Long-Term Safety and Efficacy of Epratuzumab in the Treatment of Moderate-to- Severe Systemic Lupus Erythematosus: Results From an Open-Label Extension Study.

OBJECTIVE: The primary objective was to assess the long-term safety of repeated courses of epratuzumab therapy in patients with moderate-to-severe systemic lupus erythematosus. Secondary objectives were to assess long-term efficacy and health-related quality of life (HRQOL). METHODS: Eligible patients from the 12-week, phase IIb, randomized, placebo-controlled EMBLEM study enrolled into the open-label extension (OLE) study, SL0008. In the SL0008 study, patients received 1,200 mg epratuzumab infusions at weeks 0 and 2 of repeating 12-week cycles, plus standard of care. Safety measures included treatment-emergent adverse events (TEAEs) and serious TEAEs. Efficacy measures included combined treatment response, the British Isles Lupus Assessment Group score, the Systemic Lupus Erythematosus Disease Activity Index score, and the physician's and patient's global assessment of disease activity. Total daily corticosteroid dose and HRQOL (by the Short Form 36 health survey) were also assessed. RESULTS: A total of 113 of the 203 patients (55.7%) who entered the SL0008 study continued epratuzumab therapy until study closure (total cumulative exposure: 381.3 patient-years, median exposure: 845 days, and maximum exposure: 1,185 days/approximately 3.2 years). TEAEs were reported in 192 patients (94.6%); most common were infections and infestations (68.0%, 138 patients). Serious TEAEs were reported in 51 patients (25.1%), and 14 patients (6.9%) had serious infections. In patients treated for 108 weeks (n = 116), the median corticosteroid dose was reduced from 10.0 mg/day at OLE screening to 5.0 mg/day at week 108. Improvements in efficacy and HRQOL measures in EMBLEM were maintained in the OLE, while placebo patients exhibited similar improvements in disease activity upon a switch to epratuzumab. CONCLUSION: Open-label epratuzumab treatment was well tolerated for up to 3.2 years, and associated with sustained improvements in disease activity and HRQOL, while steroids were reduced.

Neutron dosimetry in organs of an adult human phantom using linacs with multileaf collimator in radiotherapy treatments.

PURPOSE: To calculate absorbed doses due to neutrons in 87 organs/tissues for anthropomorphic phantoms, irradiated in position supine (head first into the gantry) with orientations anteroposterior (AP) and right-left (RLAT) with a 18 MV accelerator. Conversion factors from monitor units to µGy per neutron in organs, equivalent doses in organs/tissues, and effective doses, which permit to quantify stochastic risks, are estimated. METHODS: MAX06 and FAX06 phantoms were modeled with MCNPX and irradiated with a 18 MV Varian Clinac 2100C/D accelerator whose geometry included a multileaf collimator. Two actual fields of a pelvic treatment were simulated using electron-photon-neutron coupled transport. Absorbed doses due to neutrons were estimated from kerma. Equivalent doses were estimated using the radiation weighting factor corresponding to an average incident neutron energy 0.47 MeV. Statistical uncertainties associated to absorbed doses, as calculated by MCNPX, were also obtained. RESULTS: Largest doses were absorbed in shallowest (with respect to the neutron pathway) organs. In µGyMU(-1), values of 2.66 (for penis) and 2.33 (for testes) were found in MAX06, and 1.68 (for breasts), 1.05 (for lenses of eyes), and 0.94 (for sublingual salivary glands) in FAX06, in AP orientation. In RLAT, the largest doses were found for bone tissues (leg) just at the entrance of the beam in the body (right side in our case). Values, in µGyMU(-1), of 1.09 in upper leg bone right spongiosa, for MAX06, and 0.63 in mandible spongiosa, for FAX06, were found. Except for gonads, liver, and stomach wall, equivalent doses found for FAX06 were, in both orientations, higher than for MAX06. Equivalent doses in AP are higher than in RLAT for all organs/tissues other than brain and liver. Effective doses of 12.6 and 4.1 µSvMU(-1) were found for AP and RLAT, respectively. The organs/tissues with larger relative contributions to the effective dose were testes and breasts, in AP, and breasts and red marrow, in RLAT. Equivalent and effective doses obtained for MAX06/FAX06 were smaller (between 2 and 20 times) than those quoted for the mathematical phantoms ADAM/EVA in ICRP-74. CONCLUSIONS: The new calculations of conversion coefficients for neutron irradiation in AP and RLAT irradiation geometries show a reduction in the values of effective dose by factors 7 (AP) and 6 (RLAT) with respect to the old data obtained with mathematical phantoms. The existence of tissues or anatomical regions with maximum absorbed doses, such as penis, lens of eyes, fascia (part of connective tissue), etc., organs/tissues that classic mathematical phantoms did not include because they were not considered for the study of stochastic effects, has been revealed. Absorbed doses due to photons, obtained following the same simulation methodology, are larger than those due to neutrons, reaching values 100 times larger as the primary beam is approached. However, for organs far from the treated volume, absorbed photon doses can be up to three times smaller than neutron ones. Calculations using voxel phantoms permitted to know the organ dose conversion coefficients per MU due to secondary neutrons in the complete anatomy of a patient.

Ambient neutron dose equivalent outside concrete vault rooms for 15 and 18 MV radiotherapy accelerators.

In this work, the ambient dose equivalent, H*(10), due to neutrons outside three bunkers that house a 15- and a 18-MV Varian Clinac 2100C/D and a 15-MV Elekta Inor clinical linacs, has been calculated. The Monte Carlo code MCNPX (v. 2.5) has been used to simulate the neutron production and transport. The complete geometries including linacs and full installations have been built up according to the specifications of the manufacturers and the planes provided by the corresponding medical physical services of the hospitals where the three linacs operate. Two of these installations, those lodging the Varian linacs, have an entrance door to the bunker while the other one does not, although it has a maze with two bends. Various treatment orientations were simulated in order to establish plausible annual equivalent doses. Specifically anterior-posterior, posterior-anterior, left lateral, right lateral orientations and an additional one with the gantry rotated 30° have been studied. Significant dose rates have been found only behind the walls and the door of the bunker, near the entrance and the console, with a maximum of 12 µSv h(-1). Dose rates per year have been calculated assuming a conservative workload for the three facilities. The higher dose rates in the corresponding control areas were 799 µSv y(-1), in the case of the facility which operates the 15-MV Clinac, 159 µSv y(-1), for that with the 15-MV Elekta, and 21 µSv y(-1) for the facility housing the 18-MV Varian. A comparison with measurements performed in similar installations has been carried out and a reasonable agreement has been found. The results obtained indicate that the neutron contamination does not increase the doses above the legal limits and does not produce a significant enhancement of the dose equivalent calculated. When doses are below the detection limits provided by the measuring devices available today, MCNPX simulation provides an useful method to evaluate neutron dose equivalents based on a detailed description of linac, patient and bunker.

Neutron dose equivalent and neutron spectra in tissue for clinical linacs operating at 15, 18 and 20 MV.

In this work, the dose equivalent due to photoneutrons and the neutron spectra in tissue was calculated for various linacs (Varian Clinac 2100C, Elekta Inor, Elekta SL25 and Siemens Mevatron KDS) operating at energies between 15 and 20 MV, using the Monte Carlo code MCNPX (v. 2.5). The dose equivalent in an ICRU tissue phantom has been calculated for anteroposterior treatments with a detailed simulation of the geometry of the linac head and the coupled electron-photon-neutron transport. Neutron spectra at the phantom entrance and at 1-cm depth in the phantom, depth distribution of the neutron fluence in the beam axis and dose distributions outside the beam axis at various depths have also been calculated and compared with previously published results. The differences between the neutron production of the various linacs considered has been analysed. Varian linacs show a larger neutron production than the Elekta and Siemens linacs at the same operating energy. The dose equivalent due to neutrons produced by medical linacs operating at energies >15 MeV is relevant and should not be neglected because of the additional doses that patients can receive.

Ulceras escrotales causadas por el tratamiento con ácido retinoico en una leucemia promielocítica aguda ("Síndrome de Atra") / Scrotal Ulceration cauced by all-trans-retinoic acid (Atra) theraphy during acute promyelocytic leukemia

Presentamos el caso de un paciente con diagnótico de leucemia promielocítica agudo que desarrollo úlceras escrotales múltiples al ser tratado con ácido retinoico ("Vesanoid"). Al disminuir la dosis que estaba recibiendo, las úlceras se autolimitaron y resolvieron espontáneamente

Ulceras escrotales causadas por el tratamiento con ácido retinoico en una leucemia promielocítica aguda ("Síndrome de Atra") / Scrotal Ulceration cauced by all-trans-retinoic acid (Atra) theraphy during acute promyelocytic leukemia

Presentamos el caso de un paciente con diagnótico de leucemia promielocítica agudo que desarrollo úlceras escrotales múltiples al ser tratado con ácido retinoico ("Vesanoid"). Al disminuir la dosis que estaba recibiendo, las úlceras se autolimitaron y resolvieron espontáneamente(AU)

Effect of the inactivating "ball" peptide of Shaker B on intermediate conductance Ca(2+)-dependent inwardly rectifying K+ channels of HeLa cells.

The patch-clamp technique was used to study the effect of intracellularly added inactivating "ball" peptide (BP) of the Shaker B K+ channel upon Ca(2+)-dependent inwardly rectifying K+ channels of the intermediate conductance type expressed in HeLa cells. Intracellular BP caused only moderate inhibition of outward K+ currents when assayed at an intracellular Ca2+ concentration of 100 nmol/l. Increasing intracellular Ca2+ levels led in itself to some voltage-dependent blockade of K+ currents, which was absent when high extracellular K+ was used. An additional strong blockade by intracellular BP was nevertheless observed both in Na(+)- and K(+)-rich extracellular solutions. A non-inactivating BP analogue had no effect. At this higher intracellular Ca2+ concentration the inhibition of these intermediate conductance Ca(2+)-dependent channels by BP was voltage-dependent, being absent at hyperpolarizing potentials, and could be relieved by increasing extracellular K+. These data suggest that BP acts at an internal pore site in Ca(2+)-dependent intermediate conductance K+ channels of HeLa cells, and that these might possess a receptor site for the peptide similar to that of other K+ channels such as Ca(2+)-activated maxi-K+ channels.

Anticardiolipin and anti-beta2glycoprotein-I antibodies in patients with systemic lupus erythematosus: comparison between Colombians and Spaniards.

We studied the prevalence, isotype distribution, and clinical significance of anticardiolipin (aCL) and anti-beta2glycoprotein I (anti-beta2GPI) antibodies in two populations of patients with systemic lupus erythematosus (SLE), 160 Colombians and 160 Spaniards. All sera were tested in our laboratory by enzyme-linked immunosorbent assay (ELISA) for IgG, IgM, and IgA aCL, as well as IgG and IgM anti-beta2GPI. Positive results for at least 1 of the 3 aCL isotypes were found in 40 Colombians (25%) and 55 Spaniards (34%). IgG aCL was the predominant isotype in both populations. Positive results for at least 1 of the anti-beta2GPI isotypes were found in 34 Colombians (21%) and 29 Spaniards (18%). IgG anti-beta2GPI was the dominant isotype in Colombians, while IgM was predominant in Spaniards. Positivity for anti-beta2GPI in aCL-positive patients was present in 77% in the Colombian group and 50% in the Spaniard group. Among Colombians, IgG aCL and anti-beta2GPI correlated with thrombosis, fetal loss, and thrombocytopenia. Among Spaniards, IgG aCL and IgG anti-beta2GPI correlated with thrombosis, fetal loss, and livedo reticularis. For detecting thrombosis and fetal loss, aCL ELISA was more sensitive than anti-beta2GPI in Spaniards, and anti-beta2GPI ELISA was more specific than aCL in both populations.

[Long-term follow up of Doppler parameters of ventricular diastolic function after myocardial infarct]. / Evolución a largo plazo de los parámetros Doppler de función diastólica ventricular tras un infarto del miocardio.

Forty-two survivors of a first transmural, noncomplicated myocardial infarction underwent mitral flow pulsed-Doppler studies both at predischarge time and 1 year later, in order to assess the long-term evolution of diastolic parameters in the absence of reinfarction or revascularization procedures. Results showed a decrease of mean value of E wave peak velocity (59.6 +/- 14 cm/sec vs 46.8 +/- 13 cm/sec, p < 0.001). Mean value of A wave peak velocity remained stable (59.4 +/- 16 cm/sec vs 58.8 +/- 13 cm/sec, p = 0.86). The mean value of the E/A ratio showed a significant decrease during follow-up from an initial value > or = 1 to a final value < 1 (1.08 +/- 0.4 vs 0.82 +/- 0.2, p < 0.01). From the point of view of individual results, only 8 of 22 patients with an E/A ratio > or = 1 before discharge presented the same ratio value 1 year later, whereas only 1 patient with a E/A ratio < 1 before discharge presented a > 1 value of this ratio in the late study. It is concluded that during the first year of evolution after transmural, nonrevascularized, noncomplicated infarction, the left ventricle filling pattern displays a significant change from predischarge phase (mainly protodiastolic with predominant E wave) to late follow-up (mainly telediastolic with predominant A wave). Different hypotheses to explain these results are discussed.

[Erythrocyte reference values in a Coulter S-Plus STKR, in healthy adults living at 2,240 meters above sea level]. / Límites de referencia de serie roja, obtenidos en el equipo Coulter S-plus STKR, en adultos sanos residentes a 2,240 metros sobre el nivel del mar.

To determine reference values of red blood cell counts in a Coulter S-Plus STKR, we studied 122 males and 147 females selected from the hospital staff (physicians, chemists, nurses) and blood donors. Their ages ranged from 17 to 45 years. Iron and total iron binding capacity in serum, and Zn-protoporphyrin and folates in erythrocytes were measured to include only normal subjects without nutritional deficiencies. Two males (1.6%) and 21 females (14.3%) were excluded due to iron deficiency, and one man (0.7%) and one woman (0.8%) to folate deficiency. All red cell parameters, except the mean cell volume, showed a gaussian distribution (Lilliefors test). Their mean +/- standard deviation were: [formula: see text].

[Atypical chest pain with normal coronary vessels: clinical study and follow-up of 22 patients]. / Dolor torácico atípico con coronarias normales: estudio clínico y seguimiento de 22 pacientes.

22 patients with normal coronarography but with angina pectoris or angina-like chest pain without evidence of coronary spasms are reviewed. We studied clinical characteristics, basal and exercise electrocardiography and other tests used to obtain a diagnosis, although only in one patient were we able to find an esophageal pathology which caused the clinical picture. After 20.7 +/- 14.4 months follow-up no patients had myocardial infarction or acute coronary events. Most of them still experience chest pain, are physically limited and use antianginal drugs. The fact that their coronarograms were normal decreased significantly the number of admissions to hospital (2.4 +/- 3.3 vs 0.26 +/- 0.95, P less than 0.02) and the amount of drugs prescribed. The lack of improvement of most of them seems to justify the need for other studies looking for a positive diagnosis and other types of treatment.

[Clinical study of a new anti-arrhythmic drug: propafenon. Short and long-term results]. / Estudio clínico de un nuevo fármaco antiarrítmico: propafenona.

Fifty patients with atrio-ventricular arrhythmias were treated with the new antiarrhythmic drug propaferon. A dose of 70 mg (1-1.5 mg/kg), was injected slowly into a vein (2-3 min), in 16 cases. In the other 34 cases a dose of 450-900 mg/24 hours was given orally. Propafenon is a drug which acts on the permeability of the membrane and also as a local anaesthetic. Its efficiency has been demonstrated in the treatment of arrhythmias. In our series, ventricular arrhythmias were suppressed in 76.8% of the cases (33 patients), while the ventricular extrasystoles were reduced in 18.6% of the cases (8 patients). There was no action in 4.6% of the cases (2 patients). The drug was not useful in the treatment of atrial arrhythmias. Unwanted side-effects (arterial hypotension, conduction disorders, etc.), were not seen when intravenous doses of less than 2 mg/kg, were administered. However, electrocardiographic changes (widening of the QRS, prolongation of the PQ interval, etc.), were observed in those patients who received doses greater than 450 mg/24 hours. In these patients, there was a close correlation between the dose administered and the prolongation between the dose administered and the prolongation of the conduction times. We believe that the amount of myocardial degradation and the age of the patient are directly related to the appearance of conduction disorders. This relation is greater when a larger dose is administered. The advantages that this new drug has over other antiarrhythmics are the methods of administration (oral and intravenous). Both these methods may be used simultaneously to maintain a stable sinus rhythm or the rapid intravenous method may be followed by the oral maintenance one.