Maximizing Breast Cancer Therapy with Awareness of Potential Treatment-Related Blood Disorders

In this review we summarize the impact of the various modalities of breast cancer therapy coupled with intrinsic patient factors on incidence of subsequent treatment-induced myelodysplasia and acute myelogenous leukemia (t-MDS/AML). It is clear that risk is increased for patients treated with radiation and chemotherapy at younger ages. Radiation is associated with modest risk, whereas chemotherapy, particularly the combination of an alkylating agent and an anthracycline, carries higher risk and radiation and chemotherapy combined increase the risk markedly. Recently, treatment with granulocyte colony-stimulating factor (G-CSF), but not pegylated G-CSF, has been identified as a factor associated with increased t-MDS/AML risk. Two newly identified associations may link homologous DNA repair gene deficiency and poly (ADP-ribose) polymerase inhibitor treatment to increased t-MDS/AML risk. When predisposing factors, such as young age, are combined with an increasing number of potentially leukemogenic treatments that may not confer large risk singly, the risk of t-MDS/AML appears to increase. Patient and treatment factors combine to form a biological cascade that can trigger a myelodysplastic event. Patients with breast cancer are often exposed to many of these risk factors in the course of their treatment, and triple-negative patients, who are often younger and/or BRCA positive, are often exposed to all of them. It is important going forward to identify effective therapies without these adverse associated effects and choose existing therapies that minimize the risk of t-MDS/AML without sacrificing therapeutic gain.

Implications for Practice

Breast cancer is far more curable than in the past but requires multimodality treatment. Great care must be taken to use the least leukemogenic treatment programs that do not sacrifice efficacy. Elimination of radiation and anthracycline/alkylating agent regimens will be helpful where possible, particularly in younger patients and possibly those with homologous repair deficiency (HRD). Use of colony-stimulating factors should be limited to those who truly require them for safe chemotherapy administration. Further study of a possible leukemogenic association with HRD and the various forms of colony-stimulating factors is badly needed.

     

High-quality controlled trials on preventing episodes of back problems: systematic literature review in working-age adults

Background contextBack problems (BPs), with their cost and disability, are a substantial burden for individuals, employers, and society.PurposeThis systematic review of controlled trials evaluates the effectiveness of interventions to prevent BP episodes in working age adults.Data sourcesWe searched MEDLINE/EMBASE through May 2007, and COCHRANE/Trials Registry through August 22, 2008 using search terms of back pain, back injuries or sciatica, linked to prevention, control, workplace interventions, or ergonomics and searched article bibliographies.Study selectionFor systematic review inclusion, articles had to describe prospective controlled trials of interventions to prevent BPs in working-age adults, with intervention assignment either to individual participants or preexisting groups. Of 185 articles identified as potentially relevant, 20 trials (11%) met inclusion criteria.Data extractionResearchers extracted relevant information from controlled trials and graded methodological quality. Because of heterogeneity of trials, meta-analysis was not performed.ResultsOnly exercise was found effective for preventing self-reported BPs in seven of eight trials (effect size 0.39 to >0.69). Other interventions were not found to reduce either incidence or severity of BP episodes compared with controls. Negative trials included five trials of education, four of lumbar supports, two of shoe inserts, and four of reduced lifting programs.ConclusionsTwenty high-quality controlled trials found strong, consistent evidence to guide prevention of BP episodes in working-age adults. Trials found exercise interventions effective and other interventions not effective, including stress management, shoe inserts, back supports, ergonomic/back education, and reduced lifting programs. The varied successful exercise approaches suggest possible benefits beyond their intended physiologic goals.Level of evidenceSystematic review Level I evidence.     

A group intervention to reduce smoking in individuals with psychiatric disorder: brief report of a pilot study

Objectives: To evaluate a group intervention to help individuals with psychiatric disorder stop smoking.
Method: A waitlist-treatment crossover design. Outcome measures included smoking cessation, motivation to stop, the Fagerstrom Test for Nicotine Dependence (FTND), urinary cotinine and psychiatric symptoms on the General Health Questionnaire.
Results: 38 subjects participated, of whom 19 completed the waitlist and intervention phases. There were no significant differences between subjects and dropouts. During the waitlist period there were no significant changes in tobacco use. At the end of the intervention, almost a quarter had stopped smoking, ( z = -2.24, p =0.02). Subjects also showed significant improvements on state of change, FTND score and urinary cotinine levels. These improvements were maintained at three-month follow-up (n=10). Psychiatric morbidity showed no change.
Conclusions: It is possible to reduce smoking in individuals with psychiatric disorder.
Implications: Larger randomised controlled trials are indicated to determine the relative contributions of nicotine replacement, bupropion and group interventions to smoking cessation in this population.     

Infantile autism—fragile X: Molecular findings support genetic heterogeneity

Twenty-two members of 18 families with autism have been examined for the presence of mutations and abnormal methylation in the FMR-1 region at Xq27.3. All patients fulfilled diagnostic criteria of infantile autism. A characteristic pattern of insertion and methylation were detected after Southern blot analysis in 7 autistic individuals expressing the fragile site at Xq27.3. Normal DNA patterns were observed in 15 autistic boys cytogenetically negative for the fragile site. The results indicate a lack of involvement of the FMR-1 region in infantile autists negative for fragile X expression. © 1992 Wiley-Liss, Inc.     

The platelet and the neuron: Two cells in focus in migraine

Reports of platelet abnormalities in migraine are abundant, and the present paper discusses the role of platelets in the migraine aetiology. Platelets are considered good models for pre- and post-synaptic functions in serotonergic neurons. We propose that migraine is associated with a lowered threshold for stimulus response in both platelets and serotonergic neurons and that the alterations in platelet function reflect central serotonergic disturbances. The platelet abnormalities in migraine approach those found in depression, and there are several links between the two disorders. The clinical significance of platelet hyperactivity in migraineurs for the occurrence of thrombotic disorders is also discussed. Studies of platelet functions in migraine, using platelets as models for serotonergic neurons, may broaden our understanding of the neuronal processes that take place during a migraine attack. The platelet can also be an investigative tool for better understanding of the modes of action of anti-migraine drugs.     

Methylation and mutation patterns in the fragile X syndrome.

Chromosomes carrying the mutation causing the fragile X [fra(X)] syndrome have been shown to have an unstable DNA sequence close to or within the fragile site. The length variation is located within a DNA fragment containing a CGG trinucleotide repeat which is unstable in both mitosis and meiosis. We have used the probe StB12.3 from the region to analyze the mutations and the methylation patterns in 21 families segregating for the fra(X) syndrome. Among 40 fra(X) males all showed an abnormal pattern. The normal 2.8 kb band was absent in 36 individuals and replaced by a heterogeneous smear of larger size. The remaining four were shown to be "mosaics" with the presence of both mutated, unmethylated and mutated, methylated fragments. We found four normal transmitting males, one which was a great-grandson of another normal transmitting male indicating that the pre-mutation can remain stable through two meioses in the female. In nine fra(X) positive females the abnormal pattern consisted of a smear, usually seen in affected males, in addition to the normal bands. Five of these females were mentally normal. Of clinical importance is the prediction of mental impairment in females. We suggest that this is not made by the detection of the full mutation alone, but rather by the degree of methylation of the normal X chromosome. Our results suggest that difference of clinical expression in monozygotic twins may be correlated with difference in methylation pattern. Six out of 33 fra(X) negative females at risk were diagnosed as carriers. Our observations indicate that molecular heterogeneity is responsible for variable expression of the fra(X) syndrome in both males and females.     

Single cell CGH analysis reveals a high degree of mosaicism in human embryos from patients with balanced structural chromosome aberrations

We have performed comparative genomic hybridization (CGH) analysis of single blastomeres from human preimplantation embryos of patients undergoing preimplantation genetic diagnosis (PGD) for inherited structural chromosome aberrations and from embryos of IVF couples without known chromosomal aberrations. The aim was to verify the PGD results for the specific translocation, reveal the overall genetic balance in each cell and visualize the degree of mosaicism regarding all the chromosomes within the embryo. We successfully analysed 94 blastomeres from 28 human embryos generated from 13 couples. The single cell CGH could verify most of the unbalanced translocations detected by PGD. Some of the embryos exhibited a mosaic pattern regarding the chromosomes involved in the translocation, and different segregation could be seen within an embryo. In addition to the translocations, we found a high degree of numerical aberrations including monosomies, trisomies and duplications or deletions of parts of chromosomes. All of the embryos (100%) were mosaic, containing more than one chromosomally uniform cell line, or even chaotic with a different chromosomal content in each blastomere.     

Cutaneous facilitation of transmission in reflex pathways from Ib afferents to motoneurones.

1. The effect of volleys in low threshold cutaneous afferents upon transmission of synaptic action from Ib afferents to motoneurones has been investigated with intracellular recording from alpha motoneurones to hind limb muscles. 2. There was facilitation from cutaneous afferents of transmission in excitatory and inhibitory reflex pathways from Ib afferents without any evidence for difference in effect on di- and trisynaptic pathways. It is postulated that volleys in cutaneous afferents evoke excitatory action in interneurones of these reflex pathways. 3. The time course of the facilitation suggest that cutaneous afferents have disynaptic excitatory connexions with the interneurones intercalated in the disynaptic Ib inhibitory pathways to motoneurones. 4. Some observations are reported suggesting that interneuronal transmission in Ib inhibitory pathways to motoneurones might be facilitated from Ia afferents. 5. The findings are discussed in relation to the presumed role of Ib reflex action in regulating muscle tension.     

Reflex pathways from group II muscle afferents

Summary A hypothesis is forwarded regarding the role of secondary spindle afferents and the FRA (flexor reflex afferents) in motor control. The hypothesis is based on evidence (cf. Lundberg et al. 1987a, b) summarized in 9 introductory paragraphs. Group II excitation. It is postulated that subsets of excitatory group II interneurones (transmitting disynaptic group II excitation to motoneurones) may be used by the brain to mediate motor commands. It is assumed that the brain selects subsets of interneurones with convergence of secondary afferents from muscles whose activity is required for the movement. During movements depending on coactivation of static -motoneurones impulses in secondary afferents may servo-control transmission to -motoneurones at an interneuronal level. The large group II unitary EPSPs in interneurones are taken to indicate that, given an adequate interneuronal excitability, impulses in single secondary afferents may fire the interneurone and produce EPSPs in motoneurones; interneuronal transmission would then be equivalent to that in a monosynaptic pathway but with impulses from different muscles combining into one line. It is postulated that impulses in the FRA are evoked by the active movements and that the role of the multisensory convergence from the FRA onto the group II interneurones is to provide the high background excitability which allows the secondary spindle afferents to operate as outlined above. The working hypothesis is put forward that a movement governed by the excitatory group II interneurones is initiated by descending activation of these interneurones, but is maintained in a later phase by the combined effect of FRA activity evoked by the movement and by spindle secondaries activated by descending activation of static -motoneurones. As in the original follow up length servo hypothesis (Rossi 1927; Merton 1953), we assume that a movement at least in a certain phase can be governed from the brain solely or mainly via static -motoneurones. However, our hypothesis implies that the excitatory group II reflex connexions have a strength which does not allow transmission to motoneurones at rest and that the increase in the gain of transmission during an active movement is supplied by the movement itself. Group II inhibition. It is suggested that the inhibitory reflex pathways like the excitatory ones have subsets of interneurones with limited group II convergence. When higher centres utilize a subset of excitatory group II interneurones to evoke a given movement, they may mobilize inhibitory subsets to inhibit muscles not required in the movement. Inhibition may be reciprocal of extensors during flexor activation (the spinal pattern), of flexors during extensor activation or of flexors and extensors in more complex movements involving cocontraction of other flexors and extensors. It is postulated that group II inhibition depends on conjoint activation from spindle afferents and other sources (descending and/or the FRA) so that inhibition may be coupled to group II excitation of other motoneurones. Such a coupling would correspond to the --linkage in reciprocal Ia inhibition (Lundberg 1970) and is denoted --linkage in lateral group II inhibition. FRA and other reflex pathways. Results are summarized showing that the FRA evoke convergent excitation in interneurones not only in group II reflex pathways but also in other reflex pathways like the reciprocal Ia inhibitory, the nonreciprocal group I inhibitory and probably also in specialized reflex pathways from cutaneous afferents. It is inferred that facilitation of reflex transmission by impulses in the FRA evoked by the active movement may be a general principle. In this way reflex transmission to -motoneurones may be weak at rest and not disturb passive movements but have a high gain when the reflexes are required to regulate active movement.This work was supported by the Swedish Medical Research Council (project no. 94)     

Early influx of horseradish peroxidase into axons of the hypoglossal nerve during Wallerian degeneration.

Horseradish peroxidase (HRP) was applied around mouse hypoglossal nerves which were damaged by a crush or a ligature. HRP was then visualized distal to the lesions by light- and electron microscopic histochemistry. At the injury the enzyme entered axons and could also be detected several millimetres down in the distal segment. By 24 h reaction product (r.p.) was either diffusely distributed in the axoplasm or present in various vesicular organelles. Our results indicate that there is a rapid influx of macromolecules into axons after a lesion to a nerve. A similar uptake of 'wound substances' into axons distal to an injury might well have some relation to the process by which axonal breakdown is initiated during Wallerian degeneration.