PEACE V - Salvage Treatment of OligoRecurrent nodal prostate cancer Metastases (STORM): a study protocol for a randomized controlled phase II trial.

BACKGROUND: Pelvic nodal recurrences are being increasingly diagnosed with the introduction of new molecular imaging techniques, like choline and PSMA PET-CT, in the restaging of recurrent prostate cancer (PCa). At this moment, there are no specific treatment recommendations for patients with limited nodal recurrences and different locoregional treatment approaches are currently being used, mostly by means of metastasis-directed therapies (MDT): salvage lymph node dissection (sLND) or stereotactic body radiotherapy (SBRT). Since the majority of patients treated with MDT relapse within 2 years in adjacent lymph node regions, with an estimated median time to progression of 12-18 months, combining MDT with whole pelvic radiotherapy (WPRT) may improve oncological outcomes in these patients. The aim of this prospective multicentre randomized controlled phase II trial is to assess the impact of the addition of WPRT to MDT and short-term androgen deprivation therapy (ADT) on metastasis-free survival (MFS) in the setting of oligorecurrent pelvic nodal recurrence. METHODS & DESIGN: Patients diagnosed with PET-detected pelvic nodal oligorecurrence (≤5 nodes) following radical local treatment for PCa, will be randomized in a 1:1 ratio between arm A: MDT and 6 months of ADT, or arm B: WPRT added to MDT and 6 months of ADT. Patients will be stratified by type of PET-tracer (choline, FACBC or PSMA) and by type of MDT (sLND or SBRT). The primary endpoint is MFS and the secondary endpoints include clinical and biochemical progression-free survival (PFS), prostate cancer specific survival, quality of life (QoL), toxicity and time to castration-resistant prostate cancer (CRPC) and to palliative ADT. Estimated study completion: December 31, 2023. DISCUSSION: This is the first prospective multicentre randomized phase II trial assessing the potential of combined WPRT and MDT as compared to MDT alone on MFS for patients with nodal oligorecurrent PCa. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03569241, registered June 14, 2018, ; Identifier on Swiss National Clinical Trials Portal (SNCTP): SNCTP000002947, registered June 14, 2018.

Psychosocial Functioning of Children with and without Dyslexia: A Follow-up Study from Ages Four to Nine.

This longitudinal study compares developmental changes in psychosocial functioning during the transition into school of children with and without dyslexia. In addition, it examines the effects of gender and family risk for dyslexia in terms of the associations between dyslexia and psychosocial functioning. Children's psychosocial functioning (social skills, inattention and externalizing and internalizing problems) was evaluated by their parents at ages 4, 6 and 9, and diagnosis for dyslexia was made at age 8 (in grade 2). The findings indicated that children with dyslexia were already rated as having poorer social skills and being more inattentive than were typical readers before their entry into school. Significant interactions of gender and diagnosis of dyslexia emerged for social skills and inattention. The social skills of boys with dyslexia improved after school entry as compared to the level of girls without dyslexia, whereas the social skills of girls with dyslexia did not improve. Boys with dyslexia were rated as showing a high level of inattention both prior to and after school entry, whereas, for girls with dyslexia, inattention ratings increased after school entry, eventually matching the boys' levels.

Bacterial skin flora and contamination of blood components: do we defer blood donors wisely?

BACKGROUND AND OBJECTIVES: Bacterial infection through contaminated blood is currently the greatest infection risk in relation to a transfusion. Deferral of prospective blood donors with a skin disorder is a common practise, because bacteria usually originate from the donor's skin. The effectiveness of current deferral guidelines to prevent the bacterial contamination of blood has not been assessed. MATERIALS AND METHODS: We recruited 55 blood donors with a skin disorder that prevented donation, and matched three controls for each case. The donors filled out a questionnaire and one bacterial culture sample was taken from venepuncture forearm skin. RESULTS: The median total number of colony forming skin bacteria was significantly higher in the cases (224 CFUs per sample) than controls (105 CFU per sample). Staphylococcus aureus was significantly more often present on the skin in cases (49%) as compared to controls (7%). Regarding other bacterial genera, no difference between cases and controls was found. CONCLUSIONS: This study shows that our current guidelines for deferral of blood donors with skin disorders effectively identifies individuals with a high number of bacteria on their skin, as well as S. aureus carriers. However, deferral due to skin disorders had only a minor impact on blood product contamination when compared to other actions.

Inhibition of biogenic amine uptake by hydrogen peroxide: a mechanism for toxic effects of 6-hydroxydopamine.

Hydrogen peroxide, dialuric acid, or 6-hydroxydopamine inhibited the uptake of dopamine, norepinephrine, and serotonin into rat brain synaptosomal preparations. The addition of catalase protected all systems, but catalase was only partially protective for 6-hydroxydopamine acting upon catecholamine uptake. The data show that 6-hydroxydopamine generates hydrogen peroxide and that hydrogen peroxide can damage the biogenic amine uptake systems. Part of the damage caused by the 6-hydroxydopamine that accumulates in the catecholamine nerve terminals in vivo may be attributed to the hydrogen peroxide.

6-Hydroxydopamine: evidence for superoxide radical as an oxidative intermediate.

Superoxide dismutase inhibited the autoxidation of 6-hydroxydopamine as measured by the rate of formation of a quinone and the rate of oxygen consumption. These observations demonstrate the formation of the superoxide radical during the autoxidation process. This finding may be relevant to the mechanism of adrenergic nerve terminal degeneration caused by 6-hydroxydopamine.

Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine in mice.

1-Methyl-4-phenyl-1,2,5,6- tetrahydropyri dine ( MPTP ) is known to cause an irreversible destruction of the dopaminergic nigrostriatal pathway and symptoms of parkinsonism in humans and in monkeys. However, MPTP has been reported to act only minimally or not at all in several other animal species. When MPTP (30 milligrams per kilogram of body weight) was administered parenterally to mice, a decrease in concentrations of neostriatal dopamine and its metabolites, a decrease in the capacity of neostriatal synaptosomal preparations to accumulate [3H]dopamine, and a disappearance of nerve cells in the zona compacta of the substantia nigra were observed. In contrast, MPTP administration had no effect on neostriatal concentrations of serotonin and its metabolites. MPTP administration thus results in biochemical and histological changes in mice similar to those reported in humans and monkeys and similar to those seen in Parkinson's disease in humans. The mouse should prove to be a useful small animal with which to study the mode of action of MPTP .

Role for excitatory amino acids in methamphetamine-induced nigrostriatal dopaminergic toxicity.

The systemic administration of either methamphetamine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to experimental animals produces degenerative changes in nigrostriatal dopaminergic neurons or their axon terminals. This study was conducted to determine if excitatory amino acids, which appear to be involved in various neurodegenerative disorders, might also contribute to the dopaminergic neurotoxicity produced in mice by either methamphetamine or MPTP. MK-801, phencyclidine, and ketamine, noncompetitive antagonists of one subtype of excitatory amino acid receptor, the N-methyl-D-aspartate receptor, provided substantial protection against neurotoxicity produced by methamphetamine but not that produced by MPTP. These findings indicate that excitatory amino acids play an important role in the nigrostriatal dopaminergic damage induced by methamphetamine.

A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer.

BACKGROUND: To compare irinotecan with the Nordic 5-fluorouracil (5-FU) and folinic acid (FA) bolus schedule [irinotecan 180 mg/m(2) on day 1, 5-FU 500 mg/m(2) and FA 60 mg/m(2) on day 1 and 2 (FLIRI)] or the Lv5FU2 schedule [irinotecan 180 mg/m(2) on day 1, FA 200 mg/m(2), 5-FU bolus 400 mg/m(2) and infused 5-FU 600 mg/m(2) on day 1 and 2 (Lv5FU2-IRI)] due to uncertainties about how to administrate 5-FU with irinotecan. PATIENTS AND METHODS: Patients (n = 567) with metastatic colorectal cancer were randomly assigned to receive FLIRI or Lv5FU2-IRI. Primary end point was progression-free survival (PFS). RESULTS: Patient characteristics were well balanced. PFS did not differ between groups (median 9 months, P = 0.22). Overall survival (OS) was also similar (median 19 months, P = 0.9). Fewer objective responses were seen in the FLIRI group (35% versus 49%, P = 0.001) but the metastatic resection rate did not differ (4% versus 6%, P = 0.3). Grade 3/4 neutropenia (11% versus 5%, P = 0.01) and grade 2 alopecia (18% versus 9%, P = 0.002) were more common in the FLIRI group. The 60-day mortality was 2.4% versus 2.1%. CONCLUSIONS: Irinotecan with the bolus Nordic schedule (FLIRI) is a convenient treatment with PFS and OS comparable to irinotecan with the Lv5FU2 schedule. Neutropenia and alopecia are more prevalent, but both regimens are equally well tolerated.

Behavioral correlations of dopamine receptor activation.

According to the classification scheme of Kebabian and Calne, there are two types of dopamine (DA) receptors: D1 (activation of which causes increased cyclic AMP formation) and D2 (activation of which causes no increment in cyclic AMP). It is not clear what role the different receptors play in mediating motor behavior. Using drugs that act selectively at only one receptor site, we studied the effects of D1 and D2 receptor activation in two different models of parkinsonism--the rotating rat and the reserpinized mouse. Neither the D1 agonist nor the D2 agonist, given alone, could overcome reserpine akinesia, but together they restored locomotor activity. In rats with unilateral nigrostriatal lesions, both drugs induced a rotational response, each with a distinct temporal pattern. Pretreatment with alpha-methyl-paratyrosine (an inhibitor of DA synthesis) led to decrements in the rotational response induced by D2 agonists, but not that induced by D1 agonists. The mechanism by which these DA agonists induce motor activity is different; activation of both types of DA receptors seems to be necessary for normal motor behavior.

Pergolide-induced circling in rats with 6-hydroxydopamine lesions in the nigrostriatal pathway.

In rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal system we compared the behavioral effects of pergolide with those of L-dopa, bromocriptine, and lergotrile. In this animal model of parkinsonism, doses of 0.25 mg per kilogram pergolide (free base) induced vigorous circling for 24 hours. Pergolide was more potent than bromocriptine or lergotrile. Pretreatment with alpha-methylparatyrosine nearly abolished the effects of bromocriptine, markedly diminished the effects of lergotrile, and only partially diminished the effects of pergolide. These findings suggest that pergolide should be more effective than bromocriptine in the treatment of parkinsonism.

Experience with continuous enteral levodopa infusions in the treatment of 9 patients with advanced Parkinson's disease.

Nine patients with advanced Parkinson's disease were started on continuous enteral levodopa infusions during the past 3 years. Six have remained on the infusion system for 1 to 28 months. All patients experienced immediate amelioration of motor fluctuations, and 5 patients continue to obtain relief. One patient found that his ability to achieve the "on" state without unacceptable dyskinesia waned. Experience thus far indicates that continuous long-term levodopa infusions are a practical but complex form of therapy for patients failing more conventional treatment.

Continuous levodopa infusions to treat complex dystonia in Parkinson's disease.

We report the clinical spectrum of 3 patients with Parkinson's disease who experienced complex patterns of levodopa-related dystonia. Dystonia was unrelieved by multiple medication regimens but responded well to continuous, duodenal levodopa infusions. Patients were able to remain mobile without severe dystonia despite a very narrow window of benefit between the levodopa concentration necessary to achieve the "on" state and that which caused the onset of dystonic spasms.

Meige syndrome in the spectrum of Lewy body disease.

We report a patient with Meige syndrome (segmental cranial dystonia) who had neuropathologic changes of Parkinson's disease on postmortem examination. Neuropathologic examination showed typical and atypical Lewy bodies in the pigmented nuclei of the brainstem (substantia nigra, locus ceruleus), the nucleus basalis of Meynert, and the nucleus ambiguus. Neurochemical analysis of postmortem brain tissue showed evidence for decreased dopamine turnover in the substantia nigra, striatum, and nucleus accumbens. We propose that some cases of Meige syndrome may be included in the spectrum of Lewy body disease.

Ascorbic acid and the binding of DA agonists to neostriatal membrane preparations.

A considerable controversy exists over whether ascorbic acid should or should not be used in experiments in which the binding of DA agonists to neostriatal membrane preparations is being determined. Some authors claim that its presence is required. In the present study we have determined that sodium ascorbate was a very potent inhibitor of the specific binding of 3H-DA to a rat neostriatal membrane preparation. Under conditions of these binding experiments, there was no decomposition of the 3H-DA as determined by two separate techniques. These data would seem to suggest that when 3H-DA binding is being measured, ascorbate addition is detrimental.

Effects of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine on neostriatal dopamine in mice.

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) causes a destruction of the nigrostriatal dopamine pathway in humans as well as in monkeys. However, it has been reported that MPTP is inert in several small animal species. We now report that MPTP, given to mice at 30 mg/kg intraperitoneally, causes severe and long-lasting depletions of dopamine and its major metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the neostriatum.

A correlation of bombesin-responsiveness with myc-family gene expression in small cell lung carcinoma cell lines.

Bombesin is a 14 amino acid peptide originally isolated from amphibian skin; its mammalian homolog is gastrin-releasing peptide (GRP). GRP is found in a high proportion of human small cell lung cancer (SCLC) cell lines. [Tyr4]bombesin caused an increase in intracellular Ca2+ ([Ca2+]i) in 5/11 SCLC cell lines tested. Bombesin action was not inhibited by agents known to alter the plasma membrane potential, nor did replacement of external Na+ with choline affect the bombesin-induced signal. [Tyr4]bombesin did not itself affect the membrane potential. Chelation of external Ca2+ reduced but did not prevent the bombesin-evoked increase in [Ca2+]i. This suggested that in SCLC, bombesin congeners not only promote an influx of extracellular Ca2+ but also release Ca2+ from intracellular stores. [Tyr4]bombesin increased levels of inositol 1,4,5-trisphosphate within seconds of addition to SCLC cell cultures and enhanced the accumulation of inositol 1-phosphate and inositol 4-phosphate in the presence of Li+. The SCLC cell lines responsive to bombesin constitutively expressed L-myc and did not express c-myc or N-myc. In contrast, SCLC cells non-responsive to bombesin had prominent constitutive expression of c-myc or N-myc with or without L-myc expression. Responding cell lines also had constitutive expression of the preproGRP gene, while non-responding cell lines showed no evidence of GRP gene expression. These data support the concept that SCLC which constitutively express the GRP gene and L-myc but not c-myc or N-myc can be stimulated in an autocrine fashion by GRP or its congeners to increase [Ca2+]i by a pathway involving phosphatidylinositol turnover.

Effects of dopamine depletion on rotational behavior to dopamine agonists.

The contralateral rotation to various dopamine agonists was determined in rats with unilateral lesions of the left nigrostriatal pathway both with and without dopamine depletion caused by dopamine synthesis inhibition. The rotation to drugs possessing D-2 dopamine agonist activity alone was greatly diminished by dopamine depletion. In contrast, the rotation induced by drug possessing D-1 dopamine agonist activity (either D-1 alone or D-1 plus D-2) was affected to a much lesser extent by dopamine depletion.

The relationship between loss of dopamine nerve terminals, striatal [3H]spiroperidol binding and rotational behavior in unilaterally 6-hydroxydopamine-lesioned rats.

The relationship between the destruction of dopamine-containing nerve terminals, specific binding of [3H]spiroperidol and contralateral rotation in response to L-DOPA, was studied in rats with unilateral lesions of the nigrostriatal dopamine (DA) system, induced by intracerebral injections of the neurotoxin 6-hydroxydopamine (6-OHDA). Animals with significant rotational behavior in response to L-DOPA had both a greater amount of specific binding of [3H]spiroperidol in the lesioned striatum compared to the non-lesioned striatum, and at least 90% destruction of DA terminals in the lesioned striatum (less than 10% of control uptake). The nonrotators to L-DOPA had considerably less destruction of DA terminals and no significant increase in specific binding on the lesioned side. The data from this study suggest that before L-DOPA is effective as an inducer of contralateral rotational behavior, there must be both unilateral damage to the DA terminals greater than 90%, and increased specific binding.

1-Methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'CH3-MPTP)-induced degeneration of mesostriatal dopaminergic neurons in the mouse: biochemical and neuroanatomical studies.

The neurotoxic effects of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'CH3-MPTP), a substituted analog of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, were studied in BALB/cJ mice. Moderate doses of 2'CH3-MPTP produced a greater depletion of dopamine (DA) in the striatum (45%) than in the nucleus accumbens (23%), and in these same animals, there was a 35% loss of midbrain DA neurons. The greatest loss of DA cells occurred within the substantia nigra (43%), and there was also a significant loss of cells within the ventral tegmental area (28%). Higher doses of 2'CH3-MPTP decreased levels of DA more in the axon terminal/forebrain region (72%) than in the cell body/midbrain region (25%). Similar forebrain/midbrain DA depletion ratios were also found in mice that received an electrolytic lesion of the midbrain DA neurons; there was a greater Da depletion in the forebrain (29%) than in the midbrain (8%). In both 2'CH3-MPTP and electrolytically lesioned animals there was a significant increase in DA turnover in the forebrain region, as measured by the homovanillic acid/DA ratio. These data indicate that 2'CH3-MPTP: (1) destroys DA neurons within two midbrain regions containing cells which project to the striatum (i.e. mesostriatal DA neurons), rather than just nigrostriatal DA neurons; (2) produces a greater loss of DA in the axon terminal region than in the cell body region; and (3) influences the mesostriatal DA neurons in the same way as does a lesion to the cell bodies. These data are discussed with regard to the pathophysiology of 2'CH3-MPTP.