Sorafenib in metastatic uveal melanoma: efficacy, toxicity and health-related quality of life in a multicentre phase II study.

BACKGROUND: The aim of the study was to analyse efficacy, safety, and health-related quality of life (HRQoL) for sorafenib treatment in patients with metastatic uveal melanoma. METHODS: A multicentre, single-arm phase II trial was conducted. The primary objective was to determine the non-progression rate (RECIST) at 24 weeks for patients receiving sorafenib at a dose of 800 mg per day. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and HRQoL. RESULTS: Thirty-two patients were included. Ten patients showed non-progression at 24 weeks (31.2%) without objective tumour responses. The estimated 24-week PFS was 31.2% (95% CI: 14.8%-47.6%) and the estimated 24-week OS was 62.5% (95% CI: 45.4%-79.6%). Ten patients (34.3%) had at least one grade 3 or 4 adverse reaction and 12 patients (41.4%) required dose modifications due to toxicity. At 24 weeks, no patient had an improvement in global HRQoL and 87.5% experienced a permanent increase in physical fatigue. CONCLUSIONS: Sorafenib demonstrated non-progression at 24 weeks in 31.2% of patients. However, 41.4% of patients required dose modifications due to toxicity and no improvement in HRQoL was demonstrated.

Small molecule TSHR agonists and antagonists.

TSH activates the TSH receptor (TSHR) thereby stimulating the function of thyroid follicular cells (thyrocytes) leading to biosynthesis and secretion of thyroid hormones. Because TSHR is involved in several thyroid pathologies, there is a strong rationale for the design of small molecule "drug-like" ligands. Recombinant human TSH (rhTSH, Thyrogen(®)) has been used in the follow-up of patients with thyroid cancer to increase the sensitivity for detection of recurrence or metastasis. rhTSH is difficult to produce and must be administered by injection. A small molecule TSHR agonist could produce the same beneficial effects as rhTSH but with greater ease of oral administration. We developed a small molecule ligand that is a full agonist at TSHR. Importantly for its clinical potential, this agonist elevated serum thyroxine and stimulated thyroidal radioiodide uptake in mice after its absorption from the gastrointestinal tract following oral administration. Graves' disease (GD) is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate TSHR. We identified the first small molecule TSHR antagonists that inhibited TSH- and TSAb-stimulated signalling in primary cultures of human thyrocytes. Our results provide proof-of-principle for effectiveness of small molecule agonists and antagonists for TSHR. We suggest that these small molecule ligands are lead compounds for the development of higher potency ligands that can be used as probes of TSHR biology with therapeutic potential.

[Impact of therapeutic riding on gait and posture regulation]. / Der Einfluss des Therapeutischen Reitens auf den Gang und die Haltungsregulation.

BACKGROUND: Hippotherapy has become an important therapeutic option in patients suffering from motoric dysfunction. The physiologic basis of this approach is the three-dimensional transmission of the horse's motion onto the patients body. These motion stimuli are believed to exert possitve effects on the patients's postural control systems. AIM: To test the hypothesis that hippotherapy has both positive short- and lang-term effects on gait and posture control of persons suffering from motoric disabilities. METHODS: Twenty-two children and adolescents aged 9.69 +/- 4.01 years (range: 9.69 +/- 4.01 years) with motoric dysfunctions were included in a prospective matched control study. In each participant, gait and posture control were investigated on four different occasions (O1 - O4) using the Interactive balance system (IBS; Tetrax Inc., Ramat Gan, Israel) and the portable gait analysis sytem RehaWatch (Hasomed, Magdeburg, Germany). The dates of gait and posture analysis were defined as follows: O 1: immediately prior to first therapeutic riding session (TRS); O 2: immediately after first TRS; O 3: after the last day of an eight weeks period of daily TRS; O 4: seven weeks later after a TRS free interval. RESULTS: The following parameters were slightly improved (adjusted significance level of p < 0.003) after eight weeks of therapeutic riding: (O1 vs. O 3): (1) walking distance (p = 0.009, eta(2) = 0.339); (2) pace frequency (p = 0.007, eta(2) = 0.358); (3) walking speed (p = 0.006, eta(2) = 0.367), and (4) time of attachment (p = 0.007, eta(2) = 0.360). The only short-term effect observed was a significant decrease of the attachment phase (p = 0.002, eta(2) = 0.387). Interestingly, gait symmetry remained unaffected. Posturography (adjusted significance level of p < 0.01) at O 1 versus O 2 (short-term) showed a significant decrease of the performance of both the visual-nigrostriatal subsystem (p < 0.001) and the somato-sensory subsystem (p = 0.001). At O 1 versus O 3 (long-term), the following parameters were sharply decreased: (1) postural stability (p = 0.011), and (2) somatosensory performance (p = 0.011). CONCLUSIONS: In the individuals investigated, an eight weeks series of therapeutic riding did not improve posture control and had only a small positive effect on gait performance. The reasons for these rather disappointing results could have been the low number of therapeutic riding sessions (0.5 sessions per week), and the relatively short duration (30 min) of each session. It remains to be seen, whether a higher density and longer duration of therapeutic riding sessions yields better results.

[Prognostic factors for malignant uveal melanoma. Retrospective study on 2,241 patients and recent contribution of monosomy-3 research]. / Facteurs pronostiques du mélanome malin de l'uvée. Etude rétrospective sur 2,241 patients et apport récent de la recherche de la monosomie 3.

INTRODUCTION: We conducted a retrospective study on the clinical factors influencing the local and general prognosis of patients treated for uveal melanoma with a preliminary analysis of the prognostic value of monosomy 3. PATIENTS: and method: The patients sent to Curie Institute for uveal melanoma have a complete initial clinical evaluation, conservative management by radiotherapy or enucleation, and local and general long-term follow-up. Over the last 5 years, the status of chromosome 3 has been assessed by FISH in the tumors of enucleated patients. Findings concerning the initial workup, treatment, and follow-up are recorded prospectively. We conducted a retrospective study with multivariate analysis of the clinical factors influencing local recurrence, ocular conservation metastasis, and survival and studied the effect of monosomy 3. RESULTS: A total of 2241 patients were registered with a median follow-up of 72 months. Of these patients, 92.8% had conservative management with iodine 125 brachytherapy or proton beam therapy and 7.2% of the patients had enucleation (n=160). Tumors from 120 patients were studied for the status of chromosome 3 by FISH. The overall survival rate was 76.3% and the metastatic rate was 19.5%. The clinical factors influencing survival were the size and location of the tumor, age of the patient, gender, and initial treatment. The factors influencing the metastatic risk were the same plus retinal detachment and local recurrence. Monosomy 3 was a significant risk factor for metastatic disease. DISCUSSION: This study found the usual risk factors with the difference that location on the equator seems to be of worse prognosis than ciliary body involvement for survival and metastasis. In addition, the initial retinal detachment appears to be a risk factor for local recurrence and metastasis. At present, the evaluation of chromosome 3 is available for enucleated tumors but it could probably be done on needle biopsy performed during conservative management as well. CONCLUSION: This study confirms previous results on the prognostic factors of uveal melanoma and on the value of monosomy 3. The increasingly precise identification of a group of high-risk patients should allow us to propose adjuvant therapy and to adapt follow-up.

Teaching psychosomatic (biopsychosocial) medicine in United States medical schools: survey findings.

OBJECTIVE: A survey of US medical schools regarding the incorporation of psychosomatic (biopsychosocial) medicine topics into medical school curriculum was conducted. The perceived importance and success of this curriculum, barriers to teaching psychosomatic medicine, and curricular needs were also assessed. METHODS: From August 1997 to August 1999, representatives of US medical schools were contacted to complete a survey instrument either by telephone interview or by written questionnaire. RESULTS: Survey responses were received from 54 of the 118 US medical schools contacted (46%). Responses were obtained from representatives of both public (57%) and private (43%) institutions. Only 20% of respondents indicated that their schools used the term "psychosomatic medicine"; the terms "behavioral medicine" (63%) and "biopsychosocial medicine" (41%) were used more frequently. Coverage of various health habits (eg, substance use and exercise) ranged from 52% to 96%. The conceptualization and/or measurement of psychosocial factors (eg, stress and social support) was taught by 80% to 93% of schools. Teaching about the role of psychosocial factors in specific disease states or syndromes ranged from 33% (renal disease) to 83% (cardiovascular disease). Coverage of treatment-related issues ranged from 44% (relaxation/biofeedback) to 98% (doctor-patient communication). Topics in psychosomatic medicine were estimated to comprise approximately 10% (median response) of the medical school curriculum. On a scale of 1 (lowest) to 10 (highest), ratings of the relative importance of this curriculum averaged 7 (SD = 2.5; range = 2-10). Student response to the curriculum varied from positive to mixed to negative. Perceived barriers to teaching psychosomatic medicine included limited resources (eg, time, money, and faculty), student and faculty resistance, and a lack of continuity among courses. Sixty-three percent of respondents expressed an interest in receiving information about further incorporation of topics in psychosomatic medicine into their school's curriculum. CONCLUSIONS: Results of this survey reveal variable coverage of specific psychosomatic medicine topics in the medical school curriculum and differential use of nomenclature to refer to this field. There is a need for further curricular development in psychosomatic medicine in US medical schools.

Linkage of familial euthyroid goiter to the multinodular goiter-1 locus and exclusion of the candidate genes thyroglobulin, thyroperoxidase, and Na+/I- symporter.

Iodine deficiency is the most important etiological factor for euthyroid endemic goiter. However, family and twin pair studies also indicate a genetic predisposition for euthyroid simple goiter. In hypothyroid goiters several molecular defects in the thyroglobulin (TG), thyroperoxidase (TPO), and Na+/I- symporter (NIS) genes have been identified. The TSH receptor with its central role for thyroid function and growth is also a strong candidate gene. Therefore, we investigated a proposita with a relapsing euthyroid goiter and her family, in which several members underwent thyroidectomy for euthyroid goiter. Sequence analysis of the complementary DNA (cDNA) of the TPO and TSH receptor genes revealed several previously reported polymorphisms. As it is not possible to exclude a functional relevance for all polymorphisms, we opted for linkage analysis with microsatellite markers to investigate whether the candidate genes are involved in the pathogenesis of euthyroid goiter. The markers for the genes TG, TPO, and NIS gave two-point and multipoint logarithm of odds score analysis scores that were negative or below 1 for all assumed recombination fractions. As no significant evidence of linkage was found, we conclude that these candidate genes can be excluded as a major cause of the euthyroid goiters in this family. In contrast, we have found evidence for linkage of familial euthyroid goiter to the recently identified locus for familial multinodular nontoxic goiter (MNG-1) on chromosome 14q. The haplotype cosegregates clearly with familial euthyroid goiter. Our results provide the first confirmation for MNG-1 as a locus for nontoxic goiter.

Role-played interpersonal interaction: ecological validity and cardiovascular reactivity.

Conflictual role-play scenarios have been used to model brief interpersonal interaction and to elicit cardiovascular reactivity in the laboratory. Here we discuss data suggesting that role-played interactions constitute an ecologically valid laboratory task that may improve laboratory-to-field generalization of cardiovascular response. Specifically, our research indicates that young adults perceive the stress associated with role-play scenarios as similar to that encountered in everyday life. Furthermore, these stress appraisals moderate cardiovascular response to role-play in men. We also find that a social stressor (i.e. speech task) is perceived as significantly more similar to a real-life stressor as compared to other standard laboratory tasks. We propose that particular constellations of cognitive, affective, and behavioral responses to laboratory-based social stressors, such as role-played interaction, may elicit different patterns of hemodynamic response. Further understanding of interrelations among cognitive, affective, behavioral, and physiological response patterns may assist in the study of cardiovascular reactivity as a potential mechanism linking personality factors and the development of cardiovascular disease.

Plasticity of cortico-thalamic projections and functional recovery in the unilateral detelencephalized infant rat.

Previous results have shown that the unilateral removal of the telencephalon in adult rats leads to the appearance of crossed connections from the remaining telencephalon to the thalamus one week after the ablation. This study extends this finding to infant rats. The telencephalon structures were unilaterally removed in 7-day-old animals. As in adult rats the ablation induced behavioral asymmetries, including active turning behavior which ceased within the first days after the lesion. Either immediately after the ablation or one week thereafter the animals were injected with horseradish peroxidase (HRP) into the posterior part of the thalamus ipsilateral to the lesion. HRP-labeled cells appeared in the remaining contralateral cortex in animals that were injected one week after the lesion. Rapid functional recovery from the lesion-induced behavioral asymmetries, as indicated, for example, by the cessation of spontaneous turning behavior, may be related to the observed appearance of crossed projections between structures that are normally connected only ipsilaterally.