Nigrostriatal blood-brain barrier opening in Parkinson's disease.

BACKGROUND: The nigrostriatal system is especially vulnerable to neurodegeneration in Parkinson's disease (PD) and the blood-brain barrier (BBB) is a limiting factor for delivery of therapeutic agents to the brain. This pilot study aimed to demonstrate safety, feasibility and tissue penetration (by 18F-Choline-positron emission tomography (PET)) of MR-guided focused ultrasound (MRgFUS) simultaneous BBB opening (BBB-O) in the substantia nigra (SN) and putamen in PD. METHODS: Three patients underwent MRgFUS for midbrain and putamen BBB-O. Patients were evaluated clinically and underwent brain MRI with gadolinium (baseline, 24 hours, 14 days and 3 months postprocedure). In two patients, BBB-O was repeated after 2-3 weeks, and 18F-Choline-PET was performed immediately after. RESULTS: The right SN and putamen were simultaneously opened unilaterally in 3 patients once and the left SN in 1 patient in a different session. No severe clinical or neuroimaging adverse events developed in any patient. 18F-Choline-PET uptake was enhanced in the targeted SN and putamen regions. CONCLUSION: BBB-O of the nigrostriatal system is a feasible and well-tolerated approach in patients with PD. 18F-Choline-PET uptake indicates penetration into the parenchyma after BBB-O, which suggests that the opening is functionally effective. This minimally invasive technique could facilitate delivery of putative neurorestorative molecules to brain regions vulnerable to neurodegeneration.

Social Cognition and Mild Cognitive Impairment in Mid-Stage Parkinson's Disease.

Mild cognitive impairment (MCI) is a relevant non-motor feature in Parkinson's disease (PD). Social cognition (SC) is a cognitive domain that refers to the ability to decode others' intentions and to guide behavior in social contexts. We aimed to compare SC performance in mid-stage PD patients compared to a healthy population and according to their cognitive state. Fifty-two PD patients were classified as being cognitively normal (PD-CN) or having mild cognitive impairment (PD-MCI) following the Movement Disorder Society (MDS) Level II criteria. SC assessment included facial emotion recognition (FER), affective and cognitive theory of mind (ToM), and self-monitoring (RSMS test). Twenty-seven age-matched healthy controls (HC) were enrolled. PD-MCI patients scored worse than HC on affective and cognitive ToM task scores. Only cognitive ToM scores were significantly lower when compared with the PD-MCI and PD-CN groups. We found no differences in FER or self-monitoring performance. There were significant correlations between cognitive ToM and executive functions, memory, language, and attention, whereas FER and affective ToM correlated with memory. Our findings indicates that SC is normal in cognitively unimpaired and non-depressed mid-stage PD patients, whereas a decline in affective and cognitive ToM is linked to the presence of MCI.

Cognitive Reserve in Parkinson's Disease without Dementia: ß-Amyloid and Metabolic Assessment.

BACKGROUND: Cognitive reserve (CR) is the mismatch between preserved cognition and neuropathological damage. Amyloidopathy in Parkinson's disease (PD) could be associated with faster progression to dementia, but the putative protective effect of CR is unknown. OBJECTIVES: To evaluate the effect of CR on ß-amyloid burden and brain metabolism in non-demented PD subjects. METHODS: Participants with PD (n = 53) underwent a clinical evaluation, [18 F]-fluorodeoxyglucose and [18 F]-flutemetamol positron emission tomography magnetic resonances, and were classified according to CR. The metabolic pattern of 16 controls was compared to PD subjects. RESULTS: The PD subjects showed hypometabolism mainly in the bilateral posterior cortex. Superior-CR subjects (n = 22) exhibited better cognitive performance, increased amyloid burden, and higher metabolism in several right hemisphere areas compared to low-medium-CR subjects (n = 31). CONCLUSIONS: Higher CR in non-demented PD is associated with better cognitive performance, which might reduce vulnerability to the effect of ß-amyloid. Whether superior CR leads to protection against metabolic deterioration, and predominantly right hemisphere involvement, deserves further exploration.

Brain hypometabolism in non-demented microtubule-associated protein tau H1 carriers with Parkinson's disease.

BACKGROUND AND PURPOSE: The microtubule-associated protein tau (MAPT) H1 homozygosity (H1/H1 haplotype) is a genetic risk factor for neurodegenerative diseases, such as Parkinson's disease (PD). MAPT H1 homozygosity has been associated with conversion to PD; however, results are conflicting since some studies did not find a strong influence. Cortical hypometabolism is associated with cognitive impairment in PD. In this study, we aimed to evaluate the metabolic pattern in nondemented PD patients MAPT H1/H1 carriers in comparison with MAPT H1/H2 haplotype. In addition, we evaluated domain-specific cognitive differences according to MAPT haplotype. METHODS: We compared a group of 26 H1/H1 and 20 H1/H2 carriers with late-onset PD. Participants underwent a comprehensive neuropsychological cognitive evaluation and a [18F]-Fluorodeoxyglucose PET-MR scan. RESULTS: MAPT H1/H1 carriers showed worse performance in the digit span forward test of attention compared to MAPT H1/H2 carriers. In the [18F]-Fluorodeoxyglucose PET comparisons, MAPT H1/H1 displayed hypometabolism in the frontal cortex, parahippocampal, and cingulate gyrus, as well as in the caudate and globus pallidus. CONCLUSION: PD patients MAPT H1/H1 carriers without dementia exhibit relative hypometabolism in several cortical areas as well as in the basal ganglia, and worse performance in attention than MAPT H1/H2 carriers. Longitudinal studies should assess if lower scores in attention and dysfunction in these areas are predictors of dementia in MAPT H1/H1 homozygotes.

Striatal Blood-Brain Barrier Opening in Parkinson's Disease Dementia: A Pilot Exploratory Study.

BACKGROUND: Parkinson's disease (PD) exhibits a high prevalence of dementia as disease severity and duration progress. Focused ultrasound (FUS) has been applied for transient blood-brain barrier (BBB) opening of cortical regions in neurodegenerative disorders. The striatum is a primary target for delivery of putative therapeutic agents in PD. OBJECTIVE: Here, we report a prospective, single-arm, nonrandomized, proof-of-concept, phase I clinical trial (NCT03608553 amended) in PD with dementia to test the safety and feasibility of striatal BBB opening in PD patients. METHODS: Seven PD patients with cognitive impairment were treated for BBB opening in the posterior putamen. This was performed in two sessions separated by 2 to 4 weeks, where the second session included bilateral putamina opening in 3 patients. Primary outcome measures included safety and feasibility of focal striatal BBB opening. Changes in motor and cognitive functions, magnetic resonance imaging (MRI), 18 F-fluorodopa (FDOPA), and ß-amyloid PET (positron emission tomography) images were determined. RESULTS: The procedure was feasible and well tolerated, with no serious adverse events. No neurologically relevant change in motor and cognitive (battery of neuropsychological tests) functions was recognized at follow-up. MRI revealed putamen BBB closing shortly after treatment (24 hours to 14 days) and ruled out hemorrhagic and ischemic lesions. There was a discrete but significant reduction in ß-amyloid uptake in the targeted region and no change in FDOPA PET. CONCLUSIONS: These initial results indicate that FUS-mediated striatal BBB opening is feasible and safe and therefore could become an effective tool to facilitate the delivery of putative neurorestorative molecules in PD. © 2022 International Parkinson and Movement Disorder Society.

Smoking influence on early and late fetal growth.

OBJECTIVES: Smoking during pregnancy is a leading and modifiable risk factor for fetal growth restriction (FGR) and low birthweight (<10th centile). We studied the effects of smoking in the development of early and late FGR or low birthweight, as well as in uteroplacental and fetoplacental hemodynamics of growth-restricted fetuses. METHODS: Retrospective cohort study of 5,537 consecutive singleton pregnancies delivered at ≤34 + 0 ("early delivery" group, n=95) and >34 + 0 ("late delivery" group, n=5,442) weeks of gestation. Each group was divided into smokers and non-smokers. Prenatal diagnosis of FGR was based on customized fetal growth standards and fetal Doppler, and postnatal birthweight was assessed using the Olsen newborn chart. RESULTS: There were 15/95 (15.8%) and 602/5,442 (11.1%) smokers in the early and late delivery groups, respectively. In early deliveries, FGR was diagnosed in 3/15 (20%) of smokers and in 20/80 (25%) of non-smokers (p=0.68). We also found no differences in birthweights and hemodynamics. In late deliveres, FGR was detected in 30/602 (5%) smokers and 64/4,840 (1.3%) non-smokers (p<0.001). Birthweights <3rd centile and <10th centile were more common in smokers vs. non-smokers: 38/602 (6.3%) vs. 87/4,840 (1.8%) and 89/602 (14.8%) vs. 288/4,840 (6%), respectively (all p<0.01). Fetal Doppler of late FGR showed slightly higher umbilical artery resistances in smokers. CONCLUSIONS: Smoking in pregnancy is associated with FGR, low birthweight and higher umbilical artery Doppler resistances after 34 weeks of gestation, but we could not confirm this association in earlier deliveries.

What Do We Know about Theory of Mind Impairment in Parkinson's Disease?

Theory of mind (ToM) is a social cognitive skill that involves the ability to attribute mental states to self and others (what they think (cognitive ToM) and feel (affective ToM)). We aim to provide an overview of previous knowledge of ToM in Parkinson's disease (PD). In the last few years more attention has been paid to the study of this construct as a non-motor manifestation of PD. In advanced stages, both components of ToM (cognitive and affective) are commonly impaired, although in early PD results remain controversial. Executive dysfunction correlates with ToM deficits and other cognitive domains such as language and visuospatial function have also been related to ToM. Recent studies have demonstrated that PD patients with mild cognitive impairment show ToM deficits more frequently in comparison with cognitively normal PD patients. In addition to the heterogeneity of ToM tests administered in different studies, depression and dopaminergic medication may also be acting as confounding factors, but there are still insufficient data to support this. Neuroimaging studies conducted to understand the underlying networks of cognitive and affective ToM deficits in PD are lacking. The study of ToM deficit in PD continues to be important, as this may worsen quality of life and favor social stigma. Future studies should be considered, including assessment of the patients' cognitive state, associated mood disorders, and the role of dopaminergic deficit.

Blood-brain barrier opening with focused ultrasound in Parkinson's disease dementia.

MR-guided focused ultrasound (MRgFUS), in combination with intravenous microbubble administration, has been applied for focal temporary BBB opening in patients with neurodegenerative disorders and brain tumors. MRgFUS could become a therapeutic tool for drug delivery of putative neurorestorative therapies. Treatment for Parkinson's disease with dementia (PDD) is an important unmet need. We initiated a prospective, single-arm, non-randomized, proof-of-concept, safety and feasibility phase I clinical trial (NCT03608553), which is still in progress. The primary outcomes of the study were to demonstrate the safety, feasibility and reversibility of BBB disruption in PDD, targeting the right parieto-occipito-temporal cortex where cortical pathology is foremost in this clinical state. Changes in ß-amyloid burden, brain metabolism after treatments and neuropsychological assessments, were analyzed as exploratory measurements. Five patients were recruited from October 2018 until May 2019, and received two treatment sessions separated by 2-3 weeks. The results are set out in a descriptive manner. Overall, this procedure was feasible and reversible with no serious clinical or radiological side effects. We report BBB opening in the parieto-occipito-temporal junction in 8/10 treatments in 5 patients as demonstrated by gadolinium enhancement. In all cases the procedures were uneventful and no side effects were encountered associated with BBB opening. From pre- to post-treatment, mild cognitive improvement was observed, and no major changes were detected in amyloid or fluorodeoxyglucose PET. MRgFUS-BBB opening in PDD is thus safe, reversible, and can be performed repeatedly. This study provides encouragement for the concept of BBB opening for drug delivery to treat dementia in PD and other neurodegenerative disorders.

Obstetric and pediatric growth charts for the detection of fetal growth restriction and neonatal adverse outcomes in preterm newborns before 34 weeks of gestation.

INTRODUCTION: Identification of fetal growth-restricted (FGR) infants depends on the fetal or newborn charts used to identify them. We aimed to compare the prenatal and postnatal diagnosis of FGR and their ability to predict adverse perinatal outcomes. METHODS: Observational retrospective cohort study of 95 consecutive mother-infant pairs with preterm birth between 24 and 34 weeks (study period: January 2014 to December 2015). Prenatal sonographic diagnosis of FGR, based on customized fetal growth standards and fetal Doppler, was compared with the postnatal diagnosis of FGR based on a birthweight < 3rd percentile according to newborn charts (International Newborn size references for the Intergrowth twenty-first century program, and Olsen's charts). Neonatal mortality and adverse neonatal outcomes were compared among groups. RESULTS: In 23/95 (24%) cases a prenatal diagnosis of early FGR was made. Postnatal FGR was confirmed in 11/23 (48%) cases using Olsen's charts and 8/23 (35%) using Intergrowth 21st charts. One postnatal FGR case was missed by prenatal ultrasound. Bronchopulmonary dysplasia, sepsis and hypoglycemia were more frequent in pre- and postnatal FGR versus non-FGR. After adjusting for gestational age and sex, only an increased relative risk of hypoglycemia (2.0, 95%CI 1.0-2.8) was observed in infants with pre- and postnatal FGR diagnosis. Nonsignificant differences on neonatal outcomes were identified between prenatal FGR cases with normal birthweight and the non-FGR group. CONCLUSION: Only prenatal FGR cases in which a birthweight below the third percentile is confirmed by means of postnatal charts (Olsen or Intergrowth standard) are at higher risk of adverse postnatal outcome.

Obstetric and pediatric growth charts for the detection of late-onset fetal growth restriction and neonatal adverse outcomes.

OBJECTIVES: Late-onset fetal growth restriction (FGR) has heterogeneous prenatal and postnatal diagnostic criteria. We compared the prenatal and postnatal diagnosis of late-onset FGR and their ability to predict adverse perinatal outcomes. METHODS: Retrospective cohort study of 5442 consecutive singleton pregnancies that delivered beyond 34 + 0 weeks. Prenatal diagnosis of FGR was based on customized fetal growth standards and fetal Doppler while postnatal diagnosis was based on a birthweight <3rd percentile according to newborn charts (Olsen's charts and Intergrowth 21st century programme). Perinatal outcomes were analyzed depending on whether the diagnosis was prenatal, postnatal or both. RESULTS: A total of 94 out of 5442 (1.7%) were diagnosed as late-onset FGR prenatally. Olsen's chart and Intergrowth 21st chart detected that 125/5442 (2.3%) and 106/5442 (2.0%) of infants had a birthweight <3rd percentile, respectively. These charts identified 35/94 (37.2%) and 40/94 (42.6%) of the newborns with a prenatal diagnosis of late-onset FGR. Prenatally diagnosed late-onset FGR infants were at a higher risk for hypoglycemia, jaundice and polycythemia. Both prenatally and postnatally diagnosed as late-onset FGR had a higher risk for respiratory distress syndrome when compared to non-FGR. The higher risks for intensive care admission and composite adverse outcomes were observed in those with a prenatal diagnosis of late-onset FGR that was confirmed after birth. CONCLUSIONS: Current definitions of pre- and postnatal late-onset FGR do not match in more than half of cases. Infants with a prenatal or postnatal diagnosis of this condition have an increased risk of neonatal morbidity even if these diagnoses are not coincident.

Randomized Trial of Focused Ultrasound Subthalamotomy for Parkinson's Disease.

BACKGROUND: The subthalamic nucleus is the preferred neurosurgical target for deep-brain stimulation to treat cardinal motor features of Parkinson's disease. Focused ultrasound is an imaging-guided method for creating therapeutic lesions in deep-brain structures, including the subthalamic nucleus. METHODS: We randomly assigned, in a 2:1 ratio, patients with markedly asymmetric Parkinson's disease who had motor signs not fully controlled by medication or who were ineligible for deep-brain stimulation surgery to undergo focused ultrasound subthalamotomy on the side opposite their main motor signs or a sham procedure. The primary efficacy outcome was the between-group difference in the change from baseline to 4 months in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score (i.e., part III) for the more affected body side (range, 0 to 44, with higher scores indicating worse parkinsonism) in the off-medication state. The primary safety outcome (procedure-related complications) was assessed at 4 months. RESULTS: Among 40 enrolled patients, 27 were assigned to focused ultrasound subthalamotomy (active treatment) and 13 to the sham procedure (control). The mean MDS-UPDRS III score for the more affected side decreased from 19.9 at baseline to 9.9 at 4 months in the active-treatment group (least-squares mean difference, 9.8 points; 95% confidence interval [CI], 8.6 to 11.1) and from 18.7 to 17.1 in the control group (least-squares mean difference, 1.7 points; 95% CI, 0.0 to 3.5); the between-group difference was 8.1 points (95% CI, 6.0 to 10.3; P<0.001). Adverse events in the active-treatment group were dyskinesia in the off-medication state in 6 patients and in the on-medication state in 6, which persisted in 3 and 1, respectively, at 4 months; weakness on the treated side in 5 patients, which persisted in 2 at 4 months; speech disturbance in 15 patients, which persisted in 3 at 4 months; facial weakness in 3 patients, which persisted in 1 at 4 months; and gait disturbance in 13 patients, which persisted in 2 at 4 months. In 6 patients in the active-treatment group, some of these deficits were present at 12 months. CONCLUSIONS: Focused ultrasound subthalamotomy in one hemisphere improved motor features of Parkinson's disease in selected patients with asymmetric signs. Adverse events included speech and gait disturbances, weakness on the treated side, and dyskinesia. (Funded by Insightec and others; ClinicalTrials.gov number, NCT03454425.).

Cortical disinhibition in Parkinson's disease.

In Parkinson's disease, striatal dopamine depletion produces profound alterations in the neural activity of the cortico-basal ganglia motor loop, leading to dysfunctional motor output and parkinsonism. A key regulator of motor output is the balance between excitation and inhibition in the primary motor cortex, which can be assessed in humans with transcranial magnetic stimulation techniques. Despite decades of research, the functional state of cortical inhibition in Parkinson's disease remains uncertain. Towards resolving this issue, we applied paired-pulse transcranial magnetic stimulation protocols in 166 patients with Parkinson's disease (57 levodopa-naïve, 50 non-dyskinetic, 59 dyskinetic) and 40 healthy controls (age-matched with the levodopa-naïve group). All patients were studied OFF medication. All analyses were performed with fully automatic procedures to avoid confirmation bias, and we systematically considered and excluded several potential confounding factors such as age, gender, resting motor threshold, EMG background activity and amplitude of the motor evoked potential elicited by the single-pulse test stimuli. Our results show that short-interval intracortical inhibition is decreased in Parkinson's disease compared to controls. This reduction of intracortical inhibition was obtained with relatively low-intensity conditioning stimuli (80% of the resting motor threshold) and was not associated with any significant increase in short-interval intracortical facilitation or intracortical facilitation with the same low-intensity conditioning stimuli, supporting the involvement of cortical inhibitory circuits. Short-interval intracortical inhibition was similarly reduced in levodopa-naïve, non-dyskinetic and dyskinetic patients. Importantly, intracortical inhibition was reduced compared to control subjects also on the less affected side (n = 145), even in de novo drug-naïve patients in whom the less affected side was minimally symptomatic (lateralized Unified Parkinson's Disease Rating Scale part III = 0 or 1, n = 23). These results suggest that cortical disinhibition is a very early, possibly prodromal feature of Parkinson's disease.

Focused ultrasound thalamotomy for multiple sclerosis-associated tremor.

Multiple sclerosis (MS)-related tremor is frequent and can often be refractory to medical treatment, which makes it a potential source of major disability. Functional neurosurgery approaches such as thalamic deep brain stimulation (DBS) or radiofrequency thalamotomy are proven to be effective, but the application of invasive techniques in MS tremor has so far been limited. Magnetic resonance (MR)-guided focused ultrasound thalamotomy, which has already been approved for treating essential and parkinsonian tremor, provides a minimally invasive approach that could be useful in the management of MS tremor. We report for the first time a patient with medically refractory MS-associated tremor successfully treated by focused ultrasound thalamotomy.

Evaluation of a follow up protocol of infants born to mothers with antithyroid antibodies during pregnancy.

AIM: To evaluate the usefulness of a follow up intervention of newborns to mothers with antithyroid antibodies during pregnancy. RESULTS: We evaluated a 72 mother-infant pairs. Two to three blood tests were done at least in 50% of the infants included in the study during the follow up. Each patient was required to go to hospital to do the blood tests. Others hospital visits were required to medical examinations and collect the results. One patient required eight blood tests. We only could establish a correlation between thyroperoxidase antibodies (TPO-Ab) titres between controls done in mothers during pregnancy and samples obtained in newborn at 48 h of life. There was not effect of mother's TPO-Ab titres in infant's thyroid function. No cases of transitory hypothyroidism in infants were found. CONCLUSIONS: It is important to do a follow up in infants born of mothers with antithyroid antibodies during pregnancy. Transitory congenital hypothyroidism (TCH) in these infants is described in literature, with deleterious effects in neurodevelopment. Many blood tests and hospital visits were required analysing our protocol. There were no cases of TCH. Screening of CH from a heel blood sample at 48 h of life is universal in our region. Follow up protocols in these patients could be much less aggressive.

Breast cancer subtype discrimination using standardized 4-IHC and digital image analysis.

Breast cancer is a heterogeneous disease. Surrogate classification of intrinsic subtypes of invasive carcinomas by combined immunohistochemistry for estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67 (4-IHC) has increased steadily since the 2011 St Gallen symposium, due to its rapid subtyping of tumors at a reasonable cost. An important step in improving 4-IHC reproducibility and reliability will be to provide reference values from the routine use of standardized 4-IHC followed by image analysis. The aims of the current study were (1) to analyze invasive breast carcinomas using standardized 4-IHC and quantitative image analysis and (2) to compare the results obtained in the classification of biological subtypes using current Ki67 and PR threshold values proposed by different authors to sub-classifying the luminal A-like and the luminal B-like (HER2-negative) subtypes. Five hundred twenty-one tumors were analyzed by standardized immunohistochemistry, with automatic image analysis, and HER2 FISH technique. Positivity for ER was found in 82.7% and for PR in 70.1% of cases. Using the Allred scoring system, hormone receptor results showed a bimodal distribution, particularly for ER. HER2 positivity was found in 15.7% of cases, and the mean Ki67 score was 32.3%. Using the most recently proposed surrogate definitions for the classification of luminal breast cancer subtypes, the percentages of different subtypes that we found were similar to those published with genomic platforms: 40.7% luminal A-like, 32.4% luminal B-like/HER2-negative, 9.8% luminal B-like/HER2-positive, 6.0% HER2-positive, and 11.1% triple negative. Standardized 4-IHC with automatic image analysis constitutes a low-cost method for surrogate definitions of biological subtypes of breast cancer that delivers accurate results in a day.

Oral care in a neonatal intensive care unit.

OBJECTIVE: Compare the oral colonization profile of premature infants admitted at NICU before and after doing oral care routine with sterile water versus no intervention. METHODS: It was a randomized clinical trial composed of 37 premature infants admitted at the Neonatal Intensive Care Unit (NICU) with a birth weight (BW) <1500 g. They were distributed in two groups: the study group (SG) with 15 patients who received an oral hygiene with sterile water; and a control group (CG) (no intervention) formed by 22 patients. Primary outcome was oral colonization profile before and after doing oral care. RESULT: In the study group, the number of patients colonized by the Gram-positive bacteria at the beginning of the study was 53% versus 40% at the end (p=0.10). For Gram negative, 40% at the study's beginning versus 60% at the end (p=0.18). In the control group, the number of colonized patients for the Gram-positive bacteria at the onset of the study was 54.5% versus 32% patients at the end (p=0.24). For Gram negative, 32% patients at the start of the study versus 77% at the end (p = 0.003). CONCLUSION: There is a significant increase of the Gram-negative flora in those patients without oral care.

Dual-colour CISH is a reliable alternative to FISH for assessment of topoisomerase 2-alpha amplification in breast carcinomas.

Anthracyclines are among the most powerful antineoplastic drugs available for breast cancer treatment. Although HER2 amplification has been postulated to predict anthracycline benefit, numerous reports have demonstrated that HER2/TOP2A co-amplification is the clinically useful predictive marker of response to anthracyclines. The standard technique to evaluate gene status for target therapy selection is fluorescence in situ hybridization (FISH), but this technique has some disadvantages. Dual-colour chromogenic in situ hybridization (CISH) is an extension of the FISH protocol that allows bright-field microscopy and thus represents a user-friendly alternative to FISH. In order to evaluate whether dual-colour CISH is a reliable alternative to FISH in determining TOP2A gene amplification and to determine the frequency with which TOP2A and HER2 were co-amplified, we analysed 100 invasive breast cancer specimens (70 consecutive and 30 HER2-amplified samples) using tissue microarrays. Thus, a 99 % agreement was found between TOP2A status determined by dual-colour CISH and FISH, as well as a high degree of correlation in TOP2A ratios using both techniques. TOP2A gene amplification was present in 8.6 % of the 70 consecutive samples studied, all of which were HER2-amplified. Co-amplification of TOP2A was observed in 46.5 % of the additional 30 HER2-amplified samples (no TOP2A amplification was seen in non-amplified HER2 samples). We conclude that dual-colour CISH represents an excellent alternative to FISH for determination of TOP2A gene status in invasive breast cancer. Our results showing TOP2A amplification only in HER2-amplified cases also add to the evidence that TOP2A determination should be restricted to those cases.

Family history and breast cancer hormone receptor status in a Spanish cohort.

BACKGROUND: Breast cancer is a heterogenous disease that impacts racial/ethnic groups differently. Differences in genetic composition, lifestyles, reproductive factors, or environmental exposures may contribute to the differential presentation of breast cancer among Hispanic women. MATERIALS AND METHODS: A population-based study was conducted in the city of Santiago de Compostela, Spain. A total of 645 women diagnosed with operable invasive breast cancer between 1992 and 2005 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics of the tumors were collected. Hormone receptor negative tumors were compared with hormone receptor postive tumors on their clinico-pathological characteristics as well as risk factor profiles. RESULTS: Among the 645 breast cancer patients, 78% were estrogen receptor-positive (ER+) or progesterone receptor-positive (PR+), and 22% were ER-&PR-. Women with a family history of breast cancer were more likely to have ER-&PR- tumors than women without a family history (Odds ratio, 1.43; 95% confidence interval, 0.91-2.26). This association was limited to cancers diagnosed before age 50 (Odds ratio, 2.79; 95% confidence interval, 1.34-5.81). CONCLUSIONS: An increased proportion of ER-&PR- breast cancer was observed among younger Spanish women with a family history of the disease.

Severe localized lipoatrophy related to therapy with insulin analogs in type 1a diabetes mellitus.

Insulin analog-related lipoatrophy is a rare complication of this type of treatment. We report a case of severe localized lipoatrophy in different locations in a patient with type 1a diabetes mellitus associated with other autoimmune disease.