Verubulin (Azixa) Analogues with Increased Saturation: Synthesis, SAR and Encapsulation in Biocompatible Nanocontainers Based on Ca2+ or Mg2+ Cross-Linked Alginate.

Tubulin-targeting agents attract undiminished attention as promising compounds for the design of anti-cancer drugs. Verubulin is a potent tubulin polymerization inhibitor, binding to colchicine-binding sites. In the present work, a series of verubulin analogues containing a cyclohexane or cycloheptane ring 1,2-annulated with pyrimidine moiety and various substituents in positions 2 and 4 of pyrimidine were obtained and their cytotoxicity towards cancer and non-cancerous cell lines was estimated. The investigated compounds revealed activity against various cancer cell lines with IC50 down to 1-4 nM. According to fluorescent microscopy data, compounds that showed cytotoxicity in the MTT test disrupt the normal cytoskeleton of the cell in a pattern similar to that for combretastatin A-4. The hit compound (N-(4-methoxyphenyl)-N,2-dimethyl-5,6,7,8-tetrahydroquinazolin-4-amine) was encapsulated in biocompatible nanocontainers based on Ca2+ or Mg2+ cross-linked alginate and it was demonstrated that its cytotoxic activity was preserved after encapsulation.

Anticancer activity of G4-targeting phenoxazine derivatives in vitro.

G4-stabilizing ligands are now being considered as anticancer, antiviral and antibacterial agents. Phenoxazine is a promising scaffold for the development of G4 ligands. Here, we profiled two known phenoxazine-based nucleoside analogs and five new nucleoside and non-nucleoside derivatives against G4 targets from telomere repeats and the KIT promoter region. Leading new derivatives exhibited remarkably high G4-stabilizing effects (comparable or superior to the effects of the commonly used selective G4 ligands PDS and NMM) and selectivity toward G4s over duplex (superior to BRACO-19). All phenoxazine-based ligands inhibited cellular metabolic activity. The phenoxazine derivatives were particularly toxic for lung adenocarcinoma cells A549' and human liver cancer cells HepG2 (CC50 of the nucleoside analogues in the nanomolar range), but also affected breast cancer cells MCF7, as well as immortalized fibroblasts VA13 and embryonic kidney cells HEK293t (CC50 in the micromolar range). Importantly, the CC50 values varied mostly in accordance with G4-binding affinities and G4-stabilizing effects, and the phenoxazine derivatives localized in the cell nuclei, which corroborates G4-mediated mechanisms of action.

White matter lesions and brain atrophy in systemic lupus erythematosus patients: correlation to cognitive dysfunction in a cohort of systemic lupus erythematosus patients using different definition models for neuropsychiatric systemic lupus erythematosus.

Aim The aim of this study was to evaluate the extent of white matter lesions, atrophy of the hippocampus and corpus callosum, and their correlation with cognitive dysfunction (CD), in patients diagnosed with systemic lupus erythematosus (SLE). Methods Seventy SLE patients and 25 healthy individuals (HIs) were included in the study. To evaluate the different SLE and neuropsychiatric SLE (NPSLE) definition schemes, patients were grouped both according to the American College of Rheumatology (ACR) definition, as well as the more stringent ACR-Systemic Lupus International Collaborating Clinics definition. Patients and HIs underwent a 3 Tesla brain MRI and a standardized neuropsychological test. MRI data were evaluated for number and volume of white matter lesions and atrophy of the hippocampus and corpus callosum. Differences between groups and subgroups were evaluated for significance. Number and volume of white matter lesions and atrophy of the hippocampus and corpus callosum were correlated to cognitive dysfunction. Results The total volume of white matter lesions was significantly larger in SLE patients compared to HIs ( p = 0.004). However, no significant differences were seen between the different SLE subgroups. Atrophy of the bilateral hippocampus was significantly more pronounced in patients with NPSLE compared to those with non-NPSLE (right: p = 0.010; left p = 0.023). Significant negative correlations between cognitive test scores on verbal memory and number and volume of white matter lesions were present. Conclusion SLE patients have a significantly larger volume of white matter lesions on MRI compared to HIs and the degree of white matter lesion volume correlates to cognitive dysfunction, specifically to verbal memory. No significant differences in the number or volume of white matter lesions were identified between subgroups of SLE patients regardless of the definition model used.

Randomized assessment of imatinib in patients with acute ischaemic stroke treated with intravenous thrombolysis.

BACKGROUND: Imatinib, a tyrosine kinase inhibitor, has been shown to restore blood-brain barrier integrity and reduce infarct size, haemorrhagic transformation and cerebral oedema in stroke models treated with tissue plasminogen activator. We evaluated the safety of imatinib, based on clinical and neuroradiological data, and its potential influence on neurological and functional outcomes. METHODS: A phase II randomized trial was performed in patients with acute ischaemic stroke treated with intravenous thrombolysis. A total of 60 patients were randomly assigned to four groups [3 (active): 1 (control)]; the active treatment groups received oral imatinib for 6 days at three dose levels (400, 600 and 800 mg). Primary outcome was any adverse event; secondary outcomes were haemorrhagic transformation, cerebral oedema, neurological severity on the National Institutes of Health Stroke Scale (NIHSS) at 7 days and at 3 months and functional outcomes on the modified Rankin scale (mRS). RESULTS: Four serious adverse events were reported, which resulted in three deaths (one in the control group and two in the 400-mg dose group; one patient in the latter group did not receive active treatment and the other received two doses). Nonserious adverse events were mostly mild, resulting in full recovery. Imatinib ameliorated neurological outcomes with an improvement of 0.6 NIHSS points per 100 mg imatinib (P = 0.02). For the 800-mg group, the mean unadjusted and adjusted NIHSS improvements were 4 (P = 0.037) and 5 points (P = 0.012), respectively, versus controls. Functional independence (mRS 0-2) increased by 18% versus controls (61 vs. 79; P = 0.296). CONCLUSION: This phase II study showed that imatinib is safe and tolerable and may reduce neurological disability in patients treated with intravenous thrombolysis after ischaemic stroke. A confirmatory randomized trial is currently underway.

Intracranial vessel wall MRI.

There are many different methods of imaging the intracranial arteries; however, the vast majority of currently used techniques are based on luminal imaging. Although this is useful, it does have limitations as many different pathological processes can produce the same appearance. Therefore, directly imaging the site of the pathology - the vessel wall itself - offers the hope of discriminating between different disease processes. In this review, we will discuss the current status of vessel wall magnetic resonance imaging alongside its potential usefulness in differentiating between various disease entities.

First Report of Phytophthora ramorum and P. inflata in Ornamental Rhododendrons in Finland.

Phytophthora ramorum was found for the first time in Finland during the spring of 2004 on marketed plants of Rhododendron spp. originating in other EU member states. During August of 2004, the pathogen was also found in one Finnish nursery on German Rhododendron catawbiense plants and several Finnish Rhododendron spp. cultivars. P. ramorum was detected by species-specific PCR and isolated (1). It was first characterized by an abundant production of chlamydospores on PARP and V8 agar, absence of oogonia and antheridia, and elongate, ellipsoid, deciduous, semipapillate sporangia produced in soil extract water (3). A partial sequence of the ß-tubulin gene was identical to that of P. ramorum deposited in GenBank. Despite strict regulations governing the movement of plants, the pathogen has been found every year since 2004 on materials transported to Finland from other EU countries. A total of 586 samples were taken from symptomatic plants of several susceptible species from 2004 to 2006. P. ramorum was detected in 51 rhododendron samples and the number of the outbreak sites was 28. In domestic plant production, P. ramorum was found in only one nursery. The infected plants in this nursery were destroyed in 2005 according to the EU regulation 2004/426/EG. During the 2006 growing season, 84 samples from trace-forward inspections and reinspections of the nursery were tested and P. ramorum was not detected in any of the samples. In 2005, surveys for P. ramorum on Finnish Rhododendron spp. cultivars with necrotic lesions on leaves and blackened tips yielded, in addition to P. ramorum, another Phytophthora sp. On V8 agar, this homothallic species showed a stellate growth pattern with sparse aerial mycelium. Oogonia had both paragynous and amphigynous antheridia, and sporangia produced in soil extract water were ellipsoid in shape and semipapillate. A 763-bp segment of the ß-tubulin gene was sequenced and was identical to the ß-tubulin sequence of P. inflata strain IMI342898 (GenBank), which was isolated in 1990 from Syringa sp. in the UK. It is likely that this P. inflata strain has been spreading in Europe with the ornamental plant trade. To fulfill Koch's postulates, rhododenrdon plants were inoculated (2) with P. inflata or P. ramorum, typical symptoms observed, and the pathogens were reisolated from inoculated plants. Both Phytophthora species also caused necrotic lesions on Alnus glutinosa, A. incana, and Betula pendula. Pinus sylvestris was resistant to both Phytophthora spp., whereas Picea abies was susceptible to P. inflata but not P. ramorum. References: (1) EPPO Bull. 36:145, 2006. (2) E. Hansen et al. Plant Dis. 89:63, 2005. (3) S. Werres et al. Mycol. Res. 105:1155, 2001.

Differential protease, innate immunity, and NF-kappaB induction profiles during lung inflammation induced by subchronic cigarette smoke exposure in mice.

Cigarette smoke exposure is a major determinant of adverse lung health, but the molecular processes underlying its effects on inflammation and immunity remain poorly understood. Therefore, we sought to understand whether inflammatory and host defense determinants are affected during subchronic cigarette smoke exposure. Dose-response and time course studies of lungs from Balb/c mice exposed to smoke generated from 3, 6, and 9 cigarettes/day for 4 days showed macrophage- and S100A8-positive neutrophil-rich inflammation in lung tissue and bronchoalveolar lavage (BAL) fluid, matrix metalloproteinase (MMP) and serine protease induction, sustained NF-kappaB translocation and binding, and mucus cell induction but very small numbers of CD3+CD4+ and CD3+CD8+ lymphocytes. Cigarette smoke had no effect on phospho-Akt but caused a small upregulation of phospho-Erk1/2. Activator protein-1 and phospho-p38 MAPK could not be detected. Quantitative real-time PCR showed upregulation of chemokines (macrophage inflammatory protein-2, monocyte chemoattractant protein-1), inflammatory mediators (TNF-alpha, IL-1beta), leukocyte growth and survival factors [granulocyte-macrophage colony-stimulating factor, colony-stimulating factor (CSF)-1, CSF-1 receptor], transforming growth factor-beta, matrix-degrading MMP-9 and MMP-12, and Toll-like receptor (TLR)2, broadly mirroring NF-kappaB activation. No upregulation was observed for MMP-2, urokinase-type plasminogen activator, tissue-type plasminogen activator, and TLRs 3, 4, and 9. In mouse strain comparisons the rank order of susceptibility was Balb/c > C3H/HeJ > 129SvJ > C57BL6. Partition of responses into BAL macrophages vs. lavaged lung strongly implicated macrophages in the inflammatory responses. Strikingly, except for IL-10 and MMP-12, macrophage and lung gene profiles in Balb/c and C57BL/6 mice were very similar. The response pattern we observed suggests that subchronic cigarette smoke exposure may be useful to understand pathogenic mechanisms triggered by cigarette smoke in the lungs including inflammation and alteration of host defense.

Fractionated, stereotactic proton beam treatment of cerebral arteriovenous malformations.

OBJECTIVES: To evaluate the therapeutic efficiency and adverse effects of stereotactic proton beam treatment of cerebral arteriovenous malformations (AVM). MATERIAL AND METHODS: Twenty-six patients treated in Uppsala during 1991-97 were included (men = 14, women = 12; mean age = 39, range = 23-64). The nidus volumes ranged from 0.3 to 102 ml (mean = 24, median = 13). The follow-up included clinical evaluation, magnetic resonance imaging (and/or computed tomography) every 6-12 months for 3 years and final angiography. RESULTS: The volume changes at final follow-up in AVMs >25 ml were -89, -85, -44, -29, -7, 0, 0, +5 and +18 (%); in AVMs 11-24 ml, -100, -100, -97, -92 and 0 (%); and in AVMs <10 ml, -100, -100, -100, -100, -100, -99, -98, -50, -0 and +40 (%). Two patients were lost to follow-up due to cerebral haemorrhage and myocardial infarction. Radiology displayed significant perifocal oedema in one patient and slight oedema in four patients. Of nine patients with epilepsy, seven became seizure-free after therapy while two continued to suffer from seizures. CONCLUSION: Proton beam irradiation is successful in a relatively high proportion of intermediate and large-sized cerebral AVMs. The adverse effects are acceptable. The advantage of proton treatment compared with gamma knife and LINAC stereotactic irradiation is that protons can irradiate even large volumes with a very sharp dose profile against normal surroundings. Thus, proton beam irradiation is a valuable option in the treatment of AVMs larger than 10 ml.

Cellular and cordless telephones and the risk for brain tumours.

Microwave exposure from the use of cellular telephones has been discussed in recent years as a potential risk factor for brain tumours. We included in a case-control study 1617 patients aged 20-80 years of both sexes with brain tumour diagnosed between 1 January 1997 and 30 June 2000. They were alive at the study time and had histopathologically verified brain tumour. One matched control to each case was selected from the Swedish Population Register. The study area was the Uppsala-Orebro, Stockholm, Linköping and Göteborg medical regions of Sweden. Exposure was assessed by a questionnaire that was answered by 1429 (88%) cases and 1470 (91%) controls. In total, use of analogue cellular telephones gave an increased risk with an odds ratio (OR) of 1.3 (95% confidence interval (CI) 1.02-1.6). With a tumour induction period of >10 years the risk increased further: OR 1.8 (95% CI 1.1-2.9). No clear association was found for digital or cordless telephones. With regard to the anatomical area of the tumour and exposure to microwaves, the risk was increased for tumours located in the temporal area on the same side of the brain that was used during phone calls; for analogue cellular telephones the OR was 2.5 (95% CI 1.3-4.9). Use of a telephone on the opposite side of the brain was not associated with an increased risk for brain tumours. With regard to different tumour types, the highest risk was for acoustic neurinoma (OR 3.5, 95% CI 1.8-6.8) among analogue cellular telephone users.

Expression of the IL-6 family cytokines in human brain tumors.

In our RT-PCR screen for cytokine expression in human brain tumors we discovered increased levels of oncostatin M (OSM), ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF), all belonging to the interleukin-6 (IL-6) cytokine family, in most of the tumors. The expression of these cytokines in normal adult brain tissue was found to be very low or below detection limit. OSM expression was elevated in most of the tumors and immunohistochemistry analysis showed that the tumor cells contained OSM in their cytoplasm, suggesting they produce this factor. Overexpression of OSM has not previously been reported in primary human brain tumors. The IL-6 cytokine family acts through a common gp130 receptor subunit that activates the JAK/STAT signaling pathway and therefore they have been suggested to have overlapping effects. Tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase 1 (MMP-1) and MMP-3 and IL-6 have been reported to be regulated by OSM. IL-6 was low or absent in the tumors. TIMP-1, MMP-1 and MMP-3 was expressed in most tumors but with no strict correlation to OSM levels.

Meningioma treated with interferon-alpha, evaluated with [(11)C]-L-methionine positron emission tomography.

PURPOSE: In meningioma patients with postoperative residual masses, recurrent or primarily inoperable tumors, positron emission tomography (PET) with [(11)C]-L-methionine was used to evaluate treatment efficacy of IFN-alpha. EXPERIMENTAL DESIGN: Twelve patients were treated with IFN-alpha at a dose of 1.5-5 million IU s.c. daily. PET, computed tomography, and/or magnetic resonance imaging were performed in all patients before and, at regular intervals, during IFN-alpha treatment. The ratio of tumor hot-spot uptake to cerebellar uptake or to cortex uptake was calculated. This ratio estimates the relative methionine accumulation in the tumor and presumably the proliferative activity in the tumor. RESULTS: During IFN-alpha treatment, PET demonstrated a mean relative percentage of reduction in the uptake ratio (MRelR) of 22.3% in the meningiomas. In nine patients who were considered responders, defined as patients with a positive MRelR, the MRelR was 30.4%. For the three nonresponders, defined as patients with a negative MRelR, the MRelR was -1.8%. Three patients were followed for a long time: two patients for 8 years and one patient for 4 years and 6 months; the two patients followed for 8 years are still on IFN. The volumes of these tumors were constant or showed a slight decrease. No correlation was found between histopathological diagnosis (PAD) WHO grading I-III of meningiomas and response to IFN-alpha treatment. CONCLUSIONS: PET was judged a useful method to predict which patients are suitable for long-term treatment with IFN-alpha and also for dose finding. In five patients treated from 9 months to 8 years, IFN-alpha seemed to be an effective oncostatic drug. The clinical usefulness of IFN-alpha, taking adverse reactions into account, must be evaluated in a larger series of patients.

Short-term effects of radiotherapy on attention and memory performances in patients with brain tumors.

BACKGROUND: The objective of the current study was to evaluate the short-term effects of radiotherapy on attention and memory performance in patients with brain tumors. METHODS: Thirteen patients underwent a neuropsychologic examination on three occasions: at baseline before radiotherapy, which lasted for 6 weeks; within 2 weeks after the completion of radiotherapy; and 3 months after the completion of radiotherapy. Thirty healthy individuals were studied at baseline as a control group. Verbal, visuomotor, and memory tests were administered. Attentional performances were examined using CogniSpeed reaction time software. RESULTS: At baseline, the patients scored significantly lower than the controls in tests of semantic memory (Similarities; P = 0.002), visuoconstructive skill (Block Design; P = 0.028), and visual and verbal memory (recall of 20 objects: immediate, P = 0.017; delayed, P = 0.002; recall of 30 paired word associates: immediate, P = 0.002; delayed, P = 0.005). The patients performed significantly more poorly than the control group on the Two-Choice Reaction Time test (P = 0.047), the Subtraction test (P = 0.042), and the Vigilance test (P = 0.023). After radiotherapy, the performance of the patients did not worsen on any measure, whereas their conscious cognitive processing was improved (P = 0.002). CONCLUSIONS: Treatment with radiotherapy did not cause negative short-term effects on attentional and memory functions in patients with brain tumors who received a radiation dose of 54.5 grays. The cognitive deficits found in these patients were evident at baseline before radiotherapy. Thus, it seems likely that the deficits were associated with the tumor itself and/or the surgical procedures.

Pain, coping, emotional state and physical function in patients with chronic radicular neck pain. A comparison between patients treated with surgery, physiotherapy or neck collar--a blinded, prospective randomized study.

PURPOSE: To describe and explore the relationships between pain, emotional state and coping strategies in patients with chronic radicular neck pain before and after surgery or conservative treatments. METHODS: We randomize 81 conseutive patients with cervical radicular pain and nerve root compression, verified by MRI, to either surgical decompression with fusion or physiotherapy or neck collar. Emotional state was both measured with Mood Adjective Check List. Hospital Anxiety and Depression Scale and with a Coping Strategies Questionnaire. Pain was measured with VAS and function with Disability Index Rating. Measurements were made before treatment, and follow ups after 3 and 12 months post treatment. RESULTS: We found generally a low emotional state with anxiety, depression and sleep-disturbances not only connected to pain. Pain improved faster in the surgery group but after one year no differences were seen. Surgery and physiotherapy improved function with heavy work compared to collar after 3 months. Many patients used active coping before treatment, but after treatment more passive coping strategies were found. CONCLUSION: We recommend a multidisciplinary rehabilitation with cognitive behavioural therapy and psychological interventions.

Cognitive functioning and cerebrospinal fluid concentrations of neuropeptides for patients with good neurological outcomes after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Many patients exhibit cognitive disturbances after aneurysmal subarachnoid hemorrhage (SAH). Structural and functional neuroimaging has failed to demonstrate any correlation with these complaints. This study was performed to investigate whether neuropeptide concentrations in cerebrospinal fluid could be related to cognitive disturbances after SAH. METHODS: Lumbar cerebrospinal fluid was obtained, 3 to 6 months after surgery, from 17 patients who experienced good outcomes after aneurysmal SAH. The samples were analyzed for various neuropeptides using radioimmunoassays, and the peptide concentrations were evaluated in relation to scores on standardized neuropsychological tests. RESULTS: The neuropsychological test results were normal for eight individuals, whereas the remaining nine patients exhibited various degrees of cognitive impairment. There was no correlation between the concentrations of arginine vasopressin or neuropeptide Y and test performance. However, significant correlations between cognitive impairment and elevated levels of beta-endorphins (P = 0.02), corticotropin-releasing factor (P = 0.004), and delta sleep-inducing peptide (P = 0.045) were noted. CONCLUSION: Patients with cognitive impairments after aneurysmal SAH exhibited higher cerebrospinal fluid concentrations of endorphins, corticotropin-releasing factor, and delta sleep-inducing peptide than did those with normal capacity. This is probably attributable to diffuse derangement of transmitter release in the brain, resulting from the insult or ensuing complications, although a secondary increase in corticotropin-releasing factor concentrations caused by increased stress during the testing because of reduced cognitive capacity cannot be excluded.

Aggression: destructive and constructive aspects.

The concept of aggression was long relegated to the shadow of the libido in psychoanalytic theory, placed among the negative affects by some theoreticians, denied the role of a primary drive among leading writers in clinical psychology, brought to the fore as an adaptive force in ethology, and proved to be a decisive factor in the development of psychosomatic ailments. The second part of the paper reviews experiments using projective techniques, showing that highly creative subjects as opposed to ones low in creativity seem inclined to accept their aggressive impulses. A total denial of these impulses has been typical of women with breast cancer.

Evaluation of the effect of high-energy proton irradiation treatment on meningiomas by means of 11C-L-methionine PET.

A remnant meningioma of WHO grade I that is located at the base of the skull and is treated with radiotherapy has to be followed up for at least 5-10 years to evaluate the treatment effect and detect recurrence. The tumour has to grow considerably to show detectable volume increase on computed tomography (CT) or magnetic resonance imaging (MRI). Owing to the location at the base of the skull, a small increase in tumour volume may be hazardous. It is thus important to find a method to evaluate treatment effects earlier and potentially detect those tumours that have a tendency to grow. Nineteen patients with intracranial meningiomas were given irradiation with the 180-MeV proton beam at the Svedberg Laboratory, Uppsala, Sweden. The fractionation schedule used was in general a total dose of 24 Gy in four consecutive daily 6-Gy fractions. Serial 11C-Lmethionine PET examinations were used to evaluate the effect of stereotactic proton beam treatment. The radioactivity uptake in the tumour was evaluated as the ratio to the uptake in normal brain tissue. The follow-up period thus far is 36 months. In 15 of the 19 patients, 11C-L-methionine uptake was reduced 36 months after irradiation compared with the pre-treatment uptake of the tracer. In the total patient group the average reduction was 19.4%. Our results reveal that proton beam irradiation of meningiomas had an inhibitory effect on the methionine uptake in the meningiomas, although tumour size remained unchanged. The combination of unchanged tumour morphology and a reduction in methionine uptake after irradiation suggests that 11C-L-methionine PET might enable earlier evaluation of the treatment effect than is possible with CT or MRI.

Frontal lobe dysfunction in patients with non-frontal malignant gliomas: a monoaminergic dysregulation?

Previous investigations concerned with the neuropsychological function of patients with intracerebral supratentorial malignant gliomas has revealed the frequent occurrence of signs suggestive of an inhibitory frontal lobe dysfunction regardless of the intracerebral localization of the tumor and before the diagnosis was known to either the investigator or the patient. Upon closer analysis, the frontal lobe dysfunction has been verified by the demonstration of reduced blood flow in frontal areas in these patients. Since many of the findings can be related to a dysfunction of dopaminergic neurotransmission, we hypothesize that abnormal astrocytes interfere with the metabolism, transport and release of various neurotransmitters of which dopamine may be the one responsible for the most striking neuropsychological abnormalities in patients with malignant gliomas.

Stereotactic irradiation of skull base meningiomas with high energy protons.

Nineteen patients with inextirpable skull base meningioma with involvement of neurovascular structures were given irradiation with a 180 MeV proton beam at the The Svedberg Laboratory, Uppsala, Sweden. The patients were treated seated in a fixed position with a stereotactic approach. Titanium-markers to the outer table served for identification and verification of the target positioning for dose planning and irradiation. The patients were given a total dose of 24 Gy in four consecutive daily 6 Gy fractions. All patients have been followed for at least 36 months. So far no meningiomas have progressed after treatment. Two patients have developed corticosteroid responsive oedema in the target area 6 moths after treatment. Late, but not serious, symptoms of side effects have been observed in one patient.

Psychological profile related to malignant tumours of different histopathology.

In a previous preoperative study of patients with gliomas, we made the original observation that patients with high grade as opposed to those with low-grade gliomas have a psychological profile marked by extreme emotional reactivity. In this postoperative study of the psychological profiles of patients with breast cancer, the main funding was unexpectedly analogous with the findings in the brain tumour study. The patients with poorly differentiated ductal carcinomas showed a specific and, compared to the patients with well differentiated carcinomas, outstanding psychological profile marked by extreme emotional reactivity as well as by genuine creativity. Some of the present patients with well differentiated carcinomas showed personality profiles marked by compulsive inhibition, also described earlier in the literature of patients with breast cancer. The psychobiological relations between emotional reactivity and aggressiveness of tumour growth are discussed.