Outcomes of adolescents with acute lymphoblastic leukaemia.

INTRODUCTION: Compared with young children who have acute lymphoblastic leukaemia (ALL), adolescents with ALL have unfavourable disease profiles and worse survival. However, limited data are available regarding the characteristics and outcomes of adolescents with ALL who underwent treatment in clinical trials. The aim of this study was to investigate the causes of treatment failure in adolescents with ALL. METHODS: We retrospectively analysed the outcomes of 711 children with ALL, aged 1-18 years, who were enrolled in five clinical trials of paediatric ALL treatment between 1993 and 2015. RESULTS: Among the 711 children with ALL, 530 were young children (1-9 years at diagnosis) and 181 were adolescents (including 136 younger adolescents [10-14 years] and 45 older adolescents [15-18 years]). Compared with young children who had ALL, adolescents with ALL were less likely to have favourable genetic features and more likely to demonstrate poor early response to treatment. The 10-year overall survival and event-free survival rates were significantly lower among adolescents than among young children (77.9% vs 87.6%, P=0.0003; 69.7% vs 76.5%, P=0.0117). There were no significant differences in the 10-year cumulative incidence of relapse, but the 10-year cumulative incidence of treatment-related death (TRD) was significantly greater among adolescents (7.2%) than among young children (2.3%; P=0.002). Multivariable analysis showed that both younger and older adolescents (vs young children) had worse survival and greater incidence of TRD. CONCLUSION: Adolescents with ALL had worse survival because they experienced a greater incidence of TRD. There is a need to investigate optimal treatment adjustments and novel targeted agents to achieve better survival rates (without excessive toxicity) among adolescents with ALL.

Air dispersal of multidrug-resistant Acinetobacter baumannii: implications for nosocomial transmission during the COVID-19 pandemic.

AIM: To describe the nosocomial transmission of Air, multidrug-resistant, Acinetobacter baumannii, nosocomial, COVID-19 Acinetobacter baumannii (MRAB) in an open-cubicle neurology ward with low ceiling height, where MRAB isolates collected from air, commonly shared items, non-reachable high-level surfaces and patients were analysed epidemiologically and genetically by whole-genome sequencing. This is the first study to understand the genetic relatedness of air, environmental and clinical isolates of MRAB in the outbreak setting. FINDINGS: Of 11 highly care-dependent patients with 363 MRAB colonization days during COVID-19 pandemic, 10 (90.9%) and nine (81.8%) had cutaneous and gastrointestinal colonization, respectively. Of 160 environmental and air samples, 31 (19.4%) were MRAB-positive. The proportion of MRAB-contaminated commonly shared items was significantly lower in cohort than in non-cohort patient care (0/10, 0% vs 12/18, 66.7%; P<0.001). Air dispersal of MRAB was consistently detected during but not before diaper change in the cohort cubicle by 25-min air sampling (4/4,100% vs 0/4, 0%; P=0.029). The settle plate method revealed MRAB in two samples during diaper change. The proportion of MRAB-contaminated exhaust air grills was significantly higher when the cohort cubicle was occupied by six MRAB patients than when fewer than six patients were cared for in the cubicle (5/9, 55.6% vs 0/18, 0%; P=0.002). The proportion of MRAB-contaminated non-reachable high-level surfaces was also significantly higher when there were three or more MRAB patients in the cohort cubicle (8/31, 25.8% vs 0/24, 0%; P=0.016). Whole-genome sequencing revealed clonality of air, environment, and patients' isolates, suggestive of air dispersal of MRAB. CONCLUSIONS: Our findings support the view that patient cohorting in enclosed cubicles with partitions and a closed door is preferred if single rooms are not available.

Heterozygosity for a defective gene for CC chemokine receptor 5 is not the sole determinant for the immunologic and virologic phenotype of HIV-infected long-term nonprogressors.

HIV-1-infected long-term nonprogressors are a heterogeneous group of individuals with regard to immunologic and virologic markers of HIV-1 disease. CC chemokine receptor 5 (CCR5) has recently been identified as an important coreceptor for HIV-1 entry into CD4+ T cells. A mutant allele of CCR5 confers a high degree of resistance to HIV-1 infection in homozygous individuals and partial protection against HIV disease progression in heterozygotes. The frequency of CCR5 heterozygotes is increased among HIV-1- infected long-term nonprogressors compared with progressors; however, the host defense mechanisms responsible for nonprogression in CCR5 heterozygotes are unknown. We hypothesized that nonprogressors who were heterozygous for the mutant CCR5 gene might define a subgroup of nonprogressors with higher CD4+ T cell counts and lower viral load compared with CCR5 wild-type nonprogressors. However, in a cohort of 33 HIV-1-infected long-term nonprogressors, those who were heterozygous for the mutant CCR5 gene were indistinguishable from CCR5 wild-type nonprogressors with regard to all measured immunologic and virologic parameters. Although epidemiologic data support a role for the mutant CCR5 allele in the determination of the state of long-term nonprogression in some HIV-1- infected individuals, it is not the only determinant. Furthermore, long-term nonprogressors with the wild-type CCR5 genotype are indistinguishable from heterozygotes from an immunologic and virologic standpoint.

Phosphorylation of (Na+ + K+)-ATPase; stimulation and inhibition by substituted and unsubstituted amines.

(1) In view of a previously established stimulation of steady-state phosphorylation of (Na+ + K+)-ATPase by imidazole and its inhibition by tris(hydroxymethyl)aminomethane, the effect of (structure, chemical composition and charge of) a number of primary, secondary and tertiary amines (including imidazole derivatives) has been investigated. (2) Primary amines are predominantly inhibitory and diamines are more inhibitory than monoamines. The strongest inhibition is exerted by ethylenediamine (I50 in 50 mM imidazole = 25 microM, vs. 60 mM for n-propylamine). Increasing the distance between the two amino groups from 3.7 to 8.7 A increases the I50 180-fold. The optimal distance of 3-4 A indicates a similar distance between two ligand(presumably Na+)-binding sites on the enzyme. (3) Screening or substitution of the central N-atom decreases inhibition by the nitrogen compound. Triple substitution by propyl or allyl groups leads to maximal activation, amounting to about 90% of the Na+-activation level. Triethyl substitution gives suboptimal activation and tributyl substitution leads to inhibition. Substitution by polar or negatively charged carboxyl groups diminishes or even abolishes inhibition and also diminishes or abolishes activation. (4) Although occasionally positive charge is not required for inhibition, it is prerequisite for activation. Within certain families of compounds (e.g., ethylenediamine and imidazole derivatives) inhibition or activation increases with pKa, hence with positive charge. (5) The above data are interpreted in terms of inhibition, which is competitive to Na+, being governed by Coulomb interaction. Activation, on the other hand, is predominantly determined by lipophilic (van der Waals or pi-pi electron) interactions, excluding water from the phosphorylation site, hence decreasing phosphoenzyme hydrolysis and increasing the phosphoenzyme level. The requirement of charge (though hidden by substitution) implies weak additional electrostatic interaction.

The effects of seasons and light therapy on G protein levels in mononuclear leukocytes of patients with seasonal affective disorder.

BACKGROUND: Information-transducing heterotrimeric G proteins have been implicated previously in the mechanism of action of mood stabilizers and in the pathophysiology of mood disorders. Mononuclear leukocytes of patients with unipolar and bipolar depression have been characterized by reduced measures of the stimulatory and inhibitory G proteins. In this study, patients with seasonal affective disorder (SAD) were measured for mononuclear leukocyte G protein levels while depressed during the winter, following light therapy, and in remission during the summer. METHODS: Twenty-six patients with SAD and 28 healthy subjects were assessed in the study. The immunoreactivities of Gs alpha, Gi alpha, and Gbeta subunit proteins were determined by Western blot analysis of mononuclear leukocyte membranes with selective polyclonal antibodies for the various G subunit proteins, followed by densitometric quantitation using an image analysis system. RESULTS: Untreated patients with SAD and winter, atypical-type depression showed significantly reduced mononuclear leukocyte immunoreactive levels of Gs alpha and Gi alpha proteins, similar to previous observations in patients with nonseasonal major depression. The reduced G protein levels were normalized with 2 weeks of light therapy. The same patients while in remission during the summer had G protein levels that were similar to those of healthy subjects. CONCLUSIONS: G protein-immunoreactive measures in patients with SAD are suggested as a state marker for winter depression, which is normalized by light treatment and during the summer. We speculate that light may exert its effects via normalization of transducin (Gt protein) levels, which are thought to be reduced in winter depression.

Assessment of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is the archetypal autoimmune disease given its complex clinical and molecular manifestations. Like the other rheumatic diseases, appropriate management is critically dependent upon the proper assessment of disease activity, organ damage, and quality of life. Here, we describe the components of the comprehensive assessment of SLE, including accurate physical and laboratory diagnosis, monitoring of disease activity, recording of accumulated organ morbidity, and integration of these with the patient's own perceptions of health status and quality of life. In doing so, we will review the most appropriate laboratory tests and indices currently used in standard clinical care and in clinical research.

Radiobiology of pions at TRIUMF.

Radiobiological studies at TRIUMF of the effects of pion beams have been carried out using cultured cells, mice and pigs. CHO cells in gel/medium were used for RBE determinations throughout the dose distributions. The RBE was shown to increase with depth in the stopping region, while the average RBE value decreased with increasing width of the stopping peak and also increased with increasing field size. The results suggest that the effects of peak width and field size will approximately cancel out when treatment volumes are changed, provided that all three dimensions are changed more or less proportionally. The peak center RBE values ranged from 1.2-1.3 for single doses. The oxygen enhancement ratio (OER) for pions was 2.2 compared to 2.8 for X rays. Split dose recovery was found to be somewhat reduced in the peak region. In vivo studies with mouse and pig skin have been done for 1 to 20 fractions. For mouse skin, pions showed an RBE of 1.5-1.6 for fraction numbers greater than 10. The RBE for pig skin was 1.4 for early reactions, but it may be higher for medium term reactions.

The response of murine B-16 melanoma to fractionated doses of pions.

The relative biological effectiveness (RBE) of pions has been studied in mouse B-16 melanoma transplanted into C57BL/6 mice. To determine the RBE at both high and low doses per fraction, a range of fractionation schedules was used, with 1, 4 and 10 fractions. The reference 250 kV X ray dose rate was 1.5 Gy/min which was much higher than the dose rate of pions (0.25 Gy/min). The RBE varied depending on the number of fractions and, within the same fractionation schedule, also on the dose per fraction. The RBE ranged from 1.15 for single fractions at 12.5 days of growth delay, to 1.80 for 10 fractions at 5 days of growth delay, which was determined by the time taken for the tumors to reach 5 times the average of their original volume. RBEs at the iso-effect level of 10 days growth delay were 1.20, 1.29 and 1.62 for single, 4 fractions and 10 fractions, respectively. RBE values were influenced by both the number of fractions and the dose per fraction, that is, the larger the number of fractions and the smaller the dose per fraction, the larger the value of RBE. In comparison with RBE of normal mouse skin, it was suggested that pion therapy may provide advantage over conventional photontherapy for radioresistant tumors such as this melanoma with the maximum therapeutic gain factor of 1.2. alpha/beta ratios for B-16 melanoma were also obtained from the 10 day growth delay iso-effect curve, and were 10.5 Gy and 32.6 Gy for X ray and pions, respectively.

Combination therapy of pions and SPG (Sonifilan, Schizophyllan), a biological response modifier for mouse tumor systems.

Female C3H mice aged 8-10 weeks with transplanted KHT sarcoma or SCCVII tumor were used to investigate the antitumor effect of SPG (Sonifilan, Schizophyllan) alone and in combination with local irradiation of pions with 4 fractions of 400 cGy (total 1600 cGy). Daily doses of 10 mg/kg of SPG were given intramuscularly to the mice bearing KHT sarcoma for 14 consecutive days from day 7, and to mice bearing SCCVII tumor for 20 consecutive days from day 7 and thereafter three times a week for another 2 weeks. The antitumor effect was evaluated by the changes in tumor volume, survival curves, and the number of pulmonary metastatic nodules on the surface of the lungs. SPG failed to exert any antitumor effect and any life-prolonging effect for the KHT sarcoma. As for SCCVII tumor, in the group treated with pions and SPG, tumor growth decreased significantly (p less than 0.01) compared with the group treated with pion only, and life prolonging effect and metastasis-suppressing effect were also observed (p less than 0.04). In conditions of minimal residual disease brought about by pion irradiation, the adjuvant effect of a Biological Response Modifier (BRM) SPG may prove to be a promising method of cancer therapy for some tumors.

Pions, Vancouver.

Clinical treatments at TRIUMF started in November, 1979. Ten patients with malignant subcutaneous nodules had 14 lesions treated with pions and 37 other nodules treated with 280 kV X rays. Three different fractionation regimens were used with X ray doses spanning the expected RBE range of pions. The RBE for pions for acute skin reaction for 10 fractions had a mean value about 1.5, while for 3 fractions it was 1.3 maximum. No dissociation of acute and late skin effects was seen with follow-up to 27 months after treatment. Phase 1-2 studies of Pion-Boost Therapy for patients with glioblastoma multiforme will begin in May, 1982. These will be followed in August with treatments of advanced pelvic malignancies using pions only. The existing beam line at TRIUMF will be upgraded and commitments have been given to go to higher beam currents. As a result, the dose rate should increase by a factor of at least two, allowing treatment of clinically relevant volumes in acceptable times by 1983-1984.

The use of positron emission tomography in pion radiotherapy.

The radioactive debris produced by pion radiotherapy can be imaged by the technique of Positron Emission Tomography (PET) as a method of non-invasive in situ verification of the pion treatment. This paper presents the first visualization of the pion stopping distribution within a tumor in a human brain using PET. Together with the tissue functional information provided by the standard PET scans using radiopharmaceuticals, the combination of pion with PET technique can provide a much better form of radiotherapy than the use of conventional radiation in both treatment planning and verification.

Preclinical evaluation of pions in vivo: experience at TRIUMF.

This paper describes the results obtained from in vivo studies of the pion beam at the TRI University Meson Facility (TRIUMF). The studies encompass work (from 1978 to 1986), designed to evaluate the RBE for early and late effects and to assess the importance of X-ray dose rate and treatment volume on these values. Results with early responding tissues, i.e. mouse and pig skin and mouse intestine indicate a pion RBE of about 1.5 in the clinically relevant dose per fraction range of 2-3 Gy. At these doses, RBE appears to be independent of the reference X-ray dose rate. However, at high doses per fraction, the RBE values become increasingly X-ray dose rate dependent. The induction of late effects by pions has been assessed by monitoring the late dermal response of pig skin; late fibrosis was not assessed in this study. The values obtained using the chosen endpoint indicate that the RBE is not significantly higher than that seen in any of the early responding tissues for pion doses as low as 2-3 Gy per fraction. The effect of increasing the treatment volume for pion therapy has been assessed using mouse intestine. The results show that for a constant field size, RBE decreases with increasing peak width. However, if peak width is held constant and field size increased, there is evidence for an increased RBE.(ABSTRACT TRUNCATED AT 250 WORDS)

Pion therapy at TRIUMF. Treatment results for astrocytoma grades 3 and 4: a pilot study.

At TRIUMF, (located on the University of B.C. Campus), 53 patients with supratentorial astrocytoma grades 3 and 4 were treated with pions between 1982 and 1985. A 3-dimensional spot-scanning treatment technique has proven to be practical. The accuracy of the beam alignment system used for treatment was reproducible daily within 2 mm. Low pion flux has hindered optimal beam shaping but this will soon be remedied as flux improves. The overall median survival observed (53 patients) is 262 days from date of first radiation treatment. Younger (less than 49 years) patients have significantly better survival than older (greater than 50 years) patients (p = 0.001). From a base line dose of 40 Gy photons whole brain and 17.5 Gy pion boost, doses were escalated to 33 Gy pions localised to the primary tumour and the median survival improved from 198 to 436 days. Survival curves for patients treated with localised pion techniques to doses above 30 Gy are significantly better than for those treated with schedules of pions mixed with photons (p = 0.04). It appears that optimal pion dose for brain tumours is 33 Gy minimum with a possible maximum of 36 Gy and doses delivered in 15 fractions in 3 weeks. Requirements for future trials are discussed.

The survival response of a biological system to mixed radiations.

The concept of additive radiation action is applied to the process of merging of the intermediate lesions at a common stage in the radiation inactivation pathways for lesions produced by different radiations. This gives rise to a natural nonindependent effect for combined irradiation. Even though the exact nature of this common intermediate lesion is unknown, the effect of this lesion additivity can still be formulated into a mathematical model using the assumptions: (1) there exists a stage in the chain of radiation inactivation events where different types of lesion precursors, produced by different types of radiations in a mixture, inflict lesions which become functionally indistinguishable and hence additive thereafter, to produce the same end point observed; (2) all precursors of all types are simultaneously competing for the opportunity to inflict lesions at the stage indicated in assumption 1, and each precursor has equal opportunity regardless of its origin; (3) if the radiations are delivered sequentially within a sufficiently short time, the lesion precursors of both radiations arrive at the above stage at about the same time and hence inflict lesions which are additive as described in assumptions 1 and 2. The model is quantitative but contains no free-fitting parameters. It is shown to be capable of explaining a large variety of apparently unrelated published experimental results observed for mixtures of high- and low-LET radiations.

An isoeffect approach to the study of combined effects of mixed radiations--the nonparametric analysis of in vivo data.

The combined effects of mixed radiations can be examined using a system of simple isoeffect relations which are derived from a recent analysis of in vitro results obtained for a variety of radiation mixtures. Similar isoeffect analysis methods have been used for over two decades in studies of the combined action of toxic agents such as drugs and antibiotics. Because of the isoeffect approach, the method is particularly useful for the analysis of ordinal data for which conventional models that are based on parametric dose-effect relations may not be suitable. This is illustrated by applying the method to the analysis of a set of recently published in vivo data using the mouse foot skin reaction system for mixtures of neutrons and X rays. The good agreement between this method and the ordinal data also helps to provide further experimental support for the existence of a class of radiobiological data for which the simple isoeffect relations are valid.

Effect of different stopping volumes of clinical pion beams at TRIUMF on the mouse small intestine.

The survival of mouse jejunal crypt cells was measured using a microcolony assay following irradiation with one of three different pion stopping volumes. All treatments were done using the beam spot scanning system developed for clinical therapy at TRIUMF. Treatment volumes were Small, 10 ml of volume using 4 beam spots with a narrow stopping peak; Moderate, 40 ml of volume using 4 beam spots with an extended peak; Large, 1.2 liters of volume using 37 spots with an extended peak. The dose rate fluctuated considerably during treatment because of the scanning procedure. The relative biological effectiveness (RBE) values of pions were 1.11, 1.04, and 1.16 for the small, moderate, and large volumes, respectively. As the width of the stopping peak increased, from the narrow 4-cm peak of the small volume to the 12-cm peak of the moderate volume, the effectiveness of the pion beam decreased. This presumably reflects the low linear energy transfer contribution of the large number of passing pions in the wider stopping peak. The results indicate, however, a greater biological effectiveness for the large volume than for the moderate volume. Even though these fields had stopping peaks of similar width, the field size and dose rate were different. Although the increase in RBE may be partly due to an increased neutron flux from the larger volume, our results suggest that much of this apparent increase could be explained by differences in dose rate as a function of time for pions versus X rays.