The assessment and management of risks associated with exposures to short-range Auger- and beta-emitting radionuclides. State of the art and proposals for lines of research.

The assessment and management of risks associated with exposures to ionising radiation are defined by the general radiological protection system, proposed by the International Commission on Radiological Protection (ICRP). This system is regarded by a large majority of users as a robust system although there are a number of dissenting voices, claiming that it is not suitable for estimating the risks resulting from internal exposures. One of the specific issues of internal exposure involves short-range radiations such as Auger and beta particles. Auger- and beta-emitting radionuclides can be distributed preferentially in certain tissue structures and even in certain cellular organelles, according to their chemical nature and the vector with which they are associated. Given the limited range of the low-energy electrons in biological matter, this heterogeneous distribution can generate highly localised energy depositions and exacerbate radiotoxic responses at cellular level. These particularities in energy distribution and cellular responses are not taken into account by the conventional methods for the assessment of risk.Alternative systems have been proposed, based on dosimetry conducted at the cellular or even molecular level, whose purpose is to determine the energy deposition occurring within the DNA molecule. However, calculation of absorbed doses at the molecular level is not sufficient to ensure a better assessment of the risks incurred. Favouring such a microdosimetric approach for the risk assessments would require a comprehensive knowledge of the biological targets of radiation, the dose-response relationships at the various levels of organisation, and the mechanisms leading from cellular energy deposition to the appearance of a health detriment. The required knowledge is not fully available today and it is not yet possible to link an intracellular energy deposition to a probability of occurrence of health effects or to use methods based on cellular dosimetry directly.The imperfections of the alternative approaches proposed so far should not discourage efforts. Protection against exposure to Auger and low-energy beta emitters would benefit from mechanistic studies, dedicated to the study of energy depositions of the radionuclides in various cellular structures, but also from radiotoxicological studies to define the relative biological effectiveness of the various Auger emitters used in medicine and of certain low-energy beta emitters, whose behaviour may depend greatly on their chemical form during intake. The scientific expertise, as well as the human and physical resources needed to conduct these studies, is available. They could be now mobilised into international low-dose research programmes, in order to ultimately improve the protection of people exposed to these specific radionuclides.

The 15-Country Collaborative Study of Cancer Risk among Radiation Workers in the Nuclear Industry: estimates of radiation-related cancer risks.

A 15-Country collaborative cohort study was conducted to provide direct estimates of cancer risk following protracted low doses of ionizing radiation. Analyses included 407,391 nuclear industry workers monitored individually for external radiation and 5.2 million person-years of follow-up. A significant association was seen between radiation dose and all-cause mortality [excess relative risk (ERR) 0.42 per Sv, 90% CI 0.07, 0.79; 18,993 deaths]. This was mainly attributable to a dose-related increase in all cancer mortality (ERR/Sv 0.97, 90% CI 0.28, 1.77; 5233 deaths). Among 31 specific types of malignancies studied, a significant association was found for lung cancer (ERR/Sv 1.86, 90% CI 0.49, 3.63; 1457 deaths) and a borderline significant (P = 0.06) association for multiple myeloma (ERR/Sv 6.15, 90% CI <0, 20.6; 83 deaths) and ill-defined and secondary cancers (ERR/Sv 1.96, 90% CI -0.26, 5.90; 328 deaths). Stratification on duration of employment had a large effect on the ERR/Sv, reflecting a strong healthy worker survivor effect in these cohorts. This is the largest analytical epidemiological study of the effects of low-dose protracted exposures to ionizing radiation to date. Further studies will be important to better assess the role of tobacco and other occupational exposures in our risk estimates.

Long term retention and excretion of 201Tl in a patient after myocardial perfusion imaging.

201Tl is widely used in nuclear medicine to carry out myocardial perfusion imaging (MPI). However, very limited data is available on long-term distribution in the body, excretion and corresponding dose. In this study we performed a 2 month follow-up of a patient who underwent MPI, by urine analysis and in vivo measurements. The biological half-life of thallium was consequently estimated to be 11.6-27 d, which is in partial agreement with previous studies. We also estimated excretion and retention of 200Tl, 201Tl and 202Tl isotopes using the biokinetic parameters from ICRP publication 53 and compared the forecast result with actual measurements. The latter demonstrated a higher urinary excretion and a higher body retention than what was expected. Our results therefore suggest that the long-term retention and consequently the effective dose coefficient for 201Tl considered in ICRP publications 53 and 80 may be slightly underestimated.

[Survival and disease progression in 251 patients with HIV-1 infection. Study of p24 antigen and viral burden as prognosis makers. Their value at 4 years of follow-up]. / Supervivencia y progresión de la enfermedad en 251 pacientes con infección por el VIH-1. Estudio del antígeno p24 y de la carga viral como marcadores pronóstico. Su valor a los 4 años de seguimiento.

BACKGROUND: Prospective study of survival and AIDS or death progression in a cohort of 251 HIV infected patients whose seroconversion time is unknown, with a main objective: To analyse p24 antigen plasmatic levels and viral load as surrogate markers. PATIENTS: 251 patients were included, most of them undergoing antiretroviral therapy, and were followed-up consecutively in the HIV/AIDS Unity of Internal Medicine Service of the Hospital Universitario Arnau de Vilanova in Lleida. METHODS: We made clinical and analytical baseline studies and every 3 months thereafter. Related to p24 antigen 3 group were established: group I, < 20 pg/mL, group 2, 20-39 pg/mL, group 3, 40 or more pg/mL. We studied survival and progression according to baseline levels over 4 year period. Regard to viral load, we just compared this with p24 antigen in the last phase of the study (third and fourth year) for technical reasons. Survival analysis was made by Kaplan-Meier estimation. Relative risk was calculated by Cox's proportional hazards model. RESULTS: During the 48 months of follow-up 55 patients died. AIDS progression risk or death was 4.8 times higher for the p24 antigen > = 40 pg/mL group than for the p24 antigen < 20 pg/mL one; the relative risk of patients with p24 antigen between 20-39 pg/mL was 2.5 times higher than those included in the group of p24 antigen < 20 pg/mL. Related to progression study, 34 patients progressed. AIDS progression risk or death for p24 antigen > = 40 pg/mL group was 7.69 times higher compared with group 2 (p24 antigen levels between 20-39 pg/mL). The comparison with viral load by PCR determination shows controversial results. CONCLUSIONS: p24 antigen plasma level is a good survival and AIDS progress or death surrogate markers in HIV infected patients, and it is useful for 4 years or more. An isolated value < 20 pg/mL is a sign of good prognosis. Parallelism between p24 antigen plasmatic level and viral load has not been observed.

[The prognostic markers of HIV infection progression. A study of the p24 antigen in a cohort of 251 patients]. / Marcadores pronóstico de progresión en la infección por VIH. Estudio del antígeno p24 en una cohorte de 251 pacientes.

BACKGROUND: Prospective study of AIDS or death progression in a cohort of 251 HIV infected patients whose time of seroconversion is unknown, with 2 main objectives: 1. To analyse plasma level p24 antigen as a marker of progression. 2. To evaluate stability of plasma levels of p24 antigen as a marker of progression. PATIENTS AND METHODS: 251 patients were studied, most on antiretroviral therapy, who were attended at HIV/AIDS Unit of Internal Medicine Service of the Hospital Universitario Arnau de Vilanova de Lleida. Mean initial CD4 cell count were 376 x 10(6)/L (range: 0.8-1350) 51 cases had been diagnosed previously with AIDS, their were therefore excluded. Analysis of survival, according to initial plasma p24 antigen and Cd4 cell count as well as the stability of plasma level p24 antigen was performed by Kaplan-Meier test. Relative risk were calculate by Cox's proportional hazard model. RESULTS: During a follow-up period of 24 months, 38 patients progressed to AIDS or died. Relative risk (RR) of progression to AIDS or death related to the group with p24 antigen < 40 pg/ml was 5.48 when p24 antigen => 40 pg/ml (p < 0.0005). Relative risk of progression to AIDS or death for the patients with unstable plasmatic level of p24 antigen related to the group with stable plasmatic level was 4.25 (p < 0.0005). CONCLUSIONS: Plasma level and stability of p24 antigen are useful as a markers of risk of AIDS progression or death and they behaves as an independent prognostic markers in our patients. p24 antigen < 40 pg/ml is associated with a better prognosis.

[Value of quantification of p24 antigen in plasma as a prognostic marker of survival in a cohort of 251 HIV-positive patients]. / Valor de la cuantificacion plasmática del antígeno p24 como marcador pronóstico de supervivencia en una cohorte de 251 pacientes VIH +.

OBJECTIVE: To analyse plasma p24 antigen as a marker of survival in a cohort of HIV-infected patients whose time of seroconversion is unknown. DESIGN: Prospective cohort study. SETTING: AIDS Unit in a teaching hospital. PATIENTS: 251 patients were studied, most on antiretroviral therapy. Mean initial CD4 cell counts were 376 x 106/ 1 (range: 0.8-1350). 51 cases had been diagnosed previously with AIDS. METHODS: Analysis of survival, according to initial plasma p24 antigen was performed by Kaplan-Meier test. Relative risks were calculated by Cox's proportional hazards model. RESULTS: During a follow-up period of 24 months, 46 patients died. Relative risk (RR) of death related to the group with p24 antigen = < 40 pg/ml was 3.32 when p24 antigen > 40 pg/ml (p = 0.0001). CD4+ cell levels adjusting, the result was 2.47 (CI 95% 1.37-4.46) (p = 0.0027). CONCLUSIONS: Plasma levels of p24 antigen is useful as a marker of the risk of death and it behaves as a independent prognostic marker in our patients. P24 antigen = < 40 pg/ml is associated with a better prognosis.

[The prognostic markers of survival and progression in HIV-1 infection. A study of CD4+ lymphocytes, antigen p24 and viral load during 3 years in a cohort of 251 patients]. / Marcadores pronóstico de supervivencia y de progresión en la infección por el VIH-1. Estudio de linfocitos CD4+, antígeno p24 y carga viral durante 3 años en una cohorte de 251 pacientes.

BACKGROUND: Prospective study of survival and AIDS or death progression in a cohort of 251 HIV infected patients whose seroconversion time is unknown, with 1 main objective: To analyse CD4+ lymphocytes count, p24 antigen plasmatic levels and viral load as surrogate markers. PATIENTS AND METHODS: 251 patients were included, most of them undergoing antiretroviral therapy, followed consecutively in the HIV/AIDS Unity of Internal Medicine Service of the Hospital Universitario Arnau de Vilanova in Lleida. We made clinical and analytical baseline studies and every 3 months thereafter. In relation to CD4+ lymphocytes, 3 groups were established: group I, 500 or more cells/mL; group II, 200-499 cells/mL and group III, < 200 cells/mL. In the same way, with p24 antigen we established 3 group: group I, < 20 pg/mL, group II, 20-39 pg/mL, group III 40 or more pg/mL. We studied survival in relation to baseline levels and stability, the latter being understood as persistent levels in the initial group, or better, over 3 year period. Survival analysis was made by Kaplan-Meier estimation. Relative risk was calculated by Cox's proportional hazards model. RESULTS: During the 36 months of follow-up 53 patients died. AIDS progression risk or death was 4.8 times higher for the p24 antigen > = 40 pg/mL group than for the p24 antigen < 20 pg/mL one; patients with p24 antigen between 20-39 pg/mL relative risk was 2.5 times higher than those included in p24 antigen < 20 pg/mL group. These results emphasize that if we take into account the p24 antigen stability during these 36 months. In relation to progression study, 36 patients progressed. AIDS progression risk or death for p24 antigen > = 40 pg/mL group was 7.69 times higher in relation to that with p24 antigen levels between 20-39 pg/mL. The bivariable study shows that CD4 lymphocytes counts and p24 antigen level have quite an independent value. The comparison with viral load by PCR determination makes manifest discrepancy, difficult to explain. CONCLUSIONS: p24 antigen plasma level is a good survival and AIDS progress or death surrogate markers in HIV infected patients, and it is useful for 3 years or more. An isolated value < 20 pg/mL and, furthermore, the stability in successive controls under this concentration is a sign of good prognosis. Its value is emphasized with CD4+ lymphocytes count. It seem necessary that more comparative studies with viral load are required.

Risk of cancer after low doses of ionising radiation: retrospective cohort study in 15 countries.

OBJECTIVES: To provide direct estimates of risk of cancer after protracted low doses of ionising radiation and to strengthen the scientific basis of radiation protection standards for environmental, occupational, and medical diagnostic exposures. DESIGN: Multinational retrospective cohort study of cancer mortality. SETTING: Cohorts of workers in the nuclear industry in 15 countries. PARTICIPANTS: 407 391 workers individually monitored for external radiation with a total follow-up of 5.2 million person years. MAIN OUTCOME MEASUREMENTS: Estimates of excess relative risks per sievert (Sv) of radiation dose for mortality from cancers other than leukaemia and from leukaemia excluding chronic lymphocytic leukaemia, the main causes of death considered by radiation protection authorities. RESULTS: The excess relative risk for cancers other than leukaemia was 0.97 per Sv, 95% confidence interval 0.14 to 1.97. Analyses of causes of death related or unrelated to smoking indicate that, although confounding by smoking may be present, it is unlikely to explain all of this increased risk. The excess relative risk for leukaemia excluding chronic lymphocytic leukaemia was 1.93 per Sv (< 0 to 8.47). On the basis of these estimates, 1-2% of deaths from cancer among workers in this cohort may be attributable to radiation. CONCLUSIONS: These estimates, from the largest study of nuclear workers ever conducted, are higher than, but statistically compatible with, the risk estimates used for current radiation protection standards. The results suggest that there is a small excess risk of cancer, even at the low doses and dose rates typically received by nuclear workers in this study.

Supervivencia y progresión de la enfermedad en 251 pacientes con infección por el VIH-1. Estudio del antígeno p24 y de la carga viral como marcadores pronóstico. Su valor a los 4 años de seguimiento / Survival and progression in 251 patients with HIV-1 disease. Study of p24 antigen and viral load as surro gate markers. Their utility in 4 years of follow-up

Fundamento: Analizar el valor de los niveles plasmáticos de antígeno p24 y la carga viral (RNA, PCR), como marcadores pronóstico en una cohorte de pacientes infectados por el VIH-1, cuyo tiempo de seroconversión es desconocido.Pacientes: Se incluyeron 251pacientes, la mayoría con terapia antirretroviral, que fueron asistidos de forma consecutiva en la Unidad VIH/SIDA del Servicio de Medicina Interna del Hospital Universitario Arnau de Vilanova de Lleida.Métodos: Se hicieron estudios clínico-analíticos en el momento de inclusión (basal) y luego, cada 3 meses.En relación al antígeno p24, se establecieron 3 grupos: Grupo I, 40 pg/mL).Respecto al estudio de progresión, 34 pacientes lo hicieron. Nuevamente apreciamos una diferencia estadísticamente significativa (p=0,0039) entre el grupo I y los grupos II y III, pero no (p=0,37) entre el grupo II y el III.La comparación de los niveles plasmáticos de antígeno p24 con la carga viral por PCR pone de manifiesto una gran disparidad de resultados. Conclusiones: El nivel plasmático del antígeno p24 es un buen marcador pronóstico de supervivencia y de progresión a SIDA o muerte en enfermos infectados por el VIH-1 y su validez se prolonga por lo menos 4 años. Una cifra aislada <20 pg/mL es un signo de mejor pronóstico. No parece existir paralelismo entre los valores plasmáticos de antígeno p24 y la carga viral (AU)

Marcadores pronóstico de progresión en la infección por VIH.Estudio del antígeno p24 en una cohorte de 251 pacientes / Surrogate markers of progression in HIV infection: study of P24 antigen in a cohort of 252 patients

Fundamento: Estudio prospectivo de la progresión a SIDA o muerte en una cohorte de 251 pacientes infectados por el VIH, cuyo tiempo de seroconversión es desconocido, con dos objetivos primordiales: 1º. Analizar los niveles plasmáticos del antígeno p24 como marcador de progresión 2º. Valorar la estabilidad de los niveles plasmáticos del antígeno p24 como marcador de progresión. Pacientes y métodos: Se incluyeron inicialmente 251 pacientes, la mayoría con terapia antirretroviral, que fueron asistidos de forma consecutiva en la Unidad VIH/SIDA del Servicio de Medicina Interna del Hospital Universitario Arnau de Vilanova de Lleida. La media del recuento inicial de linfocitos CD4 fue de 376,283 x 106/L (rango 1,5 - 1350). 51 casos habían sido diagnosticados previamente de SIDA, por lo que fueron excluidos del estudio de progresión. Las comparaciones de las curvas de supervivencia, de acuerdo con las cifras iniciales de antígeno p24 y de linfocitos CD4, así como con la estabilidad o no de la antigenemia, se realizaron con la prueba de Kaplan-Meier. El cálculo del riesgo relativo se realizó mediante el modelo de riesgo proporcional de Cox. Resultados: Durante los 24 meses de seguimiento progresaron a SIDA o fallecieron 38 pacientes. El riesgo de progresión a SIDA o muerte para el grupo con antígeno p24 = ó > 40 pg / ml fue 5,48 veces superior al grupo con antígeno p24 < 40 pg/ml (p<0,0005). El riesgo de progresión a SIDA o muerte para el grupo con antígeno p24 inestable fue 4,25 veces superior al grupo con antígeno p24 estable (p<0,0005). Conclusiones: El nivel de antigenemia p24 y su estabilidad son unos buenos marcadores del riesgo de progresión a SIDA o muerte y se comporta como un factor pronóstico independiente en nuestro grupo de pacientes. Una cifra < 40 pg/ml aislada o mantenida se asocia con un mejor pronóstico (AU)

Marcadores pronóstico de supervivencia y de progresión en la infección por el VIH-1. Estudio de linfocitos CD4+, antígeno p24 y carga viral durante 3 años en una cohorte de 251 pacientes / Surrogate markers of survival and progression in HIV infection: study of CD4+ lymphocytes count, P24 gen and viral load in a cohort of 251 patients during 3 years

Fundamento: Analizar el valor del recuento de linfocitos CD4+, los niveles plasmáticos de antígeno p24 y la carga viral (RNA, PCR), como marcadores pronóstico en una cohorte de pacientes infectados por el VIH-1, cuyo tiempo de seroconversión es desconocido. Pacientes y métodos: Se incluyeron 251 pacientes, la mayoría con terapia antirretroviral, que fueron asistidos de forma consecutiva en la Unidad VIH/SIDA del Servicio de Medicina Interna del Hospital Universitario Arnau de Vilanova de Lleida. Se hicieron estudios clínico-analíticos en el momento de inclusión (basal) y luego, cada 3 meses. En relación con los linfocitos CD4+, se establecieron 3 grupos: Grupo I, 500 ó más células/ml; grupo II, 200-499 células/ml; grupo III, 40 pg/ml fue 4,8 veces mayor que para el grupo con antígeno 40 pg/ml fue 7,69 veces superior en relación al grupo con antígeno p24 < 20 pg/ml y 6 veces superior que el grupo con antígeno p24 entre 20 y 39 pg/ml. El estudio bivariable muestra cierta independencia entre la cifra de linfocitos CD4+ y el valor del antígeno p24. La comparación con la determinación de carga viral por PCR pone de manifiesto una discrepancia de difícil explicación. Conclusiones: El nivel plasmático del antígeno p24 es un buen marcador pronóstico de supervivencia y de progresión a SIDA o muerte en enfermos infectados por el VIH-1 y su validez se prolonga por lo menos 3 años (AU)