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Background: Breast cancer during pregnancy (PrBC) is a rare condition known for its aggressive clinical behavior. The presence of tumor-infiltrating lymphocytes (TILs) has been shown to have a significant impact on the prognosis of these patients. Despite some biological characteristics of the tumor that may differ depending on the gestational age, little is known about the dynamics of the immune landscape within the tumor microenvironment (TME) in PrBC. Therefore, in this study, our objective was to gain comprehensive insights into the relationship between gestational age at breast cancer diagnosis and the composition of the TME., Methods: n = 108 PrBC were selected from our institutional registry and categorized based on the gestational age by trimester. For all cases, TILs were profiled according to the International TILs Working Group recommendations, and subtyped by CD4, CD8, and forkhead box P3 (FOXP3) immunohistochemistry. PD-L1 was tested according to the combined positive score (CPS) using the IHC 22C3 pharmDx assay, with a cutoff value of ≥10 for positivity. The statistical approach encompassed Fisher's and Chi-squared tests, with appropriate adjustments for multiple comparisons, logistic regression models, and survival analyses based on the Kaplan-Meier method., Results: The proportion of patients with poorly differentiated (G3) neoplasms increased as the gestational age advanced (first trimester, n = 25, 56.8%; second trimester, n = 27, 69.2%; third trimester, n = 21, 87.5%; p = 0.03). The histologic subtypes as well as the hormone receptor (HR) and HER2 status did not show significant changes across different pregnancy trimesters. In the HR+/HER2- subtype, there was a higher proportion of tumors with high/moderate TILs in the early phases of pregnancy, similar to FOXP3 expression (TILs: first trimester, n = 10, 35.7%; second trimester, n = 2, 10.5%; third trimester, n = 0; p = 0.02; FOXP3: first trimester, n = 10, 40%; second trimester, n = 3, 15.8%; third trimester, n = 0; p  = 0.03). The median follow-up for our cohort was 81 months. Patients who relapsed after a breast cancer diagnosis during the first trimester were more frequently PD-L1-negative, unlike those with no disease recurrence ( n = 9, 100% vs. n = 9, 56.3%; p = 0.03; hormone therapy and n = 9, 100% vs. n = 7, 53.9%; p = 0.02; chemotherapy). No statistically significant differences were seen among the three trimesters in terms of survival outcome., Conclusion: The TME dynamics of HR+/HER2- PrBC vary based on gestational age, suggesting that immune tolerance expression during later gestational age could explain the increased aggressiveness of tumors diagnosed at that stage., Competing Interests: GV has received honoraria for consulting, advisory role, and/or speaker bureau from Merck Sharp & Dohme MSD Oncology, Pfizer, Dako, Roche/Genetech, Astellas Pharma, Novartis, Bayer, Daiichi, Sankyo, Menarini, Ventana Medical Systems Dako/Agilent Technologies, Cepheid, and Celgene. NF has received honoraria for consulting, advisory role, speaker bureau, travel, and/or research grants from MSD, Boehringer Ingelheim, Novartis, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline GSK, Gilead, Diaceutics, Adicet Bio, and Sermonix. FP from Merck, Ipsen, and Roche Diagnostics. EG-R from Thermo Fisher Scientific, Novartis, AstraZeneca, Roche, Biocartis, Exact Science, GSK, and Illumina. These companies had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; and/or in the decision to publish the results. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sajjadi, Venetis, Ivanova, Noale, Blundo, Di Loreto, Scarfone, Ferrero, Maggi, Veronesi, Galimberti, Viale, Peccatori, Fusco and Guerini-Rocco.)

Objective: The Rey Auditory Verbal Learning Test (RAVLT) is a widely used verbal memory measure that provides scores for different aspects of memory. It involves repeated auditory presentation and recall of a 15-item word list (List A) followed by presentation and recall of a distractor list (List B) and then un-cued immediate and delayed recalls (at 15 min and 1 week) of List A as well as recognition testing. Aims of this study are to provide Italian normative data for certain RAVLT Scores and Composite Indices to improve the diagnostic accuracy of the test in clinical settings and to provide further evidence on how RAVLT can differentiate different amnesia profiles due to focal lesions., Methods: We enrolled 440 healthy participants and RAVLT Single Scores and Composite Indices have been analyzed by means of multiple regression to verify the influence of age, education, and gender., Results: We computed the best linear models with RAVLT Single Scores and Composite Indices, as dependent variables, and the most suitable transformation of independent variables. By reversing the signs of the regression coefficients, the adjustment factors for each level of age and, if needed, education and gender have been computed and the adjusted scores have been standardized into Equivalent Scores., Conclusion: Using these standardized measures, we differentiate three profiles of amnesia due to selective hippocampal sclerosis with severe encoding deficit, fornix lesions with source memory problems, and temporal lobe epilepsy with consolidation failure., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We introduce the FunAndes database, a compilation of functional trait data for the Andean flora spanning six countries. FunAndes contains data on 24 traits across 2,694 taxa, for a total of 105,466 entries. The database features plant-morphological attributes including growth form, and leaf, stem, and wood traits measured at the species or individual level, together with geographic metadata (i.e., coordinates and elevation). FunAndes follows the field names, trait descriptions and units of measurement of the TRY database. It is currently available in open access in the FIGSHARE data repository, and will be part of TRY's next release. Open access trait data from Andean plants will contribute to ecological research in the region, the most species rich terrestrial biodiversity hotspot., (© 2022. The Author(s).)

Breast cancer during pregnancy (PrBC) is a rare tumor with only a little information on its immune landscape. Here, we sought to characterize the cellular composition of the tumor microenvironment (TME) of PrBC and identify its differences from early-onset breast cancer (EOBC) in non-pregnant women. A total of 83 PrBC and 89 EOBC were selected from our Institutional registry and subjected to tumor-infiltrating lymphocytes (TILs) profiling and immunohistochemistry for CD4, CD8, forkhead box P3 (FOXP3), and programmed death-ligand 1 (PD-L1) (clone 22C3). A significantly lower frequency of hormone receptor (HR)-positive tumors was observed in PrBC. The prevalence of low/null PD-L1 and CD8+TILs was higher in PrBC than in the controls, specifically in HR+/HER2- breast cancers. PrBC had a significantly higher risk of relapse and disease-related death, compared to EOBC. The presence of TILs and each TIL subpopulation were significantly associated with disease relapse. Moreover, the death rate was higher in PrBC with CD8+ TILs. The TME of PrBC is characterized by specific patterns of TIL subpopulations with significant biological and prognostic roles. Routine assessment of TILs and TILs subtyping in these patients would be a valid addition to the pathology report that might help identify clinically relevant subsets of women with PrBC.

Introduction: A late-onset obsessive-compulsive disorder (OCD) might be a challenging diagnostic issue because of the overlapping with the dementia conditions more related to frontal lobe pathology. We aim to describe and investigate how this condition might represent the isolated long-lasting symptomatology of a frontal Alzheimer's disease (AD)., Methods: An elderly woman with normal cognitive status showed a subacute onset of OCD with contamination obsession and washing compulsion. We conducted neuropsychological assessments and neuroimaging examinations at the onset and at 3-years follow-up., Results: At 3-years follow-up, the patient developed cognitive deterioration, frontal behavioural disorders and improvement of OCD. Cognitive assessment showed impairments of executive functions, episodic memory, and constructional apraxia, according to the involvement of fronto-mesial, temporal and parietal regions at neuroimaging. A clinical diagnosis of possible behavioural variant AD was assigned., Conclusion: A typical OCD might be the long-lasting initial manifestation of a possible behavioural variant AD due to dysfunctions of the anterior cingulate network.

Background: Phosphatase and tensin homolog (PTEN) loss is associated with tumorigenesis, tumor progression, and therapy resistance in breast cancer. However, the clinical value of PTEN as a biomarker in these patients is controversial. We sought to determine whether the benefit of traditional biomarkers testing is improved by the analysis of PTEN status for the identification of high-risk breast cancer., Methods: A cohort of 608 patients with breast cancer was included in this study. Based on the expression on the neoplastic cells compared to the normal internal controls by immunohistochemistry (IHC), cases were classified as PTEN-low (PTEN-L) or PTEN-retained (PTEN-WT). The former constituted the study group, while the latter the control group. Analysis of gene expression was performed on publicly available genomic data and included 4265 patients from the METABRIC and MSK cohorts retrieved from cBioPortal. The Shapiro-Wilk test was used to analyze the normal distributions of continuous variables. Relationships between PTEN status and the clinicopathologic and molecular features of the patient population were assessed using Fisher's exact test or Chi-squared/Wilcoxon rank-sum test. Survival curves were built according to the Kaplan-Meier method., Results: Alteration in PTEN status was significantly different at protein and gene levels, where the reduced protein expression was observed in 280/608 cases (46.1%) from our group, while genetic aberrations in only 315/4265 (7.4%) cases of the METABRIC and MSK cohorts. PTEN-L tumors were significantly enriched for hormone receptors (HR) and HER2 negativity (n = 48, 17.1%) compared to PTEN-WT tumors (n = 22, 6.7%; p = 0.0008). Lack of HR with or without HER2 overexpression/amplification was significantly associated with worse overall survival (OS) in PTEN-L but not in PTEN-WT breast cancers (p < .0001). Moreover, PTEN-L protein expression but not gene alterations was related to the outcome, in terms of both OS and disease-free survival (p = 0.002)., Conclusions: The combined analysis of PTEN, HER2, and HR status offers relevant information for a more precise risk assessment of patients with breast cancer., (© 2021. The Author(s).)

Breast cancer is the most common malignancy occurring during gestation. In early-stage breast cancer during pregnancy (PrBC), breast-conserving surgery (BCS) with delayed RT is a rational alternative to mastectomy, for long considered the standard-of-care. Regrettably, no specific guidelines on the surgical management of these patients are available. In this study, we investigated the feasibility and safety of BCS during the first trimester of pregnancy in women with early-stage PrBC. All patients with a diagnosis of PrBC during the first trimester of pregnancy jointly managed in two PrBC-specialized Centers were included in this study. All patients underwent BCS followed by adjuvant radiotherapy to the ipsilateral breast after delivery. Histopathological features and biomarkers were first profiled on pre-surgical biopsies. The primary outcome was the isolated local recurrence (ILR). Among 168 PrBC patients, 67 (39.9%) were diagnosed during the first trimester of gestation. Of these, 30 patients (age range, 23-43 years; median=36 years; gestational age, 2-12 weeks; median=7 weeks; median follow-up time=6.5 years) met the inclusion criteria. The patients that were subjected to radical surgery (n=14) served as controls. None of the patients experienced perioperative surgical complications. No ILR were observed within three months (n=30), 1 year (n=27), and 5 years (n=18) after surgery. Among the study group, 4 (12.3%) patients experienced ILR or new carcinomas after 6-13 years, the same number (n=4) had metastatic dissemination after 3-7 years. These patients are still alive and disease-free after 14-17 years of follow-up. The rate of recurrences and metastasis in the controls were not significantly different. The findings provide evidence that BCS in the first trimester PrBC is feasible and reasonably safe for both the mother and the baby., Competing Interests: NF has received honoraria for consulting, advisory role, honoraria, travel, accommodation, and/or speaker bureau from Merck Sharp & Dohme (MSD), Boehringer Ingelheim, and Novartis. ER has received advisory fees from Novartis, Roche, and MSD Italia; honoraria from Thermo Fisher Scientific, AstraZeneca, Roche. GV has received honoraria for consulting, advisory role, speakers’ bureau, travel, accommodation, expenses, and/or research funding from MSD Oncology, Pfizer, Dako, Roche/Genetech, Astellas Pharma, Novartis, Bayer, Daiichi Sankyo, Menarini, Ventana Medical Systems Dako/Agilent Technologies, Cepheid, and Celgene. FP has received honoraria from Ipsen and Roche Diagnostics in the last 3 years. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Blundo, Giroda, Fusco, Sajjadi, Venetis, Leonardi, Vicini, Despini, Rossi, Runza, Sfondrini, Piciotti, Di Loreto, Scarfone, Guerini-Rocco, Viale, Veronesi, Buonomo, Peccatori and Galimberti.)

It is largely unknown how South America's Andean forests affect the global carbon cycle, and thus regulate climate change. Here, we measure aboveground carbon dynamics over the past two decades in 119 monitoring plots spanning a range of >3000 m elevation across the subtropical and tropical Andes. Our results show that Andean forests act as strong sinks for aboveground carbon (0.67 ± 0.08 Mg C ha -1 y -1 ) and have a high potential to serve as future carbon refuges. Aboveground carbon dynamics of Andean forests are driven by abiotic and biotic factors, such as climate and size-dependent mortality of trees. The increasing aboveground carbon stocks offset the estimated C emissions due to deforestation between 2003 and 2014, resulting in a net total uptake of 0.027 Pg C y -1 . Reducing deforestation will increase Andean aboveground carbon stocks, facilitate upward species migrations, and allow for recovery of biomass losses due to climate change.

Background: Bladder cancer (BC) usually metastasizes to the lymph nodes, bone, lung, liver and peritoneum, but rarely in the breast., Case Report: We present a case of a 66-year-old female diagnosed with a massive bladder tumor, who presented a right mammary nodule after neo-adjuvant chemotherapy. A biopsy of the nodule did not permit a definite diagnosis of metastatic spread, which was confirmed by excision of the nodule. In the literature, we found only 7 other similar cases of BC metastasis to the breast. Currently, a non-invasive method for differentiating a breast metastasis from primary cancer is lacking, although there are some clinical and radiological aspects that may help the diagnosis. Histological examination provides diagnostic certainty., Conclusion: Breast metastases from BC are unusual and consequently difficult to identify without non-invasive tools. Clinical history and histological study play a pivotal role in determining the correct diagnosis., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Despite initial underreporting of language dysfunctions in corticobasal syndrome (CBS), aphasia is now recognized as a frequent feature of this disease. Aphasia in CBS seems clinically overlying to a non-fluent/agrammatic primary progressive aphasia (nfaPPA), which is also a clinical phenotype associated with corticobasal degeneration (CBD) pathology. However, the clinical features of aphasia in CBS still remain poorly delineated, resulting in misjudgements in the differential diagnosis from a PPA presentation of the disease., Aims: To investigate the language disorders of this syndrome, also through a systematic examination of recoding skills (reading, written spelling and repetition) and articulatory disturbances, which have been rarely examined in previous studies., Methods & Procedures: We present a clinical and neuropsychological descriptive study of the language impairments in a case series of 12 aphasic patients with a clinical diagnosis of CBS. Language assessment was conducted by means of the Esame NeuroPsicologico dell'Afasia, a comprehensive Italian battery for language functions, the Token Test, and the Apraxia of Speech Rating Scale., Outcomes & Results: The language profile of the patients showed a severe expressive language disorder, characterized by non-fluent speech, apraxia of speech (AoS) with predominant stuttering-like dysfluencies, spatial/apraxic agraphia, lack of word-finding and defective sentence repetition. Severe limb apraxia, visual-spatial deficit and alien hand syndrome were also present. Neuroimaging showed bilateral left asymmetric atrophies and hypometabolism in the frontal premotor, parietal posterior and temporal areas., Conclusions & Implications: These findings suggest that aphasia in CBS might present as a 'mixed PPA', instead of an nfaPPA as previously stated, showing a combination of features of the nfa and logopenic variants of the PPA, associated with AoS, stuttering and agraphia, which might be additional important cognitive markers for the clinical diagnosis of CBS and discriminating features of an nfaPPA presentation of a CBD. These results might also suggest specific intervention areas in the rehabilitation of patients with CBS. What this paper adds What is already known on the subject Language disorders in CBS patients usually present clinically overlying to an nfaPPA, which is also a clinical phenotype associated with CBD pathology, according to recent diagnostic criteria. However, the clinical features of aphasia in CBS still remain poorly delineated, and this raises difficulties and misjudgements for clinicians in the differential diagnosis from a PPA presentation of the disease. What this paper adds to existing knowledge This study shows that the language profile of our CBS patients was characterized by severe expressive language disorders, with non-fluent speech, apraxia of speech (AoS) with predominant stuttering-like dysfluencies, spatial/apraxic agraphia, lack of word-finding, and defective sentence repetition. These findings suggest that aphasia in CBS might present as a 'mixed PPA', rather than an nfaPPA as previously stated, showing a combination of features of the nfa and logopenic variants of the PPA associated with AoS, stuttering and agraphia. What are the potential or actual clinical implications of this work? These results suggest that AoS, stuttering and agraphia might be important additional cognitive markers for the clinical diagnosis of CBS, and discriminating features of an nfaPPA presentation of a CBD. The language disorders exhibited in the present study might also support speech and language therapists in targeting specific intervention areas in the rehabilitation of patients with CBS., (© 2020 Royal College of Speech and Language Therapists.)

Background: The purpose of this study was to explore the clinical and brain functional abnormalities in patients with mild Alzheimer's Disease (AD) and patients with amnesic Mild Cognitive Impairment (aMCI)., Methods: we used resting spect-neuropsychology correlations method., Results: We found that parieto-temporal associative cortex, mainly involving the inferior parietal lobule, posterior cingulate and middle temporal gyrus, is compromised early in AD. These results suggest that the dysfunction in these areas contributes to cognitive decline in the storage of verbal information, drawing abilities and non-verbal abstract reasoning in AD. The aMCI group showed hypoperfusion primarily involving the frontal areas bilaterally, and this correlated with the impairment in free delayed recall on a verbal memory task., Conclusion: Our results underlie the clinical differences between AD and aMCI patients that might reflect the involvement of different degenerative mechanisms in these groups., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Our knowledge about the structure and function of Andean forests at regional scales remains limited. Current initiatives to study forests over continental or global scales still have important geographical gaps, particularly in regions such as the tropical and subtropical Andes. In this study, we assessed patterns of structure and tree species diversity along ~ 4000 km of latitude and ~ 4000 m of elevation range in Andean forests. We used the Andean Forest Network (Red de Bosques Andinos, https://redbosques.condesan.org/) database which, at present, includes 491 forest plots (totaling 156.3 ha, ranging from 0.01 to 6 ha) representing a total of 86,964 identified tree stems ≥ 10 cm diameter at breast height belonging to 2341 identified species, 584 genera and 133 botanical families. Tree stem density and basal area increases with elevation while species richness decreases. Stem density and species richness both decrease with latitude. Subtropical forests have distinct tree species composition compared to those in the tropical region. In addition, floristic similarity of subtropical plots is between 13 to 16% while similarity between tropical forest plots is between 3% to 9%. Overall, plots ~ 0.5-ha or larger may be preferred for describing patterns at regional scales in order to avoid plot size effects. We highlight the need to promote collaboration and capacity building among researchers in the Andean region (i.e., South-South cooperation) in order to generate and synthesize information at regional scale., Competing Interests: The authors have declared that no competing interests exist.

Breast cancer related lymphedema (BCRL) is a detrimental condition characterized by fluid accumulation in the upper limb in breast cancer patients subjected to axillary surgery and/or radiations. Its etiology is multifactorial and include also tumor-specific pathological features, such as lymphovascular invasion (LVI) and extranodal extension (ENE). To date, no widely employed guidelines for the early diagnosis of BCRL are available. Here, we illustrate a protocol for a digitally assisted BCRL assessment using a 3D laser scanner (3DLS) and a tablet computer. It has been specifically optimized in a discovery cohort of high-risk breast cancer patients. This study provides a proof-of-principle that augmented reality tools, such as 3DLS, can be incorporated into the clinical workup of BCRL to allow for a precise, reproducible, reliable, and cheap diagnosis.

Noninvasive breast lesions encompass a heterogeneous group of risk indicators and nonobligate precursors of breast cancer, such as apocrine hyperplasia (AH) and columnar cell lesions (CCLs). Given the different expression of ER and ER-regulated genes in AH and CCL, these two alterations are currently considered discrete conditions. However, whether they share early biologic changes is not clear to date. Here, we sought to define the clinicopathologic and immunohistochemical features of a prospective series of combined lesions made up by CCLs and AH forming a continuum within single terminal duct-lobular units. The study group included 19 cases, whereas 25 cases of synchronous contiguous CCLs and AH served as control group. The different components of each case were subjected to immunohistochemical analysis for ER, PR, AR, HER2, BCL2, CCND1, MUC1, and PIP. Although CCLs and AHs arising in continuity showed opposite patterns of ER expression, the PIP-positive apocrine signature was consistently present in both components. In conclusion, apocrine changes are highly recurrent in CCLs growing within foci of AH, regardless of the ER activation. Our results suggest that PIP-positive and PIP-negative CCLs are likely to represent biologically distinct conditions and that apocrine changes might occur earlier than ER activation in the natural history of breast precursor lesions.

Breast cancer related lymphedema (BCRL) is frequent but strategies for an individualized risk assessment are lacking. We aimed to define whether tumor-specific pathological features, coupled with clinical and therapeutic data, could help identify patients at risk. Data from 368 patients with node-positive breast cancers were retrospectively collected, including 75 patients with BCRL (0.4⁻25.6 years follow-up). BCRL was assessed during the standard follow-up oncology visits using the circumferential measurement. Clinicopathologic and therapeutic factors associated with BCRL were integrated into a Cox proportional hazards regression model. Lymphovascular invasion (LVI) was more common in BCRL patients ( n = 33, 44% vs. n = 85, 29%, p = 0.01), akin extra nodal extension (ENE) of the metastasis ( n = 57, 76% vs. n = 180, 61%, p = 0.02). Sentinel lymph node excision without axillary dissection and extra-axillary radiotherapy were BCRL-unrelated. A higher number of BCRL-positive patients were treated with taxane-based chemotherapy with or without trastuzumab, compared to BCRL-negative patients ( p < 0.01). Treatment with trastuzumab and/or taxanes, adjusted for systemic infections, laterality, therapy, and pathological features (i.e., LVI and ENE), had a significant impact in BCRL-free survival ( p < 0.01). This work offers new insights on BCRL risk stratification, where the integration of clinical, therapeutic, and tumor-specific pathological data suggests a possible role of anti-human epidermal growth factor receptor 2 (HER2) therapy in BCRL pathogenesis.

In Fig. 2 of this Article, the positive part of the y axis scale should read 0, 0.02, 0.04 instead of 0, 0.04, 0.02. This has been corrected online.

Background: Breast cancers that harbor mismatch-repair (MMR) deficiency and/or microsatellite instability (MSI) might be sensitive to immune checkpoint blockade, but there are currently no specific guidelines for assessing MMR status in breast cancer. Here, we sought to define the clinical value of MMR immunohistochemistry (IHC) and MSI analysis in breast cancers., Methods: We subjected 444 breast cancers to MMR IHC and MSI analysis. Cases were classified as MMR-proficient (pMMR), MMR-deficient (dMMR), and MMR-heterogeneous (hMMR) based on the loss of immunoreactivity; MSI was defined by instability in the five indicators recommended by the National Cancer Institute for endometrial and colorectal cancers. Correlation of MMR status with patients' survival was assessed using the Kaplan-Meier estimator. Statistical tests were two-sided., Results: Loss of MMR proteins was homogeneous (dMMR) in 75 patients (17%) and heterogeneous (hMMR) in 55 (12%). Among luminal breast cancers, there were similar frequencies of dMMR and hMMR tumors. Overall, the rate of discrepancy between IHC and MSI analysis was high (91%). Women with Luminal B-like dMMR carcinomas (n = 44) showed shorter overall survival (median = 77 months, range = 0-115 months) than those with pMMR (n = 205) or hMMR (n = 35) tumors (median = 84 months, range = 0-127 months) ( P  = .008). On the contrary, patients with estrogen receptor-negative breast cancers treated with chemotherapy lived longer in cases of dMMR (n = 9) than pMMR (n = 33) or hMMR (n = 7) tumors, with 87 months of median survival (range = 73-123 months) for the former compared with 79 months (range = 8-113 months) for the latter two categories ( P  < .001)., Conclusions: Immunohistochemistry and MSI are not interchangeable tests in breast carcinomas. MMR protein loss is a more common event than MSI and shows intra-tumor heterogeneity. MMR IHC allows the identification of clinically relevant subclasses of breast cancer patients, provided that multiple areas of the tumor are analyzed.

Global warming is forcing many species to shift their distributions upward, causing consequent changes in the compositions of species that occur at specific locations. This prediction remains largely untested for tropical trees. Here we show, using a database of nearly 200 Andean forest plot inventories spread across more than 33.5° latitude (from 26.8° S to 7.1° N) and 3,000-m elevation (from 360 to 3,360 m above sea level), that tropical and subtropical tree communities are experiencing directional shifts in composition towards having greater relative abundances of species from lower, warmer elevations. Although this phenomenon of 'thermophilization' is widespread throughout the Andes, the rates of compositional change are not uniform across elevations. The observed heterogeneity in thermophilization rates is probably because of different warming rates and/or the presence of specialized tree communities at ecotones (that is, at the transitions between distinct habitats, such as at the timberline or at the base of the cloud forest). Understanding the factors that determine the directions and rates of compositional changes will enable us to better predict, and potentially mitigate, the effects of climate change on tropical forests.

Targeted therapies against the human epidermal growth factor receptor 2 (HER2) have radically changed the outcome of patients with HER2-positive breast cancers. However, a minority of cases displays a heterogeneous distribution of HER2-positive cells, which generates major clinical challenges. To date, no reliable and standardized protocols for the characterization and quantification of HER2 heterogeneous gene amplification in large cohorts have been proposed. Here, we present a high-throughput methodology to simultaneously assess the HER2 status across different topographic areas of multiple breast cancers. In particular, we illustrate the laboratory procedure to construct enhanced tissue microarrays (TMAs) incorporating a targeted mapping of the tumors. All TMA parameters have been specifically optimized for the silver in situ hybridization (SISH) of formalin-fixed paraffin-embedded (FFPE) breast tissues. Immunohistochemical analysis of the prognostic and predictive biomarkers (i.e., ER, PR, Ki67, and HER2) should be performed using automated procedures. A customized SISH protocol has been implemented to allow a high-quality molecular analysis across multiple tissues that underwent different fixation, processing, and storage procedures. In this study, we provide a proof-of-principle that specific DNA sequences could be localized simultaneously in distinct topographic areas of multiple and heterogeneously processed breast cancers using an efficient and cost-effective method.

Apathy is a common neurobehavioral symptom of other syndromes or a syndrome per se which occurs in a variety of neuropsychiatric disorders. Apathy depends on disruption of emotional, cognitive, and behavioral functions. Six brain-damaged patients were assessed, including five patients with unilateral or bilateral focal lesions of the basal ganglia or the thalamus (showing apathy due to an auto-activation deficit) and one patient with bilateral lesions in the limbic temporomesial cortex associated with a form of emotional-affective apathy. A significant and persistent improvement of apathy was observed in all patients after treatment with dopamine agonists such as pramipexole, ropinirole, and rotigotine. These results confirm preliminary reports on the beneficial effects of dopamine agonist agents on apathy and suggest that this syndrome can be treatable in many cases.

General patterns of forest dynamics and productivity in the Andes Mountains are poorly characterized. Here we present the first large-scale study of Andean forest dynamics using a set of 63 permanent forest plots assembled over the past two decades. In the North-Central Andes tree turnover (mortality and recruitment) and tree growth declined with increasing elevation and decreasing temperature. In addition, basal area increased in Lower Montane Moist Forests but did not change in Higher Montane Humid Forests. However, at higher elevations the lack of net basal area change and excess of mortality over recruitment suggests negative environmental impacts. In North-Western Argentina, forest dynamics appear to be influenced by land use history in addition to environmental variation. Taken together, our results indicate that combinations of abiotic and biotic factors that vary across elevation gradients are important determinants of tree turnover and productivity in the Andes. More extensive and longer-term monitoring and analyses of forest dynamics in permanent plots will be necessary to understand how demographic processes and woody biomass are responding to changing environmental conditions along elevation gradients through this century.

Secondary breast angiosarcomas are a well-known entity generally characterized by a poor outcome, especially in patients with advanced disease. Among the drugs with demonstrated activity, taxane derivatives are one of the most effective histology-driven treatments against angiosarcomas. We report two cases of secondary breast angiosarcoma, both characterized by a very peculiar behavior towards paclitaxel. Both patients showed local recurrence of angiosarcoma after primary surgery, and they achieved complete remission following treatment with weekly paclitaxel. When a locoregional recurrence was observed as a result of a brief treatment interruption or a treatment delay, a new complete remission was rapidly achieved with the resumption of the drug, without evidence of any significant adverse effects.

Gastrointestinal involvement is a well known complication of Ehlers-Danlos syndromes (EDSs), mainly in form of abdominal emergencies due to intestinal/abdominal vessels rupture in vascular EDS. In the last decade, a growing number of works investigated the relationship between a wide spectrum of chronic gastrointestinal complaints and various EDS forms, among which the hypermobility type (a.k.a. joint hypermobility syndrome; JHS/EDS-HT) was the most studied. The emerging findings depict a major role for gastrointestinal involvement in the health status and, consequently, management of JHS/EDS-HT patients. Nevertheless, fragmentation of knowledge limits its impact on practice within the boundaries of highly specialized clinics. In this paper, literature review on gastrointestinal manifestations in JHS/EDS-HT was carried out and identified papers categorized as (i) case-control/cohort studies associating (apparently non-syndromic) joint hypermobility and gastrointestinal involvement, (ii) case-control/cohort studies associating JHS/EDS-HT and gastrointestinal involvement, (iii) case reports/series on various gastrointestinal complications in (presumed) JHS/EDS-HT, and (iv) studies reporting gastrointestinal features in heterogeneous EDS patients' cohorts. Gastrointestinal manifestations of JHS/EDS-HT were organized and discussed in two categories, including structural anomalies (i.e., abdominal/diaphragmatic hernias, internal organ/pelvic prolapses, intestinal intussusceptions) and functional features (i.e., dysphagia, gastro-esophageal reflux, dyspepsia, recurrent abdominal pain, constipation/diarrhea), with emphasis on practice and future implications. In the second part of this paper, a summary of possible nutritional interventions in JHS/EDS-HT was presented. Supplementation strategies were borrowed from data available for general population with minor modifications in the light of recent discoveries in the pathogenesis of selected JHS/EDS-HT features., (© 2015 Wiley Periodicals, Inc.)

Joint hypermobility syndrome (JHS) and Ehlers-Danlos syndrome, hypermobility type (EDS-HT) are two clinically overlapping connective tissue disorders characterized by chronic/recurrent pain, joint instability complications, and minor skin changes. Fatigue and headache are also common, although are not yet considered diagnostic criteria. JHS/EDS-HT is a unexpectedly common condition that remains underdiagnosed by most clinicians and pain specialists. This results in interventions limited to symptomatic and non-satisfactory treatments, lacking reasonable pathophysiologic rationale. In this manuscript the fragmented knowledge on pain, fatigue, and headache in JHS/EDS is presented with review of the available published information and a description of the clinical course by symptoms, on the basis of authors' experience. Pathogenic mechanisms are suggested through comparisons with other functional somatic syndromes (e.g., chronic fatigue syndrome, fibromyalgia, and functional gastrointestinal disorders). The re-writing of the natural history of JHS/EDS-HT is aimed to raise awareness among clinical geneticists and specialists treating chronic pain conditions about pain and other complications of JHS/EDS-HT. Symptoms' clustering by disease stage is proposed to investigate both the molecular causes and the symptoms management of JHS/EDS-HT in future studies., (© 2013 Wiley Periodicals, Inc.)

Aims: The aim of this study was to assess concordance between the indocyanine green (ICG) method and (99m)Tc-radiotracer method to identify the sentinel node (SN) in breast cancer. Evidence supports the feasibility and efficacy of the ICG to identify the SN, however this method has not been prospectively compared with the gold-standard radiotracer method in terms of SN detection rate., Methods: Between June 2011 and January 2013, 134 women with clinically node-negative early breast cancer received subdermal/peritumoral injection of (99m)Tc-labeled tracer for lymphoscintigraphy, followed by intraoperative injection of ICG for fluorescence detection of SNs using an exciting light source combined with a camera. In all patients, SNs were first identified by the fluorescence method (ICG-positive) and removed. A gamma ray-detecting probe was then used to determine whether ICG-positive SNs were hot ((99m)Tc-positive) and to identify and remove any (99m)Tc-positive (ICG-negative) SNs remaining in the axilla. The study was powered to perform an equivalence analysis., Results: The 134 patients provided 246 SNs, detected by one or both methods. 1, 2 and 3 SNs, respectively, were detected, removed and examined in 70 (52.2%), 39 (29.1%) and 17 (12.7%) patients; 4-10 SNs were detected and examined in the remaining 8 patients. The two methods were concordant for 230/246 (93.5%) SNs and discordant for 16 (6.5%) SNs. The ICG method detected 99.6% of all SNs., Conclusions: Fluorescent lymphangiography with ICG allows easy identification of axillary SNs, at a frequency not inferior to that of radiotracer, and can be used alone to reliably identify SNs., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

In patients with focal lesions, patterns of learning, retrieval, and recognition deficits vary according to site of damage. Because different brain regions are affected by the underlying pathology in Alzheimer's dementia (AD) and behavioral variant fronto-temporal dementia (bvFTD), one might predict that the two disorders would result in different sorts of memory deficits on the Rey Auditory Verbal Learning Test (RAVLT). The aim of this investigation was to find a way to differentiate AD, bvFTD, and normal controls (NC) reliably based on RAVLT scores from retrospective samples of 82 Italian and 43 Australian participants. Results indicated that the groups differed on measures of learning, retroactive interference, delayed recall, and delayed recognition. Although delayed recall distinguished participants in the three groups across both samples, no one set of cut-offs could be obtained with adequate sensitivity and specificity. However, when we created a combined score (the "RAVLT Memory Efficiency Index": {[(delayed recall A/15)/(RAVLT Trials 1-5/75)] + [(delayed recognition hits/15) - (false positive/total number of distractors)]}), we were able to find cut-offs that differentiated the groups with good sensitivity and specificity across variations in RAVLT methodology, participant samples, and languages. This index will increase the usefulness of the RAVLT in differential diagnoses of early dementia.

Objectives: To evaluate severity of anosognosia and to identify its neuropsychological correlates in preclinical and clinical Alzheimer's Disease (AD)., Methods: The Clinical Insight Rating Scale, the Anosognosia Questionnaire for Dementia (AQ-D), and the Mental Deterioration Battery were used to assess anosognosia and cognitive performances in mild AD (N = 38), amnesic mild cognitive impairment (a-MCI; N = 35), and multiple domain MCI (md-MCI; N = 38)., Results: Patients with mild AD were more anosognosic than both MCI groups, which, however, did not differ from one other. A categorical diagnosis of anosognosia was made in 42% of patients with mild AD, 3% of md-MCI, but in no subjects with a-MCI. Reduced verbal episodic memory raw score was associated with decreased awareness of cognitive difficulties (AQ-D total and intellectual functioning scores) only in MCI. In mild AD, anosognosia was linked only to increased age and reduced basic activities of daily living performances., Conclusions: The diagnosis of anosognosia is frequent in patients with mild AD but not in those with MCI. In the latter case, the authors cannot speak of true anosognosia but only of decreased awareness of illness. Furthermore, reduced awareness of cognitive difficulties is linked with verbal memory performances in patients with MCI but not in those with AD, suggesting for the latter the involvement of factors other than neuropsychological. Thus, neuropsychiatric dimensions commonly present in patients with AD should be investigated along with anosognosia.

Background: Neuropsychiatric disorders are common in cognitively impaired older persons, and associated with institutionalization and caregiver stress in Alzheimer's disease (AD). Few studies have compared the occurrence of both psychiatric disorders and neuropsychiatric symptoms in patients with AD and mild cognitive impairment (MCI) subtypes. We aimed to investigate the frequency of psychiatric disorders and neuropsychiatric symptoms in AD and MCI patients, compared to controls., Methods: We included 245 outpatients of a memory clinic in Rome, Italy (119 AD; 68 multidomain-MCI; 58 amnestic-MCI) and 107 controls. Categorical disorders of depression and apathy were diagnosed with structured interviews. Symptoms were evaluated with the Neuropsychiatric Inventory (NPI). The odds ratios (OR) of patients having neuropsychiatric symptoms compared to controls were calculated with logistic regression, adjusted for sociodemographic and clinical variables., Results: A large proportion of AD (49.6%) and multidomain-MCI (44.1%) patients had depression disorder. Apathy disorder was common in AD (51.3%) but less frequent in amnestic-MCI (6.9%) and multidomain-MCI (14.7%). AD patients were three times more likely to have depression disorders (OR = 3.0, CI = 1.1-7.6) or apathy (OR = 16.9, CI = 4.6-61.8) compared to amnestic-MCI, and seven times more likely to have apathy disorder than multidomain-MCI (OR = 7.5, CI = 3.0-19.2). After apathy and depression, the most prevalent neuropsychiatric symptoms in AD and MCI were anxiety, agitation, irritability, night-time behaviors, and appetite disturbances. There was an increasing prevalence of many neuropsychiatric symptoms with increasing severity of cognitive syndromes., Conclusions: Clinicians should consider the relevance of neuropsychiatric disorders and symptoms in patients with cognitive disturbances, and incorporate a thorough psychiatric examination in the evaluation of patients.

Few studies have compared neuropsychiatric disorders and functional abilities in the early stage of DLB and AD and their influence on caregiver distress. The aim of this study is to assess neuropsychiatric disorders, functional abilities and caregiver distress in DLB and in AD subjects. Sixteen subjects affected by probable DLB and 12 subjects affected by probable AD were enrolled. All subjects underwent a wide neuropsychological examination. Caregiver's distress was also assessed. Subjects affected by DLB performed better in long-term memory tests, whereas AD subjects performed better in attentive and executive function tests. The Neuropsychiatric Inventory (NPI) total score was significantly higher in DLB subjects than in AD subjects. Furthermore, DLB subjects scored worse than AD subjects in both Activities of Daily Living scale (ADL) and Instrumental Activities of Daily Living scale (IADL) scales. Overall caregiver distress was higher in DLB than in AD subjects. High distress was observed in DLB caregivers alone and was caused by delusion, hallucinations, anxiety and apathy. DLB subjects have a different neuropsychological profile, more psychiatric symptoms and more serious functional deficits than AD subjects in the early cognitive decline, furthermore DLB caregivers are more stressed than AD caregivers.

A large number of brain-damaged patients with heterogeneous category-specific deficits have been reported in literature. This has given rise to different theories concerning the processing of semantic knowledge. In this paper we report the case of K.C. who, after a bout of herpes simplex encephalitis, displayed a category-specific impairment restricted to the knowledge of animals, irrespective of input modality. K.C.'s magnetic resonance imaging (MRI) showed multiple bilateral antero-mesial and inferior temporal lesions. Although she was impaired for both the perceptual (visual and auditory) and functional/associative attributes of animals, she performed normally in an object-reality decision task involving pictures of animals and nonanimals. The dissociation between K.C.'s intact structural description system and her impaired semantic knowledge is interpreted according to hierarchical interactive theory (HIT), which assumes that conceptual knowledge is hierarchically organized in separate but interactive multiple knowledge substores. K.C.'s results indicate that her access to a presemantic structural description system was intact so that her impairment on animal semantic knowledge arose later at a conceptual stage of the object recognition system. Furthermore, K.C.'s deficits indicate selective disruption of a special class of animate concepts within the broad category of living things, which seems best explained by the "domain-specific knowledge theory" proposed by Caramazza and Shelton.

A series of eleven patients with aneurysms of distal anterior cerebral artery, microsurgically operated and submitted to accurate neuropsychological testing, is reviewed. Of these, ten patients had an aneurysm at the bifurcation of distal ACA into pericallosal and callosomarginal branches and only one patient had an aneurysm at the beginning of the fronto-polar artery. All our patients were operated by an interhemispheric approach, that was associated in 3 cases to a pterional approach in order to clip a second aneurysm in other location. The postoperative grade was satisfactory in any of the eleven patients. The aneurysms of distal ACA may be surgically obliterated through a variety of approaches but the exposure via the interhemispheric fissure is used by many neurosurgeons. In our experience the interhemispheric approach allows the exposure of feeding artery and the control of proximal vessel without morbidity. Some authors have modified the interhemispheric approach to improve, in their opinion, surgical exposure, introducing partial resection of anterior portion of corpus callosum, used, by them, especially for the aneurysms just beneath the genu of corpus callosum. Although resection of the anterior 2.5 cm of the corpus callosum can be performed without causing any neurological deficit, as reported by the same authors, the use of this technique might not be necessary. The present paper deals with current surgical techniques and their modification for the treatment of distal anterior cerebral artery (ACA) aneurysms.

Forty patients with unilateral frontal or posterior brain damage and 20 normal control subjects were tested on an ambiguous figures task (AFT). For each figure they were asked to recognize both ambiguous images. Subjects failing to recognize the second aspect of an ambiguous figure were prompted with the name of the image not yet perceived. The Wisconsin Card Sorting Test (WCST) was also administered to all subjects. Frontal patients exhibited greater difficulty in shifting from one aspect of an ambiguous figure to the other than did patients with more posterior lesions and control subjects. In addition, frontal-posterior and control differences were highly significant for number of prompts given. For the frontal patients, significant correlations were found between the number of prompts on the AFT and the number of perseverative errors on the WCST. Poor performance on the AFT can be considered as a "frontal lobe sign" of perceptual persevation.