Acceptability of virtual reality to screen for dementia in older adults.

BACKGROUND: Early detection of dementia and cognitive decline is crucial for effective interventions and overall wellbeing. Although virtual reality (VR) tools offer potential advantages to traditional dementia screening tools, there is a lack of knowledge regarding older adults' acceptance of VR tools, as well as the predictors and features influencing their adoption. This study aims to (i) explore older adults' perceptions of the acceptability and usefulness of VR diagnostic tools for dementia, and (ii) identify demographic predictors of adoption and features of VR applications that contribute to future adoption among older adults. METHODS: A cross-sectional study was conducted involving community-dwelling older adults who completed online questionnaires covering demographics, medical history, technology acceptance, previous usage, and perceived usefulness and barriers to VR adoption. Multiple linear regression was employed to assess relationships between sociodemographic factors, prior technology use, perceived ease, usefulness, and intention to adopt VR-based diagnostic tools. RESULTS: Older adults (N = 77, Mage = 73.74, SD = 6.4) were predominantly female and born in English-speaking countries. Perceived usefulness of VR applications and educational attainment emerged as significant predictors of the likelihood to use VR applications for dementia screening. Generally, older adults showed acceptance of VR applications for healthcare and dementia screening. Fully immersive applications were preferred, and older adults were mostly willing to share electronic information from screening with their healthcare providers. CONCLUSIONS: The field of research on VR applications in healthcare is expanding. Understanding the demographic characteristics of populations that stand to benefit from healthcare innovations is critical for promoting adoption of digital health technologies and mitigating its barriers to access.

Exploring the usability of the virtual reality module LEAF CAFÉ: a qualitative think-aloud study.

BACKGROUND: The global healthcare system faces increasing strain from our ageing population, primarily due to the growing prevalence of age-related health conditions such as dementia. While modern healthcare technology offers potential solutions, it frequently lacks user-friendliness for older adults. Virtual Reality (VR) has emerged as a promising tool for diagnosing cognitive impairment, offering innovative solutions where traditional methods may fall short. This study explores older adults' perspectives on the usability of a newly designed VR module for cognitive assessment. METHODS: During a 100-min session, participants were asked to engage and complete recall and recognition tasks within the VR module (think-aloud approach) and provide feedback upon completion (semi-structured interviews). Audio materials were transcribed for analysis and recordings of the users' interactions with the module were annotated to provide additional context. These combined textual data were analysed using content coding and thematic analysis to identify themes that reflect how participants used the module's features and what features are desirable to support that process better. RESULTS: Participants (N = 10; Mean age = 73.3, SD = 7.53, range = 65-83 years) perceived the VR module as user-friendly and endorsed its potential as a cognitive screener due to its engaging and immersive nature. Older adults highlighted three key aspects of the module: the usefulness of the platform's ability to offer a comprehensive and reliable evaluation of an individual's cognitive abilities; the need to present concise and relevant content to optimise engagement and use; and the importance of overcoming barriers to support implementation. Suggested game improvements centred on food recognition and adjusting difficulty levels. Barriers to implementation included technology challenges for older adults and concerns about the game's suitability for everyday scenarios. Participants stressed the need for reliable implementation strategies, proposing locations such as libraries and advocating for home-based screening. CONCLUSION: Continued improvements in accessibility suggest that VR tools could help with diagnosing cognitive impairment in older adults. Using a simulated environment to assess cognitive status might fill the gap between current diagnostic methods, aiding treatment planning and early intervention. However, these findings should be approached cautiously, as more research is needed to fully grasp the potential impact of VR tools in this context.

Passive monitoring of avian habitat on working lands.

Intensive agricultural landscapes pose a challenge to wildlife managers, policymakers, and landowners hoping to increase the diversity of desired wildlife species, such as grassland birds, which require urgent conservation action. In intensive agricultural landscapes, like those of the Midwestern United States, most land area is privately owned and operated and managed primarily for production. Thus, conducting ecological research in intensive agricultural landscapes requires collaborative approaches aimed at farm owners and operators. Recent advances in acoustic data collection and high-resolution habitat mapping, including low-cost acoustic recorders and satellite remote sensing, may be well positioned to address this challenge by enabling expanded assessments and monitoring of wildlife populations and habitats across regions. This study examined fine-grained habitat characteristics and their relationship with avian biodiversity in intensive agricultural landscapes at 44 agricultural sites across the state of Iowa. Passive acoustic monitoring and manual identification of bird species allowed for measurement of vocalizing bird richness. High-resolution mapping of noncrop vegetation provided detailed information on small noncrop vegetation habitat complexes within row-crop agriculture. Measures of image texture provided characterizations of compositional heterogeneity within noncrop vegetation. General linear Poisson modeling demonstrated robust associations between noncrop vegetation and vocalizing bird richness, yet variation in grassland bird richness was not well predicted by noncrop vegetation. Noncrop vegetation texture demonstrated potential as a predictor of vocalizing bird richness, though not better than or when combined with noncrop vegetated area, indicating it may not be an independent measure of habitat quality. Passive acoustic monitoring resulted in useful data at 44 out of 60 originally selected sites, with some lost to failed recorders and/or collaboration issues. Challenges remain in detecting habitat characteristics that promote grassland birds in row crop landscapes. Working toward probabilistic research design across privately owned working landscapes and incorporating more detailed management practice information would improve the transferability of this approach to farmland management and policy.

A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma.

The genetic hallmark of Burkitt lymphoma (BL) is the t(8;14)(q24;q32) and its variants leading to activation of the MYC oncogene. It is a matter of debate whether true BL without MYC translocation exists. Here, we identified 59 lymphomas concordantly called BL by 2 gene expression classifiers among 753 B-cell lymphomas. Only 2 (3%) of these 59 molecular BL lacked a MYC translocation, which both shared a peculiar pattern of chromosome 11q aberration characterized by interstitial gains including 11q23.2-q23.3 and telomeric losses of 11q24.1-qter. We extended our analysis to 17 MYC-negative high-grade B-cell lymphomas with a similar 11q aberration and showed this aberration to be recurrently associated with morphologic and clinical features of BL. The minimal region of gain was defined by high-level amplifications in 11q23.3 and associated with overexpression of genes including PAFAH1B2 on a transcriptional and protein level. The recurrent region of loss contained a focal homozygous deletion in 11q24.2-q24.3 including the ETS1 gene, which was shown to be mutated in 4 of 16 investigated cases. These findings indicate the existence of a molecularly distinct subset of B-cell lymphomas reminiscent of BL, which is characterized by deregulation of genes in 11q.

A retrospective international study on primary extranodal marginal zone lymphoma of the lung (BALT lymphoma) on behalf of International Extranodal Lymphoma Study Group (IELSG).

Primary lymphoma of the lung is a rare entity. Clinical features, optimal treatment, role of surgery and outcomes are not well defined, and the follow-up is variable in published data. Clinical data of 205 patients who were confirmed to have bronchus mucosa-associated lymphoid tissue lymphoma from December 1986 to December 2011 in 17 different centres worldwide were evaluated. Fifty-five per cent of the patients were female. The median age at diagnosis was 62 (range 28-88) years. Only 9% had a history of exposure to toxic substances, while about 45% of the patients had a history of smoking. Ten per cent of the patients had autoimmune disease at presentation, and 19% patients had a reported preexisting lung disease. Treatment modalities included surgery alone in 63 patients (30%), radiotherapy in 3 (2%), antibiotics in 1 (1%) and systemic treatment in 128 (62%). Patients receiving a local approach, mainly surgical resection, experienced significantly improved progression-free survival (p = 0.003) versus those receiving a systemic treatment. There were no other significant differences among treatment modalities. The survival data confirm the indolent nature of the disease. Local therapy (surgery or radiotherapy) results in long-term disease-free survival for patients with localized disease. Systemic treatment, including alkylating-containing regimens, can be reserved to patients in relapse after incomplete surgical excision or for patients with advanced disease. Copyright © 2015 John Wiley & Sons, Ltd.

Endotoxicity of lipopolysaccharide as a determinant of T-cell-mediated colitis induction in mice.

BACKGROUND & AIMS: The intestinal microbiota is an important determinant of the mucosal response. In patients with inflammatory bowel diseases, the mucosal immune system has inappropriate interactions with the intestinal microbiota. We investigated how the composition of the intestinal microbiota affects its endotoxicity and development of colitis in mice. METHODS: Germ-free C57BL/6J-Rag(1tm1Mom) (Rag1(-/-)) mice were colonized with 2 different types of complex intestinal microbiota. Colitis was induced in Rag1(-/-) mice by transfer of CD4(+)CD62L(+) T cells from C57BL/6J mice. Colonic tissues were collected and used for histologic analysis and cell isolation. Activation of lamina propria dendritic cells and T cells was analyzed by flow cytometry. RESULTS: After transfer of CD4(+)CD62L(+) T cells, mice with intestinal Endo(lo) microbiota (a low proportion of Enterobacteriaceae, high proportion of Bacteroidetes, and low endotoxicity) maintained mucosal immune homeostasis, and mice with highly endotoxic Endo(hi) microbiota (a high proportion of Enterobacteriaceae and low proportion of Bacteroidetes) developed colitis. To determine whether the effects of Endo(hi) microbiota were related to the higher endotoxic activity of lipopolysaccharide (LPS), we compared LPS from Enterobacteriaceae with that of Bacteroidetes. Administration of Escherichia coli JM83 (wild-type LPS) to the mice exacerbated colitis, and Escherichia coli JM83 + htrBPG (mutated LPS, with lower endotoxicity, similar to that of Bacteroidetes) prevented development of colitis after transfer of the T cells to mice. CONCLUSIONS: The endotoxicity of LPS produced by the intestinal microbiota is a determinant of whether mice develop colitis after transfer of CD4(+)CD62L(+) T cells. This finding might aid the design of novel biologics or probiotics to treat inflammatory bowel disease.

Analysis of incomplete excisions of basal-cell carcinomas after breadloaf microscopy compared with 3D-microscopy: a prospective randomized and blinded study.

Basal-cell carcinomas may show irregular, asymmetric subclinical growth. This study analyzed the efficacy of 'breadloaf' microscopy (serial sectioning) and three-dimensional (3D) microscopy in detecting positive tumor margins. Two hundred eighty-three (283) tumors (51.2%) were put into the breadloaf microscopy group; 270 tumors (48.8%) into the 3D microscopy group. The position of any detected tumor outgrowths was identified in clock face fashion. The time required for cutting and embedding the specimens and the examination of the microscopic slides was measured. Patient/tumor characteristics and surgical margins did not differ significantly. Tumor outgrowths at the excision margin were found in 62 of 283 cases (21.9%) in the breadloaf microscopy group and in 115 of 270 cases (42.6%) in the 3D microscopy group, constituting a highly significant difference (p < 0.001). This difference held true with incomplete excision of fibrosing (infiltrative/sclerosing/morpheaform) tumors [32.9% in the breadloaf microscopy group and 57.5% in the 3D microscopy group (p = 0.003)] and also with solid (nodular) tumors [16.1 and 34.2%, respectively (p < 0.001)]. The mean overall examination time required showed no important difference. In summary, for detection of tumor outgrowths, 3D microscopy has almost twice the sensitivity of breadloaf microscopy, particularly in the situation of aggressive/infiltrative carcinomas.

Impact of tumour volume on prediction of progression-free survival in sinonasal cancer.

BACKGROUND: The present study aimed to analyse potential prognostic factors, with emphasis on tumour volume, in determining progression free survival (PFS) for malignancies of the nasal cavity and the paranasal sinuses. PATIENTS AND METHODS: Retrospective analysis of 106 patients with primary sinonasal malignancies treated and followed-up between March 2006 and October 2012. Possible predictive parameters for PFS were entered into univariate and multivariate Cox regression analysis. Kaplan-Meier curve analysis included age, sex, baseline tumour volume (based on MR imaging), histology type, TNM stage and prognostic groups according to the American Joint Committee on Cancer (AJCC) classification. Receiver operating characteristic (ROC) curve analysis concerning the predictive value of tumour volume for recurrence was also conducted. RESULTS: The main histological subgroup consisted of epithelial tumours (77%). The majority of the patients (68%) showed advanced tumour burden (AJCC stage III-IV). Lymph node involvement was present in 18 cases. The mean tumour volume was 26.6 ± 21.2 cm(3). The median PFS for all patients was 24.9 months (range: 2.5-84.5 months). The ROC curve analysis for the tumour volume showed 58.1% sensitivity and 75.4% specificity for predicting recurrence. Tumour volume, AJCC staging, T- and N- stage were significant predictors in the univariate analysis. Positive lymph node status and tumour volume remained significant and independent predictors in the multivariate analysis. CONCLUSIONS: Radiological tumour volume proofed to be a statistically reliable predictor of PFS. In the multivariate analysis, T-, N- and overall AJCC staging did not show significant prognostic value.

Prevalence of Achromobacter xylosoxidans in pulmonary mucosa-associated lymphoid tissue lymphoma in different regions of Europe.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) comprises 7-8% of B-cell lymphomas and commonly originates from a background of long-standing chronic inflammation. An association with distinct bacteria species has been confirmed for several anatomical sites of MALT lymphoma. For pulmonary MALT lymphoma, however, a clear link with an infectious agent or autoimmune disorder has not yet been reported. Using a 16S rRNA gene-based approach, we have recently identified Achromobacter (Alcaligenes) xylosoxidans in eight of nine cases of pulmonary MALT lymphoma. A. xylosoxidans is a gram-negative betaproteobacterium with low virulence, but high resistance to antibiotic treatment. To further examine a potential association with A. xylosoxidans, 124 cases of pulmonary MALT lymphoma and 82 control tissues from six European countries were analysed using a specific nested PCR. Although prevalence rates for A. xylosoxidans varied significantly from country to country, they were consistently higher for MALT lymphoma as compared to controls. Overall, 57/124 (46%) pulmonary MALT lymphomas and 15/82 (18%) control tissues were positive for A. xylosoxidans (P = 0·004). Whether the significant association of A. xylosoxidans with pulmonary MALT lymphoma demonstrated in our study points to a potential causal role in the pathogenesis of this lymphoma will require further studies.

ALK-positive cancer: still a growing entity.

 Since the discovery of ALK-positive anaplastic large-cell lymphoma in 1994 many other types of tumors showing ALK expression were disclosed. They form a heterogeneous group, including lung, renal and soft tissue tumors. The biological function of ALK, its role in carcinogenesis and impact exerted on the clinical outcome have been studied by many research groups. New drugs specifically dedicated for ALK inhibition, for example, crizotinib, have been synthesized and have become a viable treatment option for ALK-positive lung adenocarcinoma, and potentially for other ALK-positive cancers. This review summarizes the current state of knowledge concerning ALK-positive neoplasms, focusing on the clinical aspects of the subject.

Three dimensional (3D) histology in daily routine: practical implementation and its evaluation.

BACKGROUND: The continuous evaluation of the edges of a tumor by means of three-dimensional (3D) histology often appears complicated and require the surgeon and dermatopathologist to work together closely. We present clear rules that allow communication between all parties involved and then verify their application in daily routine. METHODS: Tissue processing, interpretation of results, as well as communication between the surgeon and the dermatopathologist are based on an algorithm with the aid of exact times and embedding cassettes, which allow precise topographic orientation. We evaluated the use of this method in daily clinic practice, taking into account 947 operated basal cell carcinomas in regard to the development of recurrent tumors. RESULTS: At a median follow-up of 47 months, 10 of the 947 operated basal cell carcinomas (1.1 %) recurred. Sclerodermiform basal cell carcinomas and basal cell carcinomas which could not be curatively resected (R0 resection) during the initial surgery showed a significantly higher recurrence rate (p < 0.05 and p < 0.001). CONCLUSIONS: Standardized rules for dealing with excised tissue allow an effective application of 3D histology in daily clinical practice. 3D histology results in low recurrence rates. Sclerodermiform basal cell carcinomas which could not be curatively resected (R0 resection) were identified as a risk group for the development of recurrent tumors.

Building digital solutions to support brain health prescribing in primary care: Where to begin?

National and international policy goals on healthy ageing and dementia risk reduction are yet to be fully realised in community healthcare settings. Disease modification strategies through lifestyle and social interventions are viable, evidence-based solutions to reduce age-related disease burden. However, prescribing lifestyle interventions targeting dementia risk in primary care remains deficient. Using digital technologies to support older individuals and healthcare professionals through formal health checks and lifestyle management is likely to enable shared understanding and consequences of personalized care and treatment options. These tailored solutions may bridge the translation gap and support healthy ageing.

Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance.

PURPOSE: The antibody-drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET). EXPERIMENTAL DESIGN: Membranous NECTIN-4 protein expression was measured (H-score) by IHC in PRIM and corresponding MET (N = 137) and in a multicenter EV-treated cohort (N = 47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4-negative/weak (H-score 0-99) versus moderate/strong (H-score 100-300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9-induced polyclonal NECTIN-4 knockouts. RESULTS: In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P < 0.001; median H-score = 40; interquartile range, 0-140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (log-rank P < 0.001). CONCLUSIONS: Membranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/progressive lesion) before initiation of EV. See related commentary by Aggen et al., p. 1377.

Incidence of preclinical manifestations of mantle cell lymphoma and mantle cell lymphoma in situ in reactive lymphoid tissues.

Recently, the occurrence of cyclin D1-positive B cells with mantle cell lymphoma phenotype in the inner mantle zones of morphologically inconspicuous lymph nodes has been described and termed mantle cell lymphoma 'in situ'. Prevalence and clinical significance of this lesion and related minimal mantle cell lymphoma infiltrates in reactive lymphoid tissues of healthy individuals, and of mantle cell lymphoma patients are unknown. All 1292 reactive lymph nodes from unselected consecutive surgical specimens of 131 patients without a history of lymphoma obtained over a 3-month period were stained for cyclin D1. In addition, all morphologically reactive lymph nodes and benign-appearing extranodal lymphoid infiltrates of patients diagnosed with mantle cell lymphoma in the years 2000-2011 were studied. Samples predating the lymphoma diagnosis for at least 2 months were available from 37/423 (9%) patients. A mantle cell lymphoma 'in situ' was not identified in any of the two groups. However, in four patients with subsequent mantle cell lymphoma diagnosis, an early manifestation of mantle cell lymphoma was detected retrospectively, antedating the lymphoma diagnosis for 2-86 months. In six mantle cell lymphoma patients, only small groups of cyclin D1-positive cells in morphologically reactive extranodal infiltrates were detected >2 months before the diagnosis of mantle cell lymphoma (range 3-59 months). Mantle cell lymphoma 'in situ' is an extremely rare phenomenon in morphologically reactive lymph nodes, in line with the low prevalence of t(11;14)-positive cells described in the peripheral blood of a healthy population. In mantle cell lymphoma patients, however, immunohistochemically detectable infiltrates of mantle cell lymphoma cells antedating the lymphoma diagnosis were found in a significant proportion of cases (10/37=27%). These consisted either of early mantle cell lymphoma with mantle zone growth pattern, or small extranodal accumulations of cyclin D1+ cells, whereas typical mantle cell lymphoma 'in situ' was not detected.

Systemic IgG4-related sclerosing disease: spectrum of imaging findings and differential diagnosis.

OBJECTIVE: The purposes of this article are to provide a practical review of the spectrum of imaging findings in patients with systemic IgG4-related sclerosing disease and to address the differential diagnoses. CONCLUSION: IgG4-related sclerosing disease is a systemic disorder that can involve almost any organ. The imaging findings consist of diffuse and focal organ infiltration and encasement by inflammatory and fibrotic tissue. Awareness of the spectrum of imaging findings in IgG4-related disease should prompt further evaluation for systemic manifestations to avoid misdiagnosis.

Perfusion and flow extraction product as potential discriminators in untreated follicular and diffuse large B cell lymphomas using volume perfusion CT with attempt at histopathologic explanation.

OBJECTIVE: The purpose of this article is to measure perfusion parameters, including transit constant (K(trans)), in untreated follicular and diffuse large B cell lymphoma using volume perfusion CT, to establish their discriminating role and to search for a possible histopathologic background. SUBJECTS AND METHODS: Between January 2010 and June 2011, 46 consecutive patients with untreated histologically confirmed follicular lymphoma (n = 16) or diffuse large B cell lymphoma (n = 30) were enrolled. A 40-second volume perfusion CT of the tumor bulk using 6.9-cm z-axis coverage and a total of 26 volume measurements was performed. Blood flow (BF), blood volume (BV), and K(trans) were determined. Tumor size was recorded as the product of long- and short-axis diameters. In 13 of 46 patients, pathologic specimens of an appropriate size were available for assessment of microvessel density (MVD) and microvascular luminal diameter for comparison with volume perfusion CT measurements. RESULTS: Mean BF, BV, and K(trans) values were significantly higher in follicular lymphoma than in diffuse large B cell lymphoma, even after controlling for patient age and tumor size (p < 0.05, respectively). Although MVD was slightly, but not significantly, higher in follicular lymphoma versus diffuse large B cell lymphoma (p > 0.05), microvascular luminal diameter was significantly larger in follicular lymphoma than in diffuse large B cell lymphoma (p < 0.05). We defined cutoff values for BF, BV, and K(trans). If the cutoff points are met for all three parameters, the overall accuracy for correctly identifying diffuse large B cell lymphoma and follicular lymphoma was 90.5% and 87.5%, respectively. CONCLUSION: Volume perfusion CT allows assessment of differences in vascularity of follicular and diffuse large B cell lymphomas, reflecting vascular luminal variability and histopathologic anatomy.

Geographic variation in the prevalence of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly: a comparative analysis of a Mexican and a German population.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma of the elderly was included as a provisional entity in the 2008 WHO lymphoma classification. Most reports of this disease come from Asia and little is known about it in other regions of the world, including Latin America. Therefore, in this study, 305 diffuse large B-cell lymphomas in patients above 50 years were analyzed, 136 from Mexico and 169 from Germany. EBV was detected by Epstein-Barr early RNA (EBER) in situ hybridization. Only cases with EBER+ in the majority of tumor cells were regarded as EBV+ diffuse large B-cell lymphoma. The prevalence of EBV+ diffuse large B-cell lymphoma in Mexican patients was found to be 7% (9 of 136), whereas only 2% (4 of 169) of the German cases were positive. The median age at diagnosis was 66 years in the Mexican cohort, as opposed to 77 years in the German group. The site of presentation was in both groups predominantly nodal in nine cases (70%) and extranodal in four cases (30%). Of the 13 EBV+ cases, 10 (77%) were classified as polymorphic and 3 (23%) as monomorphic type. The polymorphic cases showed a non-germinal center B-cell immunophenotype (CD10- MUM1+). Twelve cases (92%) were LMP1 positive and two (15%) expressed EBNA2. An interesting finding was the high frequency of EBV type B with the LMP1 30 bp deletion found in the Mexican cases (50%). Eight of the 11 evaluable cases were B-cell monoclonal by polymerase chain reaction. In summary, we found a similar prevalence of EBV+ diffuse large B-cell lymphoma of the elderly in a Mexican population compared with what has been reported in Asian countries, and in contrast to the low frequency in Western populations (1-3%). However, compared with the Asian series, the Mexican patients were younger at diagnosis, presented predominantly with nodal disease and rarely expressed EBNA2 protein.

Prevalence of follicular lymphoma in situ in consecutively analysed reactive lymph nodes.

AIMS: Follicular lymphoma (FL) in situ is defined as strongly bcl-2-positive B cells in germinal centres of morphologically inconspicuous lymph nodes. The prevalence and biological and clinical significance of this lesion are still not clear. Therefore we aimed at the detection of the prevalence of this phenomenon in an unselected series of lymph nodes, as a surrogate for the normal population. METHODS AND RESULTS: All 1294 reactive lymph nodes from unselected consecutive surgical specimens of 132 patients in a 3-month period were stained for bcl-2 protein. The t(14;18) translocation was investigated by fluorescence in-situ hybridization (FISH) analysis. FL in situ was identified in 22 lymph nodes in 3/132 patients (2.3%) without evidence or history of malignant lymphoma, and confirmed by detection of the t(14;18) translocation by FISH. Interestingly, in one patient, a lymph node excised 2 years before also contained FL in situ. CONCLUSIONS: We found a prevalence of 2.3% for FL in situ lesions in an unselected series of lymph nodes, as a surrogate for the normal population. Taking into account the incidence of manifest FL, the risk of progression of this lesion is probably limited. It can be speculated that some FL in situ lesions do indeed represent an early step in lymphomagenesis, whereas others persist without further progression to overt FL. The underlying mechanisms, however, remain to be elucidated.

Epstein-Barr virus-positive diffuse large B-cell lymphomas of the elderly.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly has been included in the 2008 WHO classification as a new provisional entity and is defined as blastic, clonal B-cell proliferation associated with EBV occurring in patients over 50 years of age, presumably due to senescence of the immune system. Secondary immunodeficiencies must be excluded. Morphologically, the predominant polymorphic subtype shows a mixed proliferation of large transformed cells, plasma cells, plasmablasts, lymphocytes, and commonly Reed-Sternberg (RS)-like cells, whereas the monomorphic subtype reveals sheets of large cells. An additional characteristic feature is large areas of "geographical" necrosis. EBV+ DLBCL of the elderly is positive for pan-B cell markers and often for CD30. EBV infection detected by Epstein Barr early RNA in situ hybridization should be present in the majority of tumor cells. Most cases express LMP1 and up to 32% EBNA2, the latter a sign of an impaired immune system. The most challenging differential diagnosis is EBV+ classical Hodgkin lymphoma in older patients. Strong, homogeneous expression of B-cell markers, including transcription factors OCT2 and BOB.1, and lack of CD15 support a diagnosis of EBV+ DLBCL. EBV+ DLBCL of the elderly accounts for 8% to 10% of DLBCL in Asian countries, but seems to be uncommon in Western populations, indicating an ethnic or geographic predisposition. Clinically, patients may present with nodal or extranodal involvement. B-symptoms and poor performance status are common, and prognosis is significantly inferior compared with EBV- cases. Whether EBV+DLBCL of the elderly represents a true entity or only a DLBCL variant remains to be determined.

Epidermal growth factor receptor in adrenocortical tumors: analysis of gene sequence, protein expression and correlation with clinical outcome.

Adrenocortical carcinoma is a rare but highly malignant neoplasm with still limited treatment options. Epidermal growth factor receptor (EGFR) has been shown to be overexpressed in many solid tumors, but its expression in adrenocortical carcinoma has been studied only in a limited number of cases. Therefore, we analyzed the expression of EGFR in 169 adrenocortical carcinoma samples and compared it with 31 adrenocortical adenomas. Additionally, in 30 cases of adrenocortical carcinoma, exons 18-21 of the EGFR gene were cloned and sequenced. EGFR expression was found in 128 of 169 adrenocortical carcinoma samples (76%), and in 60 of these samples (=36%) strong membrane staining was detected. However, there was no significant correlation with clinical outcome. In addition, all 30 sequenced cases revealed unmutated EGFR genes. In contrast, only 1 out of 31 adrenocortical adenomas weakly expressed the EGFR (3%). In summary, EGFR was overexpressed in more than three-quarters of adrenocortical carcinoma cases of this series. However, no mutations of the EGFR gene were found and EGFR expression was not of prognostic relevance. As EGFR is hardly expressed in adrenocortical adenomas, our results suggest that its expression in adrenocortical tumors indicates a malignant phenotype, which may be used in the differential diagnosis between adrenocortical adenomas and carcinomas.