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PubMed1986

Progress against cancer?

We assessed the overall progress against cancer during the years 1950 to 1982. In the United States, these years were associated with increases in the number of deaths from cancer, in the crude cancer-related mortality rate, in the age-adjusted mortality rate, and in both the crude and the age-adjusted incidence rates, whereas reported survival rates (crude and relative) for cancer patients also increased. In our view, the best single measure of progress against cancer is change in the age-adjusted mortality rate associated with all cancers combined in the total population. According to this measure, we are losing the war against cancer, notwithstanding progress against several uncommon forms of the disease, improvements in palliation, and extension of the productive years of life. A shift in research emphasis, from research on treatment to research on prevention, seems necessary if substantial progress against cancer is to be forthcoming.

Age Factors↗
PubMed1983

A monoclonal antibody-enzyme immunoassay for serum carcinoembryonic antigen with increased specificity for carcinomas.

A two-site monoclonal antibody-enzyme immunoassay (MEIA) for carcinoembryonic antigen (CEA) was developed that uses two monoclonal anti-CEA antibodies, which recognize two different epitopes in the peptide moiety of CEA. The assay was sensitive to 0.5 micrograms/liter and had a measuring range of 0.5-200 micrograms of CEA per liter. It was highly specific inasmuch as none of three known CEA-related substances, "nonspecific crossreacting antigens 1 and 2" (NCA-1 and NCA-2) and biliary glycoprotein I (BGP I), reacted in the assay. NCA-2 (meconium antigen) is very similar to CEA. None of five commercially available CEA assays were able to differentiate between CEA and NCA-2. With one exception (colon), normal tissue extracts did not react in the MEIA even when tested at very high concentrations. Sera from a total of 180 healthy individuals and patients with malignant and nonmalignant disease were analyzed for CEA levels by using the MEIA and in parallel a conventional radioimmunoassay. A significant increase in specificity for carcinomas was obtained with the MEIA. This was essentially due to a decrease of MEIA CEA values in sera from patients with nonmalignant disease. The CEA values in the group of carcinoma patients (colon, pancreas, lung, and breast) were the same in the two assays.

Antibodies, Monoclonal↗
PubMed1993

Antioncogenes and human cancer.

The antioncogenes, or tumor suppressor genes, as negative regulators of cell division, stand in contrast to oncogenes. For most human cancers, the more frequently mutated genes are the antioncogenes, the principal exception being the leukemias and lymphomas. Persons heterozygous for germ-line mutations in antioncogenes are strongly predisposed to one or more kinds of cancer, and most dominantly inherited cancer is attributable to such heterozygosity. Seven antioncogenes have been cloned through the study of these persons, and several others have been mapped. An eighth one was mapped and cloned through the investigation of tumors and is not yet known in hereditary form. Three dominantly inherited forms of cancer are not attributable to mutations in antioncogenes. The corresponding nonhereditary forms of most cancers generally reveal abnormalities of the same antioncogenes that are found in the hereditary forms but may also show additional ones. Some cancers, especially the embryonal tumors of children, have a small number of antioncogene mutations; some others, such as most sarcomas, have more, and the common carcinomas have the most, reflecting a hierarchy of controls over growth of stem cell populations. Still more members of this gene category remain to be mapped and cloned through the study of cancer families and of tumors. The genes that have been cloned act at diverse points in the signal transduction pathway in cells, from the outer cell membranes to sites of gene transcription, in some cases as negative regulators of oncogene expression.

Breast Neoplasms↗
PubMed1999

E1A sensitizes cells to tumor necrosis factor-induced apoptosis through inhibition of IkappaB kinases and nuclear factor kappaB activities.

The adenovirus E1A protein has been implicated in increasing cellular susceptibility to apoptosis induced by tumor necrosis factor (TNF); however, its mechanism of action is still unknown. Since activation of nuclear factor kappaB (NF-kappaB) has been shown to play an anti-apoptotic role in TNF-induced apoptosis, we examined apoptotic susceptibility and NF-kappaB activation induced by TNF in the E1A transfectants and their parental cells. Here, we reported that E1A inhibited activation of NF-kappaB and rendered cells more sensitive to TNF-induced apoptosis. We further showed that this inhibition was through suppression of IkappaB kinase (IKK) activity and IkappaB phosphorylation. Moreover, deletion of the p300 and Rb binding domains of E1A abolished its function in blocking IKK activity and IkappaB phosphorylation, suggesting that these domains are essential for the E1A function in down-regulating IKK activity and NF-kappaB signaling. However, the role of E1A in inhibiting IKK activity might be indirect. Nevertheless, our results suggest that inhibition of IKK activity by E1A is an important mechanism for the E1A-mediated sensitization of TNF-induced apoptosis.

Adenovirus E1A Proteins↗
PubMed2003

[Fluence-modulated radiotherapy with an optimization-integrated sequencer].

On the basis of two clinical cases, we present fluence-modulated radiotherapy with a sequencer integrated into the optimization of our treatment-planning software HYPERION. In each case, we achieved simple relations for the dependence of the total number of segments on the complexity of the sequencing, as well as for the dependence of the dose-distribution quality on the number of segments. For both clinical cases, it was possible to obtain treatment plans that complied with the clinical demands on dose distribution and number of segments. Also, compared to the widespread concept of equidistant steps, our method of sequencing with fluence steps of variable size led to a significant reduction of the number of segments, while maintaining the quality of the dose distribution. Our findings substantiate the value of the integration of the sequencer into the optimization for the clinical efficiency of IMRT.

Humans↗
PubMed2001

Prostatic MR imaging. Accuracy in differentiating cancer from other prostatic disorders.

PURPOSE: We assessed the accuracy of MR imaging in differentiating between cancer and other prostatic disorders, and evaluated the diagnostic criteria for various prostatic diseases. MATERIAL AND METHODS: A total of 74 endorectal coil MR studies were performed on 72 patients. Twenty patients had prostatic cancer, 20 benign prostatic hyperplasia (BPH), 4 acute bacterial prostatitis, 5 chronic bacterial prostatitis (2 also belonging to the previous category), 19 chronic non-bacterial prostatitis/chronic pelvic pain syndrome, and 6 were symptomless voluntary controls. All studies were interpreted by two experienced radiologists in random order. Radiologists were blinded to all clinical data including the age of the patients. Based on MR findings, both radiologists filled in a form covering diagnostic criteria and diagnosis. RESULTS: Accuracy in diagnosing prostate cancer was 74%. Sensitivity was 50% and specificity 83%, and positive and negative predictive values were 53 and 82%, respectively. Bacterial prostatitis showed some features similar to carcinoma. Abundant BPH rendered cancer detection more difficult. No diagnostic criterion was clearly better than the others. Interobserver agreement on the MR diagnosis ranged from moderate to good. CONCLUSION: Without knowledge of accurate clinical data, MR seems to be too insensitive in detecting prostate cancer to be used as a primary diagnostic tool.

Aged↗
PubMed2003

Costs of radiotherapy.

A systematic assessment of radiotherapy for cancer was conducted by The Swedish Council on Technology Assessment in Health Care (SBU) in 2001. The assessment included an overview of the capacity for radiotherapy in terms of infrastructure of cancer care and an estimation of the costs of radiotherapy in Sweden. A postal questionnaire distributed to all 16 centres of radiotherapy in Sweden showed the following results: In 2000 there were 57 accelerators with complementary equipment in operation, 24 of which had been installed 10 or more years ago earlier. The total cost of external radiation therapy was estimated at SEK 427 million in the year 2000, or approximately 5% of the estimated total cost of oncology care in Sweden. The total cost of brachytherapy was estimated at SEK 43 million or about one-tenth of that of external radiotherapy. The total cost of external radiotherapy has increased since the last inquiry (1991) by about 16% more than the general inflation in Sweden, but at the same time the volume of fractions has increased by about 37%. Thus, an increase in the efficiency of external radiotherapy, calculated per fraction, was achieved in the 1990s. At the department level, there was a clear correlation between cost of salaries and output of fractions of external radiotherapy, thus indicating the adaptation of manpower to the volume of patients. There was an even higher correlation between the number of accelerators and the volume of fractions of radiotherapy, which suggests the occurrence of certain economies of scale in Swedish external radiotherapy.

Aged↗
PubMedDate not supplied

Rat PSP94 inhibits the growth and viability of the rat adenocarcinoma cell line PAIII in vitro.

Previous studies have shown that human PSP94 can inhibit the growth of prostate cancer cells both in vitro and in vivo. To further validate this potential and investigate the protein within a homologous setting, we examined the effects of rat PSP94 on the growth of the rat prostate adenocarcinoma cell line PAIII in vitro. To generate rat PSP94, we used both a plasmid-based expression system and a recombinant rat PSP molecule. Rat PSP was shown to inhibit the growth and survival of PAIII cells in a dose-dependent manner with > 90 percent reductions in both observed. TUNEL and Annexin-V assays confirmed PAIII cell death to be via apoptosis.

Adenocarcinoma↗
PubMedDate not supplied

Medical diagnosis by high resolution NMR of human specimens.

NMR has progressed relatively recently from a technique used almost exclusively by chemists and physicists to a viable tool for medical diagnosis. NMR applications have developed from analysis of cells, tissues, and biological fluids, to in vivo analysis. We discuss some examples of its clinical successes, as well as some of the challenges encountered along the way.

Breast Neoplasms↗
PubMed2000

Constrained treatment planning using sequential beam selection.

In this paper an algorithm is described for automated treatment plan generation. The algorithm aims at delivery of the prescribed dose to the target volume without violation of constraints for target, organs at risk and the surrounding normal tissue. Pre-calculated dose distributions for all candidate orientations are used as input. Treatment beams are selected in a sequential way. A score function designed for beam selection is used for the simultaneous selection of beam orientations and weights. In order to determine the optimum choice for the orientation and the corresponding weight of each new beam, the score function is first redefined to account for the dose distribution of the previously selected beams. Addition of more beams to the plan is stopped when the target dose is reached or when no additional dose can be delivered without violating a constraint. In the latter case the score function is modified by importance factor changes to enforce better sparing of the organ with the limiting constraint and the algorithm is run again.

Algorithms↗
PubMed2001

A multiobjective gradient-based dose optimization algorithm for external beam conformal radiotherapy.

A multiobjective gradient-based algorithm has been developed for the purpose of dose distribution optimization in external beam conformal radiotherapy. This algorithm is based on the concept of gathering the values of all objectives into a single value. The weighting factors of the composite objective values are varied in different steps, allowing the reconstruction of the trade-off surfaces (three or more objectives) or curves (two objectives) which define the boundary between the feasible and non-feasible domain regions. The analysis of these curves allows the decision-maker to select the solution that best fits the clinical goals. In contrast to all the other algorithms, our method provides not a single solution but a sample of solutions representing all possible clinical importance factors (weights) for the objectives used. The application of this algorithm to two test cases shows that a correct selection for the importance factors to multiply the individual objectives in the global objective value is not trivial and that the location and shape of the boundary region between the feasible and non-feasible solution regions are case dependent. Provided that the individual objective functions are analytically differentiable and that the number of objectives is the range of two to three, the computation times are acceptable for clinical use. Furthermore, the optimization for a unique combination of importance factors within the aggregate objective function is performed in less than 1 min.

Algorithms↗
PubMed2002

Multiobjective anatomy-based dose optimization for HDR-brachytherapy with constraint free deterministic algorithms.

In high dose rate (HDR) brachytherapy, conventional dose optimization algorithms consider multiple objectives in the form of an aggregate function that transforms the multiobjective problem into a single-objective problem. As a result, there is a loss of information on the available alternative possible solutions. This method assumes that the treatment planner exactly understands the correlation between competing objectives and knows the physical constraints. This knowledge is provided by the Pareto trade-off set obtained by single-objective optimization algorithms with a repeated optimization with different importance vectors. A mapping technique avoids non-feasible solutions with negative dwell weights and allows the use of constraint free gradient-based deterministic algorithms. We compare various such algorithms and methods which could improve their performance. This finally allows us to generate a large number of solutions in a few minutes. We use objectives expressed in terms of dose variances obtained from a few hundred sampling points in the planning target volume (PTV) and in organs at risk (OAR). We compare two- to four-dimensional Pareto fronts obtained with the deterministic algorithms and with a fast-simulated annealing algorithm. For PTV-based objectives, due to the convex objective functions, the obtained solutions are global optimal. If OARs are included, then the solutions found are also global optimal, although local minima may be present as suggested.

Algorithms↗
PubMed2005

Optimization of intensity-modulated radiation therapy with biological objectives.

IMRT treatment planning via biological objectives gives rise to constrained nonlinear optimization problems. We consider formulations with nonlinear objectives based on the equivalent uniform dose (EUD), with bound constraints on the beamlet weights, and describe fast, flexible variants of the two-metric gradient-projection approach for solving them efficiently and in a mathematically sound manner. We conclude that an approach that calculates the Newton component of the step iteratively, by means of the conjugate-gradient algorithm and an implicit representation of the Hessian matrix, is most effective. We also present an efficient heuristic for obtaining an approximate solution with a smoother distribution of beamlet weights. The effectiveness of the methods is verified by testing on a medium-scale clinical case.

Algorithms↗
PubMed2001

Advancing perspectives on prostate cancer: multihormonal influences in pathogenesis.

Nonandrogenic hormones are implicated in the growth and function of the prostate, which is itself an endocrine gland that synthesizes and secretes hormones and growth factors, including follicle-stimulating hormone (FSH) and prostatic inhibin peptide (PIP). Findings of increased FSH concentrations and receptor expression in diseased prostate tissue suggest a role for FSH in prostate cancer growth. Not only does PIP suppress circulating levels of FSH, but it responds to and modulates prostatic FSH, suggesting a close interlinkage of these compounds in controlling both healthy and diseased prostate cells. Other focuses of endocrinologic research include androgen receptors, vitamin D, growth factors (including insulin-like growth factors I and II), and retinoids. Issues such as optimal therapy timing, intermittent administration, and the adoption of a multihormonal approach to the management of prostate cancer remain to be resolved.

Follicle Stimulating Hormone↗
PubMed1999

Tissue factor assays as diagnostic tools for cancer? Correlation between urinary and monocyte tissue factor activity.

Monocyte and urinary tissue factors (mTF and uTF) are both elevated in a number of pathologic conditions, including cancer. This study validates the best available uTF and mTF assays as diagnostic tools for cancer and examines if uTF levels reflect monocyte activation. Using kinetic chromogenic assays for uTF and mTF (measured on fresh resting cells [baseline], unstimulated cells, and lipopolysaccharide [LPS]-stimulated cells), we assessed TF levels in normal individuals, surgical controls, and patients with benign and malignant diseases. Each benign disease group was stratified as inflammatory or noninflammatory. Controls and benign noninflammatory results were indistinguishable. The malignant and inflammatory groups showed raised uTF levels over controls (p < 0.001). mTF levels differ similarly. For mTF and uTF assays, there was no significant difference between the malignant and inflammatory groups. The relative operating characteristic (ROC) curve plots sensitivity against false positive rate (1-specificity) for all possible cutoff values of a diagnostic test. Assay performance is assessed as the area under the curve (AUC). The ROC curve for the uTF assay displayed both sensitivity and specificity for cancer, the AUC being 0.83. Of the three mTF levels, LPS-stimulated cells gave the optimum curve (AUC = 0.71). uTF showed a weak to moderate association with mTF levels but correlated best and was statistically significant when compared with levels in the LPS-stimulated cells. uTF represents an intrinsic, kidney-derived, physiologic concentration rather than that of preactivated or postactivated monocytes. In conclusion, both uTF and LPS-stimulated mTF levels showed sensitivity and specificity in detecting cancer and inflammatory diseases. However, the two forms of TF appear to be independently derived.

Adolescent↗
PubMed1997

Molecular cloning and gene expression analysis of PSP94 (prostate secretory protein of 94 amino acids) in primates.

Prostate secretory protein of 94 amino acids (PSP94) has shown the potential to be a diagnostic biomarker and a therapeutic agent for prostate cancer. Primates have been the main animal models for studying the biology of this molecule. We have cloned and analyzed the cDNA and promoter region of PSP94 from baboon (Papio anubis). Sequence divergence among baboon, monkey, pig, and human, in both the exons and 5'-flanking region indicates rapid evolution of the PSP94 gene. There are conserved steroid hormone response elements (SHRE) in the promoter region of all three primate species. Multiple, alternative transcripts starting near these SHREs and upstream to the TATA box were identified by reverse transcriptase polymerase chain reaction (RT-PCR) and rapid amplification of 5'-cDNA ends (5' RACE) in primate prostatic tissues. This differential transcription initiation may be linked to androgen regulation of PSP94 gene expression. PSP94 transcripts were detected by RT-PCR in a wide variety of mucus-secreting tissues. However, the alternative transcripts were found only in the prostate. The distribution of the PSP94 protein in baboon secretory tissues was also examined by Western blot analysis using a polyclonal antibody against the human homolog. A positive immunoreactive band was detected, but it was weak, due probably to epitope divergence between the two species. In all young, healthy primate animals tested, the level of immunoreactive PSP94 in prostate tissues was lower than expected. In addition, RT-PCR combined with Southern blot analysis on prostate tissues in these animals failed to detect the PSP57 mRNA produced by alternative splicing of PSP94 primary transcript. These observations can be explained by the sexual immaturity and incomplete prostate development in these young primates. This explanation was supported by histological examination of their prostate during PSP94 immunohistochemistry.

Amino Acid Sequence↗