Concurrent chemoradiation strategies in the management of unresectable stage III non-small-cell lung cancer

Locally advanced or unresectable stage III non-small-cell lung cancer (NSCLC) patients treated with combined-modality therapy with chemotherapy plus thoracic radiation have improved survival compared to those treated with radiotherapy alone. Furthermore, recent studies in good performance status, stage III patients have shown that concurrent chemoradiotherapy improves survival compared to sequential chemoradiotherapy. However, the optimal chemoradiation approach continues to evolve and is the subject of this review. Since the majority of patients completing chemoradiotherapy will succumb to distant metastatic disease, active systemic agents targeting this tumor compartment are required. Recent data suggest that full-dose chemotherapy designed to eradicate distant micrometastases given either as induction or consolidation has the potential to yield improved patient outcomes. Many of these chemotherapeutic agents are also potent radiosensitizers, hence providing enhanced local control. The integration of these chemotherapeutic agents into chemoradiotherapy programs in stage III NSCLC is the focus of current trials. Ongoing research with novel therapeutic agents with activity against distant micrometastases, refined radiation techniques, and enhanced imaging methodologies to aid in accurate staging are being pursued and should lead to improved survival and toxicity outcomes in this disease.     

Trends in use of adjuvant multi-agent chemotherapy and tamoxifen for breast cancer in the United States: 1975-1999

BACKGROUND: Understanding trends in the dissemination of findings from clinical research can help in estimating their population-level benefits. We evaluated trends in the use of adjuvant multi-agent chemotherapy, tamoxifen, and the combination of both treatments for early-stage breast cancer in the United States from 1975 through 1999. METHODS: Data on treatment of 217 508 patients diagnosed from 1975 through 1999 with stages I, II, and IIIA breast cancer were obtained from eight registries of the Surveillance, Epidemiology, and End Results (SEER) Program. Models of dissemination were developed from these data after adjustment based on information from a series of population-based Patterns of Care (POC) studies that randomly selected case patients from the SEER registries. The POC studies included 7116 patients diagnosed from 1987 through 1991 and in 1995 who were eliminated from the SEER data used in this analysis. RESULTS: The modeled disseminations were generally compatible with the POC-observed proportions of each treatment. The use of multi-agent chemotherapy was higher among premenopausal women, and the use of tamoxifen was higher among postmenopausal women. The use of multi-agent chemotherapy for postmenopausal women diagnosed with lymph node-positive stage II+ or stage IIIA cancer reached a peak in 1983 and then decreased through 1986, indicating its substitution with tamoxifen. After 1986, the combined use of multi-agent chemotherapy and tamoxifen increased for almost all stages and ages. After the early 1990s, tamoxifen use in postmenopausal women with stage II+ or stage III breast cancer declined. CONCLUSIONS: The observed dissemination patterns suggest that the results of clinical trials are disseminated fairly rapidly to community-based physicians and their patients.     

Phase II trial of Paclitaxel and Dacarbazine with filgrastim administration in advanced malignant melanoma

A Phase II trial was conducted in patients with advanced malignant melanoma with intravenous Paclitaxel and Dacarbazine (DTIC). The initial starting dose for Paclitaxel was 135 mg/m² followed by DTIC 800 mg/m². Due to the lack of myelosuppression and other toxicities, the starting dose for Paclitaxel was escalated to 250 mg/m² and the dose for DTIC escalated to l000 mg/m². Twenty-five patients were enrolled in this study. Among the 25 patients assessable for response, three patients had a partial response with a response rate of 12% (CI 3-31%) and one patient had stable disease. Three additional patients showed evidence of anti-tumor activity with minor responses. For patients who had no prior chemotherapy or biochemotherapy, the response rate was 20%. Toxicity was generally tolerable and included mainly neurotoxicity from Paclitaxel. At the doses and schedule used, the combination of Paclitaxel and DTIC did not appear to increase the response rate compared to each agent used singly.     

Evidence for a neuroanatomical difference within the olivo-cerebellar pathway of adults with dyslexia

Recent behavioural evidence has indicated that cerebellar impairment may be strongly associated with dyslexia. Previous neuroanatomical research has shown the presence of anomalies within the cerebral cortex of brains of dyslexic people. This paper reports equivalent analyses on the cerebella of the same brain specimens. Cross sectional areas and cell packing densities of Purkinje cells in the cerebellar cortex, and cells in the inferior olivary and dentate nuclei of four dyslexic and four control brains were measured using the dissector method. A significant difference in mean cell area in medial posterior cerebellar cortex was identified, with the dyslexic cells having larger mean area. Furthermore, analysis of cell size distributions not only confirmed the significant differences in the posterior lobe, with an increased proportion of large neurons and fewer small neurons for the dyslexics, but also revealed significant differences in the anterior lobe, again with a pattern of more large and fewer small cells. Similar distributional differences were seen in the inferior olive. No differences were found in the flocculonodular lobe or the dentate nucleus. While caution is necessary in generalising from the results given the small number of specimens, together with the age difference, the neuroanatomical data established here provides further converging evidence of cerebellar abnormality in dyslexia.     

Sensation of effort is altered in Huntington's disease

In this study, we investigated sensation of effort in Huntington disease (HD). We tested the hypothesis that the basal ganglia are involved in processing effort sensation. The experimental paradigm consisted in a contralateral matching procedure where normal subjects (N=6) and HD patients (N=6) were required to lift a reference weight with their non-dominant index, and then compare the target-weight with variable weights lifted by the dominant index. Two kinds of sequences were administered: (1) increasing, where the first weight was lighter than the reference weight and progressively increased in 20g steps, (2) decreasing, where trials started with a heavier weight and progressively decreased. We calculated the discrimination threshold (DT) across sequences as the weight for which the subject's response changed sign. The difference between the higher and the lower threshold was defined as "uncertain area". We predicted that controls should overestimate the reference weight lifted by their non-dominant hand because the same effort produces more force when applied to stronger muscles. If the basal ganglia mediates sensation of effort, patients' capability to discriminate weights should be degraded. As expected, normal subjects overestimated the reference weight lifted by their non-dominant index and showed a restricted uncertain area, thus, indicating that were able to discriminate minimal differences in generated forces. By contrast, patients with HD underestimated the reference weight lifted by their non-dominant hand and showed a broad uncertain area, thus, demonstrating that they could detect only important differences in the matched efforts. These results suggest that effort sensation critically involves the basal ganglia. In normal conditions, in parallel with the efferent command of force, an efferent copy reflecting the magnitude of the voluntary motor command is transmitted to sensory centres. This signal and/or the integration of sensory feedback which generates what is experienced as the sense of effort, would be altered in HD.     

Biological mechanisms in the relationship between depression and heart disease

Psychological depression is shown to be associated with several aspects of coronary artery disease (CAD), including arrhythmias, myocardial infarction, heart failure and sudden death. The physiological mechanisms accounting for this association are unclear. Hypothalamic–pituitary–adrenal dysregulation, diminished heart rate variability, altered blood platelet function and noncompliance with medial treatments have been proposed as mechanisms underlying depression and cardiovascular disease. Recent evidence also suggests that reduced baroreflex sensitivity, impaired immune function, chronic fatigue and the co-morbidity of depression and anxiety may be involved in the relationship between depression and cardiovascular dysregulation. An experimental strategy using animal models for investigating underlying physiological abnormalities in depression is presented. A key to understanding the bidirectional association between depression and heart disease is to determine whether there are common changes in brain systems that are associated with these conditions. Such approaches may hold promise for advancing our understanding of the interaction between this mood disorder and CAD.     

Biomedical assessment and instrumental evaluation of healthy infant skin

The skin forms a critical structural boundary and a perceptual interface for the organism, yet the definition "healthy skin" is surprisingly difficult to describe. The present study's goal was to generate a technical definition of healthy infant skin by quantifying specific biophysical parameters before and after bathing in infants and correlating such parameters to a perceptual maternal evaluation. Fifty-two healthy infants, 3-6 months old, were evaluated before and after freshwater bathing. Diapered skin had a higher transepidermal water loss (TEWL), surface hydration, moisture accumulation rate (MAT), and friction than nondiapered skin before the bath (p < 0.01). Bathing dramatically altered the biophysical properties at both skin sites, with decreased MAT and lower friction, indicating a drier skin surface (p < 0.01). Visual redness and dryness decreased after bathing (p < 0.01). Blinded grading of optical images showed a significant preference for the skin after bathing (p < 0.01). This study provides the first quantitative technical definition of healthy infant skin with positive correlation to perceptual assessment by independent observers (mothers). The findings support the hypothesis that water binding properties of the stratum corneum are altered by occlusion (diapering) and that bathing introduces acute changes in stratum corneum water interactions, leading to a drier skin surface and a preferred skin appearance.     

Paternal germline mosaicism in Herlitz junctional epidermolysis bullosa

We studied a single patient with the lethal (Herlitz) type of junctional epidermolysis bullosa (H-JEB). Screening for mutations in the LAMB3 gene in the patient revealed the previously described hotspot mutation R635X and a novel one basepair deletion in exon 10. The single basepair deletion 1094delA could be detected in the clinically unaffected mother, while the nonsense mutation R635X could not be found in the peripheral blood DNA of either parent. After excluding non-paternity by microsatellite analysis using random markers on chromosomes 3, 8 and 18, we determined that the mutation R635X in the proband was most likely the result of a de novo event or alternatively, germline mosaicism. The parents requested prenatal diagnosis for a second pregnancy, and while the maternal mutation 1094delA could not be detected in DNA from the fetus, unexpectedly, the mutation R635X was present in the chorionic villus DNA. These findings were most consistent with paternal germline mosaicism for the recessive mutation R635X. The results have had a significant impact on the genetic counseling in this family. To our knowledge, this study represents the first documented case of germline mosaicism in junctional epidermolysis bullosa, and serves as a reminder that germline mosaicism should be considered in cases in which a 'new' mutation is found in the offspring of a clinically and/or genetically unaffected parent.     

A genome-wide scan for linkage to chromosomal regions in 382 sibling pairs with schizophrenia or schizoaffective disorder

OBJECTIVE: Some genome-wide scans and association studies for schizophrenia susceptibility genes have yielded significant positive findings, but there is disagreement between studies on their locations, and no mutation has yet been found in any gene. Since schizophrenia is a complex disorder, a study with sufficient power to detect a locus with a small or moderate gene effect is necessary. METHOD: In a genome-wide scan of 382 sibling pairs with a diagnosis of schizophrenia or schizoaffective disorder, 396 highly polymorphic markers spaced approximately 10 centimorgans apart throughout the genome were genotyped in all individuals. Multipoint nonparametric linkage analysis was performed to evaluate regions of the genome demonstrating increased allele sharing, as measured by a lod score. RESULTS: Two regions with multipoint maximum lod scores suggesting linkage were found. The highest lod scores occurred on chromosome 10p15-p13 (peak lod score of 3.60 at marker D10S189) and the centromeric region of chromosome 2 (peak lod score of 2.99 at marker D2S139). In addition, a maximum lod score of 2.00 was observed with marker D22S283 on chromosome 22q12, which showed evidence of an imprinting effect, whereby an excess sharing of maternal, but not paternal, alleles was present. No evidence of linkage was obtained at several locations identified in previous studies, including chromosomes 1q, 4p, 5p-q, 6p, 8p, 13q, 15p, and 18p. CONCLUSIONS: The findings of this large genome-wide scan emphasize the weakness and fragility of linkage reports on schizophrenia. No linkage appears to be consistently replicable across large studies. Thus, it has to be questioned whether the genetic contribution to this disorder is detectable by these strategies and the possibility raised that it may be epigenetic, i.e., related to gene expression rather than sequence variation. Nevertheless, the positive findings on chromosome 2, 10, and 22 should be pursued further.     

Maternal bonding behaviour in schizophrenia and schizoaffective disorder,considering premorbid personality traits

OBJECTIVE: Bonding between mother and child is described as a complex two-way process ensuring the needs of the child for nurture and protection. As such, it is dependent on the contribution of mother and child [1-3] whereby characteristics of personality of the child may have consequences on maternal bonding behaviour. In the current study the perception of maternal behaviour, premorbid personality traits and relationships between maternal behaviour and personality traits were investigated in schizophrenic and schizoaffective patients and their same-sex, healthy siblings. METHODS: We recruited 36 schizophrenic and schizoaffective patients and their same-sex healthy siblings. Information about maternal bonding behaviour was assessed by the Parental Bonding Instrument, information about premorbid personality traits was obtained from their mothers using the "Giessen-Test". RESULTS: Compared to their siblings, patients showed less social resonance, more permeability, less social competence and a more depressed and anxious mood. Furthermore, patients described their mothers to be less caring and to be more overprotective than their siblings described them. But there were strong associations between maternal bonding behaviour and premorbid personality traits. These findings were supported by missing significant differences in maternal care behaviour between patients and siblings when using premorbid characteristics as covariates. Significant high maternal overprotection perceived by patients with schizophrenia and schizoaffective disorders still remained after correcting for the influence of premorbid personality traits. CONCLUSION: The results suggest that premorbid personality traits should be considered not only in analyses of maternal care behaviour in schizophrenic and schizoaffective patients but also when studying other psychiatric patient groups.