Mathematical Aspects of a New Synergy Theory Applicable to Malstressor-Dominated Mixtures which Include Damage-Ameliorating Countermeasures.

In radiobiology, and throughout translational biology, synergy theories for multi-component agent mixtures use 1-agent dose-effect relations (DERs) to calculate baseline neither synergy nor antagonism mixture DERs. The most used synergy theory, simple effect additivity, is not self-consistent when curvilinear 1-agent DERs are involved, and many alternatives have been suggested. In this paper we present the mathematical aspects of a new alternative, generalized Loewe additivity (GLA). To the best of our knowledge, generalized Loewe additivity is the only synergy theory that can systematically handle mixtures of agents that are malstressors (tend to produce disease) with countermeasures - agents that oppose malstressors and ameliorate malstressor damage. In practice countermeasures are often very important, so generalized Loewe additivity is potentially far-reaching. Our paper is a proof-of-principle preliminary study. Unfortunately, generalized Loewe additivity's scope is restricted, in various unwelcome but perhaps unavoidable ways. Our results illustrate its strengths and its weaknesses. One area where our methodology has potentially important applications is analyzing counter-measure mitigation of galactic cosmic ray damage to astronauts during interplanetary travel.

Hypo-fractionated boost in locally advanced non-small cell lung cancer: temporal distribution of boost fractions.

To propose new schemas for radiation boosting of primary tumors, in locally advanced non-small cell lung cancers (NSCLC), in conjunction with standard chemoradiotherapy. To investigate the effect of temporal distributions of the boost fractions on tumor control. NSCLC cases, previously treated with 60 Gy in 30 fractions, were retrospectively planned by adding a radiation boost (25 Gy in 5 fractions) to the primary tumor. Several integrated and sequential boosting schedules were considered. Biological doses were calculated for targets and organs at risk (OAR). Tumor control probabilities (TCP) were calculated using an empirical model and a stochastic model that accounts more systematically for tumor growth kinetics and cell kill. For heterogeneous patient populations, the TCPs for different boost schedules ranged from 82% to 84% and from 73% to 74% for integrated and sequential boosting respectively. For individual tumors with specific growth parameters, the TCP varied by up to 19% between the different schedules. The TCP for sequential boosting was expected to be up to 67% lower than front integrated boosting. The gap in TCP between schedules was higher for tumors with higher clonogenic cell numbers, lower radio-sensitivity, shorter doubling times and lower cell loss. The proposed boosting schemas are dosimetrically feasible and biologically effective. We suggest that the boosts are most effective when given during the first week of treatment and least effective when given sequentially after the end of treatment. The effect of boost scheduling and the effectiveness of front boosting are expected to be most significant for tumors with high clonogenic cell numbers, fast growing rates, low cell loss and low radio-sensitivity. Ultimately, animal studies and clinical trials, guided by biology modeling as presented in the present work, will be needed to verify the effectiveness of fine tuning temporal distributions of radiotherapy fractions.

Defining AML and MDS second cancer risk dynamics after diagnoses of first cancers treated or not with radiation.

Risks of acute myeloid leukemia (AML) and/or myelodysplastic syndromes (MDS) are known to increase after cancer treatments. Their rise-and-fall dynamics and their associations with radiation have, however, not been fully characterized. To improve risk definition we developed SEERaBomb R software for Surveillance, Epidemiology and End Results second cancer analyses. Resulting high-resolution relative risk (RR) time courses were compared, where possible, to results of A-bomb survivor analyses. We found: (1) persons with prostate cancer receiving radiation therapy have increased RR of AML and MDS that peak in 1.5-2.5 years; (2) persons with non-Hodgkin lymphoma (NHL), lung and breast first cancers have the highest RR for AML and MDS over the next 1-12 years. These increased RR are radiation specific for lung and breast cancer but not for NHL; (3) AML latencies were brief compared to those of A-bomb survivors; and (4) there was a marked excess risk of acute promyelocytic leukemia in persons receiving radiation therapy. Knowing the type of first cancer, if it was treated with radiation, the interval from first cancer diagnosis to developing AML or MDS, and the type of AML, can improve estimates of whether AML or MDS cases developing in this setting are due to background versus other processes.

Biological effects of proton radiation: an update.

Proton radiation provides significant dosimetric advantages when compared with gamma radiation due to its superior energy deposition characteristics. Although the physical aspects of proton radiobiology are well understood, biological and clinical endpoints are understudied. The current practice to assume the relative biological effectiveness of low linear energy transfer (LET) protons to be a generic value of about 1.1 relative to photons likely obscures important unrecognised differentials in biological response between these radiation qualities. A deeper understanding of the biological properties induced by proton radiation would have both radiobiological and clinical impact. This article briefly points to some of the literature pertinent to the effects of protons on tissue-level processes that modify disease progression, such as angiogenesis, cell invasion and cancer metastasis. Recent findings hint that proton radiation may, in addition to offering improved radio-therapeutic targeting, be a means to provide a new dimension for increasing therapeutic benefits for patients by manipulating these tissue-level processes.

Radiation-induced cancer: a modern view.

Diagnostic medical radiation has been the most rapidly increasing component of population background radiation exposure in Western countries over the past decade. This trend is set to increase as CT scanning is readily available with burgeoning use in everyday clinical practice. Consequently, the issue of cancer induction from the doses received during diagnostic medical exposures is highly relevant. In this review we explain current understanding of potential cancer induction at low doses of sparsely ionising radiation. For cancers that may be induced at low doses, a mechanistic description of radiation-induced cancer is discussed, which, in combination with extrapolation of data based on population cohort studies, provides the basis of the currently accepted linear no-threshold model. We explore the assumptions made in deriving risk estimates, the controversies surrounding the linear no-threshold model and the potential future challenges facing clinicians and policy-makers with regards to diagnostic medical radiation and cancer risk, most notably the uncertainties regarding deriving risk estimates from epidemiological data at low doses.

A new view of radiation-induced cancer.

Biologically motivated mathematical models are important for understanding the mechanisms of radiation-induced carcinogenesis. Existing models fall into two categories: (1) short-term formalisms, which focus on the processes taking place during and shortly after irradiation (effects of dose, radiation quality, dose rate and fractionation), and (2) long-term formalisms, which track background cancer risks throughout the entire lifetime (effects of age at exposure and time since exposure) but make relatively simplistic assumptions about radiation effects. Grafting long-term mechanisms on to short-term models is badly needed for modelling radiogenic cancer. A combined formalism was developed and applied to cancer risk data in atomic bomb survivors and radiotherapy patients and to background cancer incidence. The data for nine cancer types were described adequately with a set of biologically meaningful parameters for each cancer. These results suggest that the combined short-long-term approach is a potentially promising method for predicting radiogenic cancer risks and interpreting the underlying biological mechanisms.

B-type natriuretic peptide, a marker of asymptomatic left ventricular dysfunction in type 2 diabetic patients.

AIM: To evaluate BNP in assessing LV functions in asymptomatic type 2 diabetic patients. METHODS: BNP was measured in 91 consecutive patients with type 2 diabetes mellitus. According to Doppler echocardiography, patients were first separated into three categories: normal LV function, or isolated diastolic or systolic LV dysfunction. As some patients with diastolic dysfunction were treated for hypertension, the population was divided into four groups: groups 1, 2 and 3 all had no antihypertensive treatment, and had normal LV function, and isolated diastolic and systolic LV dysfunction, respectively; and group 4 were being treated with antihypertensive drugs and had diastolic LV dysfunction. RESULTS: In group 1, BNP levels (13+/-2 ng/L) were lower than in group 2 (87+/-20 ng/L, P<0.0001) or group 3 (213+/-32 ng/L, P<0.0001), but were similar to those of group 4 (32+/-6 ng/L, P=0.14). ROC analysis revealed a rule-out value of 23 ng/L for group 1 versus group 2, and of 239 ng/L for group 2 versus group 3. In groups 1, 2 and 3 taken together, BNP levels were correlated with urinary albumin excretion rate (r=0.80, P<0.0001) and pulse pressure (r=0.65, P<0.0001). In group 4, patients receiving ACE inhibitors had lower BNP levels than those receiving ss-blockers. CONCLUSION: BNP can be used to pre-screen asymptomatic type 2 diabetic patients with LV dysfunction, and may reveal vascular remodelling in type 2 diabetes mellitus.

What can we learn about patient safety from information sources within an acute hospital: a step on the ladder of integrated risk management?

OBJECTIVE: To assess the utility of data already existing within hospitals for monitoring patient safety. SETTING: An acute hospital in southern England. DESIGN: Mapping of data sources proposed by staff as potentially able to identify patient safety issues followed by an in-depth analysis of the content of seven key sources. Data source analysis: For each data source: scope and depth of content in relation to patient safety, number and type of patient safety incidents identified, degree of overlap with incidents identified by different sources, levels of patient harm associated with incidents. RESULTS: A wide range of data sources existing within the hospital setting have the potential to provide information about patient safety incidents. Poor quality of coding, delays in reports reaching databases, the narrow focus of some data sources, limited data-collection periods and lack of central collation of findings were some of the barriers to making the best use of routine data sources for monitoring patient safety. An in-depth analysis of seven key data sources (Clinical Incident database, Health and Safety Incident database, Complaints database, Claims database and Inquest database, the Patient Administration System and case notes) indicated that case notes have the potential to identify the largest number of incidents and provide the richest source of information on such incidents. The seven data sources identified different types of incidents with differing levels of patient harm. There was little overlap between the incidents identified by different sources. CONCLUSION: Despite issues related to the quality of coding, depth of information available and accessibility, triangulating information from more than one source can identify a broader range of incidents and provide additional information related to professional groups involved, types of patients affected and important contributory factors. Such an approach can provide a focus for further work and ultimately contributes to the identification of appropriate interventions that improve patient safety.

Full-color painting reveals an excess of radiation-induced dicentrics involving homologous chromosomes.

PURPOSE: To determine the ratio of homologous to heterologous dicentric chromosomes induced in human cells by ionizing radiation. This ratio is influenced by, and thus potentially informative about, underlying DNA damage/repair/misrepair processes and also the geometry of individual chromosome domains within the interphase nucleus. MATERIALS AND METHODS: 24-color mFISH (multiplex fluorescent in situ hybridization) was used to determine the ratio of 1-color (homologous) to 2-color (heterologous) dicentrics produced in human lymphocytes or fibroblasts by gamma-rays, alpha particles, or iron ions at various doses. Assuming that randomness independent of homology holds, the expected homologue:heterologue ratio for diploid human male cells is approximately 0.024, as shown by deriving a formula applicable to simple interchanges and then extending the result, via Monte Carlo simulation, to the general situation where complex aberrations are also considered. RESULTS AND CONCLUSIONS: There was a substantial excess of homologous dicentrics, with probability of occurrence by chance less than 0.02 for each of the three radiations and only about 10(-8) for all the data combined. Overall, approximately 18 homologous dicentrics were expected but 47 were found, including 11 involving chromosome 1. Observed excesses were similar for both sparsely and densely ionizing radiations. Geometric proximity of homologues is a possible explanation for the overabundance; in that case more extensive statistics should eventually uncover a linear energy transfer (LET) dependence. An alternative possibility, not ruled out by the present data, is homology-dependent misrepair.

Chromosome spatial clustering inferred from radiogenic aberrations.

PURPOSE: Analysing chromosome aberrations induced by low linear energy transfer (LET) radiation in order to characterize systematic spatial clustering among the 22 human autosomes in human lymphocytes and to compare their relative participation in interchanges. MATERIALS AND METHODS: A multicolour fluorescence in situ hybridization (mFISH) data set, specifying colour junctions in metaphases of human peripheral blood lymphocytes 72 h after in vitro exposure to low LET radiation, was analysed separately and in combination with previously published results. Monte Carlo computer simulations and mathematical modelling guided data analysis. RESULTS AND CONCLUSIONS: Statistical tests on aberration data confirmed two clusters of chromosomes, [1, 16, 17, 19, 22] and [13, 14, 15, 21, 22], as having their members being on average closer to each other than randomness would predict. The first set has been reported previously to be near the centre of the interphase nucleus and to be formed mainly by gene-rich chromosomes, while the second set comprises the nucleolus chromosomes. The results suggest a possible interplay between chromosome positioning and transcription. A number of other clusters suggested in the literature were not confirmed and considerable randomness of chromosome-chromosome juxtapositions was present. In addition, and consistent with previous results, it was found that chromosome participation in interchanges is approximately proportional to the two-thirds power of the DNA content.

Quantitative analysis of radiation-induced chromosome aberrations.

We review chromosome aberration modeling and its applications, especially to biodosimetry and to characterizing chromosome geometry. Standard results on aberration formation pathways, randomness, dose-response, proximity effects, transmissibility, kinetics, and relations to other radiobiological endpoints are summarized. We also outline recent work on graph-theoretical descriptions of aberrations, Monte-Carlo computer simulations of aberration spectra, software for quantifying aberration complexity, and systematic links of apparently incomplete with complete or truly incomplete aberrations.

Analysis of alpha-particle induced chromosome aberrations in human lymphocytes, using pan-centromeric and pan-telomeric probes.

PURPOSE: The aim of the present study has been the evaluation of the incomplete chromosome aberrations induced after alpha-particle irradiation by the simultaneous detection of all centromeres and telomeres present in human lymphocytes. Moreover, a study on the lengths of the different acentric fragments is presented. MATERIALS AND METHODS: Attached lymphocytes were irradiated at doses of 0.2, 0.5, 0.7 and 1 Gy using a 241Am source. Flourescent in-situ hybridization (FISH) techniques were applied using pan-centromeric and pan-telomeric probes. All abnormal cells were digitalised and analysed using a Cytovision FISH workstation. The description of all abnormalities observed, and the length of the acentric fragments was recorded. RESULTS: A total of 378 incomplete chromosomes plus incomplete acentrics was found. Cases with more than 92 telomeres were not detected. The ratio between total incomplete elements and multicentrics was 1.00. The total number of acentric (ace) fragments was 822; 57% of them were complete fragments ace (+,+), 26% incomplete fragments ace (+,-), and 17% interstitial fragments ace(-,-); the mean relative lengths were 2.91 +/- 0.06, 1.91 +/- 0.07 and 1.63 +/- 0.07, respectively. In all three cases a secondary peak in the length distribution was found, corresponding to a relative length between 3.5 and 4. CONCLUSION: The percentage of incomplete rejoinings is higher after alpha-particle exposure than that described previously for low-linear energy transfer (LET) radiation exposures. The results seem to indicate that compared to low-LET radiation, after alpha-particle exposure centromere-containing elements are more likely to be repaired.Many interstitial fragments are large linear forms that cannot be considered as non-distinguishable acentric rings.

Mode calculations for a terahertz quantum cascade laser.

We calculate the loss and confinement factors of modes in terahertz quantum cascade laser structures at frequencies of 1-4 THz. The determination of the total loss splits naturally into the calculation of free carrier losses in the active region and the waveguide losses. For both, we employ the Drude model. In the case of waveguide losses, we incorporate it into the formalism of the optical scattering matrix and trace the net threshold gain for laser operation in the waveguide for various frequencies as a function of thickness and doping of the buried contact layer. The results indicate that at lower frequencies and high doping, the preferred mode switches character from extended to tightly confined. This may have consequences for the creation of simplified longer-wavelength devices.

Domestic radon risks may be dominated by bystander effects--but the risks are unlikely to be greater than we thought.

Radon risks derive from exposure of bronchio-epithelial cells to alpha particles. Alpha-particle exposure can result in bystander effects when irradiated cells emit signals resulting in damage to nearby unirradiated bystander cells. Bystander effects can cause downwardly-curving dose-response relations and inverse dose-rate effects. We have extended a quantitative mechanistic model of bystander effects to include protracted exposure, with inverse dose-rate effects attributed to replenishment, during exposure, of a subpopulation of cells which are hypersensitive to bystander signals. In this approach, bystander effects and the inverse dose-rate effect are manifestations of the same basic phenomenon. The model was fitted to dose- and dose-rate dependent radon-exposed miner data; the results suggest that one directly-hit target cell can send bystander signals to about 50 neighboring cells and that, in the case of domestic radon exposures, the risk could be dominated by bystander effects. The analysis concludes that a naive linear extrapolation of radon miner data to low doses, without accounting for dose rate/bystander effects, would result in an underestimation of domestic radon risks by about a factor of approximately 4. However, recent domestic radon risk estimates (BEIR VI) have already applied a phenomenological correction factor of approximately 4 for inverse dose-rate effects, and have thus already implicitly taken into account corrections which we here suggest are due to bystander effects. Thus current domestic radon risk estimates are unlikely to be underestimates as a result of bystander effects.

Do low dose-rate bystander effects influence domestic radon risks?

PURPOSE: Radon risks derive from exposure of bronchio-epithelial cells to high-linear energy transfer (LET) alpha-particles. alpha-particle exposure can result in bystander effects, where irradiated cells emit signals resulting in damage to nearby unirradiated bystander cells. This can result in non-linear dose-response relations, and inverse dose-rate effects. Domestic radon risk estimates are currently extrapolated from miner data, which are at both higher doses and higher dose-rates, so bystander effects on unhit cells could play a large role in the extrapolation of risks from mines to homes. Therefore, we extend an earlier quantitative mechanistic model of bystander effects to include protracted exposure, with the aim of quantifying the significance of the bystander effect for very prolonged exposures. MATERIALS AND METHODS: A model of high-LET bystander effects, originally developed to analyse oncogenic transformation in vitro, is extended to low dose-rates. The model considers radiation response as a superposition of bystander and linear direct e It attributes bystander effects to a small subpopulation of hypersensitive cells, with the bystander contribution dominating the direct contribution at very low acute doses but saturating as the dose increases. Inverse dose-rate effects are attributed to the replenishment of the hypersensitive subpopulation during prolonged irradiation. RESULTS: The model was fitted to dose- and dose-rate-dependent radon-exposed miner data, suggesting that one directly hit target bronchio-epithelial cell can send bystander signals to about 50 neighbouring target cells. The model suggests that a naïve linear extrapolation of radon miner data to low doses, without accounting for dose-rate, would result in an underestimation of domestic radon risks by about a factor of 4, a value comparable with the empirical estimate applied in the recent BEIR-VI report on radon risk estimation. CONCLUSIONS: Bystander effects represent a plausible quantitative and mechanistic explanation of inverse dose-rate effects by high-LET radiation, resulting in non-linear dose-response relations and a complex interplay between the effects of dose and exposure time. The model presented provides a potential mechanistic underpinning for the empirical exposure-time correction factors applied in the recent BEIR-VI for domestic radon risk estimation.

Integrated care pathways: outcome from inpatient rehabilitation following nontraumatic spinal cord lesion.

BACKGROUND: Integrated care pathways (ICPs) map the predicted course of an episode of patient care. They detail the expected interventions during the episode and document departures from the expected pathway (variance). This study describes the use of an ICP to audit the rehabilitation of patients with nontraumatic spinal cord injury admitted between 1997 and 1999. METHODS: The ICPs and outcomes of 85 patients with nontraumatic spinal cord injury admitted to the Neurorehabilitation Unit at the National Hospital for Neurology and Neurosurgery, Queen Square, London were analysed. Data extracted included diagnosis, level of the lesion and duration of stay. The numbers and categories of goals and the rates of goal achievement were extracted and the variance patterns analysed. RESULTS: An average of 28 patients were admitted each year. The level of disability on admission and the duration of stay decreased over the three-year period, while the average patient age increased from 48 to 54 years. None of these changes were statistically significant. On average each patient had three new goals set each week. Ninety per cent of all goals were achieved; this was not dependent on the category of goal. Sixteen patients (19%) accounted for 58% of all nonachieved goals. These patients tended to have acute-onset disability. The number of variances fell from 15 to 7 over the three-year period. CONCLUSIONS: The pathway enables monitoring of the rehabilitation process. As the Unit becomes more experienced there is a trend to shorter, more focused admissions with fewer variances. Specific groups of patients with particular needs can be identified. Future patients benefit from closure of the 'audit loop' and the implementation of clinical change based on information obtained from the ICP.

[Patient information and the cardiologist]. / L'information du patient et le cardiologue.

AIM OF THE STUDY: The patient's information prior to paraclinical testings is a part of the medical deontology and takes on increasing legal importance since new laws. METHODS: From December 2001 to January 2002, we administered to cardiologists through the website of the French Society of Cardiology a questionnaire in order to determine the way the information is dispensed to patients and to compare the results to the survey performed in 2000. RESULTS: Among the 293 answers obtained, 243 were utilizable. The answers were obtained from cardiologists working on private medicine (27.5%), public medicine (52.8%) or mixed (19.7%). Information was more frequently dispensed for invasive procedures: coronary angiography (92.2%), cardiac pacing (76.8%) than non invasive assessments: transesophageal echocardiography (47.6%) and treadmill test (44.7%). The most frequent information document given to patients was the one edited by the French Society of Cardiology (71.6%). In the great majority of cases, there is the prescribing cardiologist (35.9%) and/or the one performing the assessment who dispenses the information, generally the day prior the examination (73.5%) with additive explanations (91.4%). Few patients refuse the examination after information. The situation where the assessment is performed on a patient without the faculty of understanding modalities and the necessity of that examination is in emergency (45%). In 63.4% of cases, the cardiologist requires the patients signature on the information document. CONCLUSION: Information dispensation prior to an examination is generally well done by cardiologists. The evidence of the information's dispensation is not at ease and most of cardiologists require written document from their patients, which is not legally necessary.

Computer analysis of mFISH chromosome aberration data uncovers an excess of very complicated metaphases.

PURPOSE: To analyse spectra of chromosome aberrations induced in vitro by low LET radiation, in order to characterize radiation damage mechanisms quantitatively. METHODS: Multiplex fluorescence in situ hybridization (mFISH) allows the simultaneous identification of each homologous chromosome pair by its own colour. mFISH data, specifying number distributions for colour junctions in metaphases of human peripheral blood lymphocytes 72 hours after exposure in vitro to a 3 Gy gamma-ray dose, were combined with similar, previously published results. Monte Carlo computer implementations of radiobiological models for chromosome aberration production guided quantitative analyses, which took into account distribution of cells among different metaphases and lethal effects or preferential elimination of some aberrations at cell division. RESULTS AND CONCLUSIONS: Standard models of DNA damage induction/repair/misrepair explain the main trends of the data as regards the fraction of metaphases having a particular number of colours involved in colour junctions. However, all standard models systematically under-predict the observed fraction of metaphases where a large number of different chromosomes participate in aberrations. An early appearance of chromosomal instability could explain most of the discrepancies.

Testicular metastasis from ileal carcinoid: report of a case.

PURPOSE: This report presents a patient with testicular metastasis from an ileal carcinoid. METHODS: This was a retrospective case review with literature review. RESULTS: The patient underwent right orchiectomy for a solid mass. Pathology revealed carcinoid tumor. Octreotide scan showed increased concentration in the right lower quadrant of the abdomen. Computerized tomography results were negative. Colonoscopy with biopsy revealed carcinoid of the terminal ileum. The patient underwent an elective resection of the terminal ileum and the right colon. Pathology revealed carcinoid tumor with vascular and lymphatic invasion present, and eight lymph nodes were positive. The patient had adjuvant treatment with octreotide. CONCLUSION: Carcinoid tumors have been reported to metastasize to numerous areas. This is the first report of testicular metastasis from ileal carcinoid. Primary carcinoids of the testicle have been reported also. The clinician should be aware of this rare metastatic event. When pathology reveals carcinoid of the testicle, metastatic disease should be excluded before the tumor is identified as primary.