineages. Recent advances in stem cell research have demonstrated the existence of tumour-initiating, cancer stem cells (CSCs) in non-solid and solid tumours. These cells are defined as CSCs because they show functional properties that resemble those of their normal counterpart to a significant extent. This concept applies to CSCs from brain tumours and, particularly, to glioblastoma stem-like cells, which self-renew under clonal conditions and differentiate into neuron- and glia-like cells, and into aberrant cells, with mixed neuronal/astroglia phenotypes. Notably, across serial transplantation into immunodeficient mice, glioblastoma stem-like cells are able to form secondary tumours which are a phenocopy of the human disease. A significant effort is underway to identify both CSC-specific markers and the molecular mechanism that underpin the tumorigenic potential of these cells, for this will have a critical impact on the understanding of the origin of malignant brain tumour and the discovery of new and more specific therapeutic approaches. Lately, the authors have shown that some of the bone morphogenetic proteins can reduce the tumorigenic ability of CSCs in GBMs. This suggests that mechanisms regulating the physiology of normal brain stem cells may be still in place in their cancerous siblings and that this may lead to the development of cures that selectively target the population CSCs found in the patients' tumour mass.

Inhibitory effects of Gleditsia sinensis fruit extract on telomerase activity and oncogenic expression in human esophageal squamous cell carcinoma

Previous studies have shown that the anomalous fruit extract of Gleditsia sinensis (GSE) exhibited apoptotic properties in various solid and non-solid tumors in vitro. However, the inhibitory actions of GSE on oncogenic expression and telomerase activity in esophageal squamous cell carcinoma (ESCC) have not been studied before. In the present study, the anti-cancer effects of GSE were demonstrated in three ESCC cell lines (HKESC-1, HKESC-2 and SLMT-1) by MTS and anchorage-independent clongen-icity assays, expression studies on oncogenes at 11q13 (CCND1, INT2, FGF4 and EMS1) and real-time quantitative telomeric repeat amplification protocol assay to show the inhibitory effect of GSE on telomerase in ESCC. The means of MTS50 of GSE for the ESCC cell lines and non-tumor NIH 3T3 cells were 21 and 163 microg/ml respectively. The anchorage-independent clongenicity assay showed that SLMT-1 cells lost their colony-forming potential which was dose-dependent to GSE. Moreover, GSE demonstrated dose-dependent suppression on the expression of INT2, EMS1 and FGF4, and inhibition of telomerase activity in the ESCC cell lines. Our overall results thus provide the first evidence that the anti-cancer effects of GSE on ESCC involve the suppression of oncogenic expression and inhibition of telomerase activity. Our findings also offer a new opportunity for the future development of GSE as a novel anti-cancer agent for ESCC and possibly for other cancers.

Early increase in serum levels of the angiogenesis-inhibitor endostatin and of basic fibroblast growth factor in melanoma patients during disease progression

Increased serum levels of angiogenesis-related factors such as endostatin, vascular endothelial cell growth factor (VEGF) or basic fibroblast growth factor (bFGF) have been demonstrated for a variety of solid and nonsolid tumours. Therefore, these factors have been suggested as diagnostic and in some studies as prognostic tumour markers. The purpose of the present study was to investigate a possible correlation of endostatin, VEGF or bFGF serum levels with disease progression in melanoma. Especially, we compared these factors to the established melanoma marker S-100 B, which increases in advanced disease but often fails to indicate early metastatic spread to regional lymph nodes. Sera from 197 melanoma patients and 35 healthy controls were measured by enzyme-linked immunosorbent assay; 72 patients had primary tumours (American Joint Committee on Cancer stages I and II), 55 had regional lymph node metastasis (stage III) and 70 patients had distant organ metastasis (stage IV). Endostatin, VEGF and bFGF serum levels were significantly elevated in stage IV disease, compared with the control group. In stage III, endostatin and bFGF, but not VEGF or S-100 B, were significantly increased. However, follow-up of this patient group did not show a correlation with the future clinical course including time until progression or overall survival, arguing against a role of endostatin, VEGF or bFGF as prognostic markers. These data indicate that endostatin or bFGF might be useful as diagnostic markers for the early detection of locoregional metastasis.

Completing a Life: Comfort Level and Ease of Use of a CD-ROM Among Seriously III Patients

To evaluate use of a CD-ROM titled Completing a Life among patients diagnosed with serious illnesses for comfort level with content and ease of computer use. A prospective pilot study collected a convenience sample of 50 people diagnosed with life-limiting illnesses during a six-month period. The hematology/oncology department of a large healthcare system located in a metropolitan area in the midwestern United States. Convenience sample of 50 patients diagnosed with life-limiting illnesses. Of the patients enrolled (age range = 38-93 years), 72% were female, 68% were Caucasian, 50% were diagnosed with breast cancer or nonsolid tumors, and 40% were newly diagnosed. Subjects viewed the CD-ROM and completed pre- and post-intervention surveys. Comfort level with educational media, comfort level of information viewed, and areas of CD-ROM viewed compared to age and stage of illness. Ninety percent of patients reported that they were somewhat or very comfortable with the CD-ROM as a learning tool, and ease of use was rated at 98%. Patients' comfort level with the material increased from 76% to 90% after they viewed the CD-ROM. The pilot study suggests that the Completing a Life CD-ROM can be used with patients facing serious or life-limiting illnesses as an additional resource tool for information. Nurses typically provide the bulk of educational material for their patients. With limited resources available regarding management of life-limiting illnesses, this resource may provide an excellent addition to resources currently available.