Genomic and epigenomic basis of breast invasive lobular carcinomas lacking CDH1 genetic alterations.

CDH1 (E-cadherin) bi-allelic inactivation is the hallmark alteration of breast invasive lobular carcinoma (ILC), resulting in its discohesive phenotype. A subset of ILCs, however, lack CDH1 genetic/epigenetic inactivation, and their genetic underpinning is unknown. Through clinical targeted sequencing data reanalysis of 364 primary ILCs, we identified 25 ILCs lacking CDH1 bi-allelic genetic alterations. CDH1 promoter methylation was frequent (63%) in these cases. Targeted sequencing reanalysis revealed 3 ILCs harboring AXIN2 deleterious fusions (n = 2) or loss-of-function mutation (n = 1). Whole-genome sequencing of 3 cases lacking bi-allelic CDH1 genetic/epigenetic inactivation confirmed the AXIN2 mutation and no other cell-cell adhesion genetic alterations but revealed a new CTNND1 (p120) deleterious fusion. AXIN2 knock-out in MCF7 cells resulted in lobular-like features, including increased cellular migration and resistance to anoikis. Taken together, ILCs lacking CDH1 genetic/epigenetic alterations are driven by inactivating alterations in other cell adhesion genes (CTNND1 or AXIN2), endorsing a convergent phenotype in ILC.

Does Non-Classic Lobular Carcinoma In Situ at the Lumpectomy Margin Increase Local Recurrence?

BACKGROUND: The clinical significance of nonclassic, lobular carcinoma in situ (NC-LCIS) at the surgical margin of excisions for invasive cancer is unknown. We sought to determine whether NC-LCIS at or near the margin in the setting of a concurrent invasive carcinoma is associated with risk of ipsilateral breast tumor recurrence (IBTR) and locoregional recurrence (LRR). METHODS: Patients with stage 0-III breast cancer and NC-LCIS who underwent lumpectomy between January 2010 and January 2022 at a single institution were retrospectively identified. NC-LCIS margins were stratified as <2 mm, ≥2 mm, or within shave margin. Rates of IBTR and LRR were examined. RESULTS: A total of 511 female patients (median age 60 years [interquartile range (IQR) 52-69]) with NC-LCIS and an associated ipsilateral breast cancer with a median follow-up of 3.4 years (IQR 2.0-5.9) were identified. Final margins for NC-LCIS were ≥2 mm in 348 patients (68%), <2 mm in 37 (7.2%), and within shave margin in 126 (24.6%). Crude incidence of IBTR was 3.3% (n = 17) and that of LRR was 4.9% (n = 25). There was no difference in the crude rate of IBTR by NC-LCIS margin status (IBTR rate: 3.7% ≥2 mm, 0% <2 mm, 3.2% within shave margin, p = 0.8) nor in LRR (LRR rate: 4.9% ≥2 mm, 2.7% <2 mm, 5.6% within shave margin, p = 0.9). CONCLUSIONS: For completely excised invasive breast cancers associated with NC-LCIS, extent of margin width for NC-LCIS was not associated with a difference in IBTR or LRR. These data suggest that the decision to perform reexcision of margin after lumpectomy should be driven by the invasive cancer, rather than the NC-LCIS margin.

Is Surgical Excision of Focal Atypical Ductal Hyperplasia Warranted? Experience at a Tertiary Care Center.

BACKGROUND: The core-needle biopsy (CNB) diagnosis of atypical ductal hyperplasia (ADH) generally mandates follow-up excision, but controversy exists on whether small foci of ADH require surgical management. This study evaluated the upgrade rate at excision of focal ADH (fADH), defined as 1 focus spanning ≤ 2 mm. METHODS: We retrospectively identified in-house CNBs with ADH as the highest-risk lesion obtained between January 2013 and December 2017. A radiologist assessed radiologic-pathologic concordance. All CNB slides were reviewed by two breast pathologists, and ADH was classified as fADH and nonfocal ADH based on extent. Only cases with follow-up excision were included. The slides of excision specimens with upgrade were reviewed. RESULTS: The final study cohort consisted of 208 radiologic-pathologic concordant CNBs, including 98 fADH and 110 nonfocal ADH. The imaging targets were calcifications (n = 157), a mass (n = 15), nonmass enhancement (n = 27), and mass enhancement (n = 9). Excision of fADH yielded seven (7%) upgrades (5 ductal carcinoma in situ (DCIS), 2 invasive carcinoma) versus 24 (22%) upgrades (16 DCIS, 8 invasive carcinoma) at excision of nonfocal ADH (p = 0.01). Both invasive carcinomas found at excision of fADH were subcentimeter tubular carcinomas away from the biopsy site and deemed incidental. CONCLUSIONS: Our data show a significantly lower upgrade rate at excision of focal ADH than nonfocal ADH. This information can be valuable if nonsurgical management of patients with radiologic-pathologic concordant CNB diagnosis of focal ADH is being considered.

Multi-institutional Assessment of Pathologist Scoring HER2 Immunohistochemistry.

The HercepTest was approved 20+ years ago as the companion diagnostic test for trastuzumab in human epidermal growth factor 2 (HER2) or ERBB2 gene-amplified/overexpressing breast cancers. Subsequent HER2 immunohistochemistry (IHC) assays followed, including the now most common Ventana 4B5 assay. Although this IHC assay has become the clinical standard, its reliability, reproducibility, and accuracy have largely been approved and accepted on the basis of concordance among small numbers of pathologists without validation in a real-world setting. In this study, we evaluated the concordance and interrater reliability of scoring HER2 IHC in 170 breast cancer biopsies by 18 breast cancer-specialized pathologists from 15 institutions. We used the Observers Needed to Evaluate Subjective Tests method to determine the plateau of concordance and the minimum number of pathologists needed to estimate interrater agreement values for large numbers of raters, as seen in the real-world setting. We report substantial discordance within the intermediate categories (<1% agreement for 1+ and 3.6% agreement for 2+) in the 4-category HER2 IHC scoring system. The discordance within the IHC 0 cases is also substantial with an overall percent agreement (OPA) of only 25% and poor interrater reliability metrics (0.49 Fleiss' kappa, 0.55 intraclass correlation coefficient). This discordance can be partially reduced by using a 3-category system (28.8% vs 46.5% OPA for 4-category and 3-category scoring systems, respectively). Observers Needed to Evaluate Subjective Tests plots suggest that the OPA for the task of determining a HER2 IHC score 0 from not 0 plateaus statistically around 59.4% at 10 raters. Conversely, at the task of scoring HER2 IHC as 3+ or not 3+ pathologists' concordance was much higher with an OPA that plateaus at 87.1% with 6 raters. This suggests that legacy HER2 IHC remains valuable for finding the patients in whom the ERBB2 gene is amplified but unacceptably discordant in assigning HER2-low or HER2-negative status for the emerging HER2-low therapies.

Mixed and Purely Hyperechoic Breast Masses: A Radiologic-Pathologic Review.

Breast US is a mainstay of modern-day breast imaging, especially in the diagnostic and interventional realm. The BI-RADS atlas described six echo patterns relative to the subcutaneous mammary fat: anechoic, hypoechoic, complex cystic and solid, isoechoic, heterogeneous, and hyperechoic. Hyperechoic breast masses demonstrate increased echogenicity relative to subcutaneous mammary fat or equal to fibroglandular tissue. Pathologically, the hyperechoic pattern at breast US results from the intermingling of different components: adipose tissue, fibrous tissue or stroma, secretions, blood or vascularity, and calcifications. Most hyperechoic masses are benign, especially homogeneously hyperechoic masses. However, hyperechogenicity does not exclude malignancy. Two echo patterns have been identified in hyperechoic malignant lesions, including those with a hypoechoic center and hyperechoic rim known as the rim pattern and a mass with hyperechoic areas distributed through the mass known as a dispersed pattern. This article aims to illustrate the echogenic patterns of breast lesions and various benign and malignant hyperechoic breast lesions with radiologic-pathologic correlation and to increase awareness of heterogeneously hyperechoic breast lesions as a manifestation of malignancy.

Investigating the transfer rate of waterpipe additives to smoke as an integral part of toxicological risk assessments.

Waterpipe, also known as hookah, narghile or narghila, shisha or hubbly bubbly, is a tobacco-smoking device. Waterpipe tobacco is heated and consumed by a process of inhaling tobacco smoke, that bubbles through water before being inhaled. To date, limited studies have examined the transfer of waterpipe additives from tobacco to smoke. This study was designed to investigate the filtration ability of water in the waterpipe's bowl to define exposure to additives in waterpipe smoke, which is an essential requirement to perform toxicological risk assessments of waterpipe additives. Within this study, a standard smoking protocol (ISO 22486) was used to evaluate the transfer of > 40 additives from experimental and commercially available samples. These results are the first to provide such an extensive dataset of information showing transfer rates varying between 6% and 61% depending on the additive. Various physicochemical parameters of the additives including water solubility, partition coefficient, molecular weight, boiling point, and vapor pressure were also evaluated to seek to identify any correlation to transfer rate that may be later used to predict transfer. The amount of additive transfer from waterpipe tobacco to the smoke was found to be moderately correlated to vapor pressure (Pearson correlation coefficient = 0.33) with subsequent multivariate analysis using step-wise selection indicating 39% of the transfer rate variance can be explained collectively by the additive boiling point, molecular weight, vapor pressure and water solubility. These findings underscore the complexity of additive transfer and highlight the necessity of exposure assessment for meaningful waterpipe additive risk assessments.

Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue.

IMPORTANCE: Trastuzumab deruxtecan (T-DXd) has shown efficacy in patients with breast cancer with ERBB2 immunohistochemistry (IHC) scores of 1+ or 2+ but not 0 as read in central pathology laboratories. The drug is currently being tested in large randomized clinical trials with registration intent for this patient population. OBJECTIVE: To determine the suitability of the current standard ERBB2 IHC assays to select patients with low ERBB2 positivity for treatment with T-DXd. DESIGN AND SETTING: Assessment of data from College of American Pathologists surveys and assessment of analytic data from a Yale University-based study of concordance of 18 pathologists reading 170 breast cancer biopsies. RESULTS: The total survey data set included scores over 2 years from 1391 to 1452 laboratories of 40 ERBB2 cores from each laboratory (20 cores twice a year for a total of 80). College of American Pathologists surveys show that 19% of cases read by the laboratories generate results with less than or equal to 70% concordance for IHC ERBB2 score 0 vs 1+. When 18 pathologists read the scanned slides from a selected set of breast cancer biopsies using a 4-point scale, there was only 26% concordance between 0 and 1+ compared with 58% concordance between 2+ and 3+. CONCLUSIONS AND RELEVANCE: In this study using a current standard ERBB2 IHC assay, the scoring accuracy for ERBB2 IHC in the low range (0 and 1+) was poor. This inaccuracy in the real world could lead to misassignment of many patients for treatment with T-DXd.

Morphologic subtypes of lobular carcinoma in situ diagnosed on core needle biopsy: clinicopathologic features and findings at follow-up excision.

Lobular carcinoma in situ (LCIS) is currently classified as classic (CLCIS), florid (FLCIS), and pleomorphic (PLCIS). Given the rarity of FLCIS and PLCIS, information on their clinico-pathologic features and biologic potential remains limited. We evaluated the upgrade rates at excision of FLCIS and PLCIS diagnosed on inhouse core needle biopsy (CNB) and their clinical presentation and follow-up. Over a period of 11 and a half years, there were a total of 36 inhouse CNBs with pure PLCIS (n = 8), FLCIS (n = 24), or LCIS with pleomorphic features (LCIS-PF) (n = 4). The upgrade rates to invasive carcinoma or ductal carcinoma in situ (DCIS) were 25% for PLCIS (2/8), 17% for FLCIS (4/24), and 0% for LCIS-PF (0/4). The overall upgrade rate of PLCIS and FLCIS combined was 19% (6/32). All but one case (not upgraded at excision) were radiologic-pathologic concordant. Apocrine features, previously reported only in PLCIS, were also noted in FLCIS. HER2 overexpression was seen in 13% of cases. This study highlights the more aggressive biologic features of PLCIS and FLCIS compared to CLCIS and supports surgical management for these lesions.

Interobserver Variation of PD-L1 SP142 Immunohistochemistry Interpretation in Breast Carcinoma: A Study of 79 Cases Using Whole Slide Imaging.

CONTEXT.­: The Ventana programmed death ligand-1 (PD-L1) SP142 immunohistochemical assay (IHC) is approved by the US Food and Drug Administration as the companion diagnostic assay to identify patients with locally advanced or metastatic triple-negative breast cancer for immunotherapy with atezolizumab, a monoclonal antibody targeting PD-L1. OBJECTIVE.­: To determine interobserver variability in PD-L1 SP142 IHC interpretation in invasive breast carcinoma. DESIGN.­: The pathology database was interrogated for all patients diagnosed with primary invasive, locally recurrent, or metastatic breast carcinoma on which PD-L1 SP142 IHC was performed from November 2018 to June 2019 at our institution. A subset of cases was selected using a computerized random-number generator. PD-L1 IHC was evaluated in stromal tumor-infiltrating immune cells using the IMpassion130 trial criteria, with positive cases defined as immunoreactivity in immune cells in 1% or more of the tumor area. IHC was interpreted on whole slide images by staff pathologists with breast pathology expertise. Interobserver variability was calculated using unweighted κ. RESULTS.­: A total of 79 cases were assessed by 8 pathologists. Interobserver agreement was substantial (κ = 0.727). There was complete agreement among all 8 pathologists in 62% (49 of 79) of cases, 7 pathologists or more in 84% (66 of 79) of cases, and 6 pathologists or more in 92% (73 of 79) of cases. In 4% (3 of 79) of cases, all of which were small biopsies, pathologists' interpretations were evenly split between scores of positive and negative. CONCLUSIONS.­: The findings show substantial agreement in PD-L1 SP142 IHC assessment of breast carcinoma cases among 8 pathologists at a single institution. Further study is warranted to define the basis for discrepant results.

Comparison of local rosmarinic acid and topical dexpanthenol applications on wound healing in a rat experimental wound model.

BACKGROUND: The aim of the study was to compare the effects of rosmarinic acid and dexpanthenol in a rat experimental wound model. MATERIALS AND METHODS: Twenty-four Wistar albino rats weighing 200-250 g were randomly divided into three groups. After 2-cm full-thickness skin defects were created, the wounds were washed with sterile 0.9% NaCl solution. After washing, the control group was left untreated, the second group received 5% dexpanthenol cream, and the third group received 10% rosmarinic acid cream. Before excision, the skin was evaluated macroscopically by measuring the reduction in wound size; after excision, histological examination (epithelisation, inflammation, fibrosis, granulation) was performed. RESULTS: Macroscopic comparison of the wound sizes showed that group 3 showed a statistically significant difference in wound size reduction compared to the other two groups. Histopathological examination showed that there was no statistically significant difference between the groups. We found that the rosmarinic acid group had greater wound size reduction than the other two groups. However, epithelialisation was detected in fewer cases. CONCLUSIONS: We believe that rosmarinic acid can be used as a topical cream for wound healing, as it leads to significant reduction in wound size, resulting in fewer scars.

Histopathologic features of breast cancer in Li-Fraumeni syndrome.

Breast cancer is the most common malignancy in female patients with Li-Fraumeni syndrome (LFS), a rare autosomal dominant hereditary syndrome characterized by germline TP53 mutations. Recent studies have shown that the majority of these tumors are estrogen receptor (ER) positive with frequent HER2 co-expression. However, the morphologic features of these tumors have not been as well studied as other germline-associated breast cancers. We evaluated the pathologic features of 27 invasive and in situ carcinomas from patients with known germline TP53 mutations collected through the Li-Fraumeni Consortium. Overall, 60% of cases were HER2 positive and 44% showed ER co-expression. Most DCIS was high nuclear grade with central necrosis and associated periductal fibrosis and lymphocytic response. Invasive carcinomas were mostly of ductal type (NOS), modified Scarff-Bloom-Richardson (mSBR) high grade, with marked nuclear atypia and high mitotic rate. Prominent tumor infiltrating lymphocytes, syncytial growth pattern, or pushing borders were not seen in these tumors. High p53 IHC expression was seen in tumors from individuals with germline TP53 missense mutations whereas little or no protein expression (<1% nuclear expression, null pattern) was seen in tumors from carriers of non-missense mutations. In this study, we report in detail the morphologic features of invasive and in situ carcinomas in LFS. We found that these tumors share features with cancers harboring somatic TP53 mutations but are distinct from BRCA-associated breast cancers.

Prospective multi-institutional evaluation of pathologist assessment of PD-L1 assays for patient selection in triple negative breast cancer.

The US Food and Drug Administration (FDA) approved the PD-L1 immunohistochemical assay, SP142, as a companion test to determine eligibility for atezolizumab therapy in patients with advanced triple negative breast cancer (TNBC) but data in lung cancer studies suggest the assay suffers from poor reproducibility. We sought to evaluate reproducibility and concordance in PD-L1 scoring across multiple pathologists. Full TNBC sections were stained with SP142 and SP263 assays and interpreted for percentage (%) immune cell (IC) staining by 19 pathologists from 14 academic institutions. Proportion of PD-L1 positive cases (defined as ≥1% IC) was determined for each assay as well as concordance across observers. We utilized a new method we call Observers Needed to Evaluate Subjective Tests (ONEST) to determine the minimum number of evaluators needed to estimate concordance between large numbers of readers, as occurs in the real-world setting. PD-L1 was interpreted as positive with the SP142 assay in an average 58% of cases compared with 78% with SP263 (p < 0.0001). IC positive continuous scores ranged from 1 to 95% (mean = 20%) and 1 to 90% (mean = 10%) for SP263 and SP142, respectively. With SP142, 26 cases (38%) showed complete two category (<1% vs. ≥1%) concordance; with SP263, 38 cases (50%) showed complete agreement. The intraclass correlation coefficient (ICC) for two category scoring of SP263 and SP142 was 0.513 and 0.560. ONEST plots showed decreasing overall percent agreement (OPA) as observer number increased, reaching a low plateau of 0.46 at ten observers for SP263 and 0.41 at eight observers for SP142. IC scoring with both assays showed poor reproducibility across multiple pathologists with ONEST analysis suggesting more than half of pathologists will disagree about IC scores. This could lead to many patients either receiving atezolizumab when they are unlikely to benefit, or not receiving atezolizumab when they may benefit.

Methods of improving the quality of life in patients with stable maculopathy-pilot results of a new study.

PURPOSE: To present pilot results of the project in which the primary goal is to optimize way how to increase the quality of life of patients with the stable maculopathy by implanting intraocular Scharioth macular lens (SML) and modulating visual plasticity by a transcranial electrical stimulation (tES) together with a visual rehabilitation. MATERIALS AND METHODS: The study will include 20 patients with stable maculopathy (mainly age-related macular degeneration - AMD) who underwent cataract surgery in past and are eligible for SML implantation. The duration of the project is 3 years. During the first year of the project 17 patients were screened, SML implantation was recommended to 4 of them. They met the indication criteria of SML implantation and SML was implanted into the better seeing eye. The third postoperative day, the tES sessions started and were applied 20 times in the first month after SML implantation. The stimulation was delivered in double blind design (a stimulated and a shame group). Visual exercises and rehabilitation took place during the tES. The patients were examined ophthalmologically and also using electrophysiological methods. RESULTS: Before the implantation, the best corrected distance visual acuity was 0.23. At near it was Jaeger number 15 uncorrected, with +3.0 sphere dioptres J.No.10.5 and with +6.0 sph dpt J.No. 4.5. After the surgery and visual rehabilitation BCVA was 0.13 after 3 weeks, 0.2 after 2 months and 0.14 after 6 months. At near it was uncorrected J.No.7.5 after 3 weeks, J.No.7 after 2 months and J.No.5 after 6 months. CONCLUSION: According to a few participants, the impact of SML implantation together with intensive visual rehabilitation on vision at near and on satisfaction of patients with AMD could not be significantly established. Nevertherless, these patients are limited in their daily activities and SML is one of the solutions for them. The project is ongoing and blinded still, there is also a need of more participants to assess the effect of tES on vision, the results will be presented. We have proven the safety of methods used in the project.

Fibromatosis of the Breast: Diagnostic Accuracy of Core Needle Biopsy.

OBJECTIVES: Fibromatosis of the breast is an uncommon neoplasm with potential for local recurrence. Treatment has traditionally been surgical excision with current trends toward conservative management. Given the option of observation after diagnosis by core needle biopsy (CNB), we sought to evaluate the accuracy of CNB for diagnosing fibromatosis. METHODS: We identified a total of 31 cases in which fibromatosis had been diagnosed or included in the differential diagnosis on a CNB, an excision, or both. Morphology and immunohistochemical results were reviewed. RESULTS: Aberrant nuclear immunoreactivity for ß-catenin and absent staining for CD34 were the most useful studies to diagnose fibromatosis, and one or both were performed in 21 (68%) cases. High molecular weight cytokeratins and p63 were helpful to exclude spindle cell carcinoma. Of 26 cases confirmed as fibromatosis on excision, 22 (85%) were diagnosed as fibromatosis or fibromatosis was favored in the differential diagnosis on CNB. More frequent use of immunohistochemistry would likely have resulted in a greater number of definitive diagnoses. Fibromatosis was rarely mistaken for other nonmalignant stromal lesions, with no cases misdiagnosed as carcinoma. CONCLUSIONS: CNB can be an accurate method of diagnosing fibromatosis, allowing observation for a select group of patients.

A Randomized Phase II Neoadjuvant Study of Cisplatin, Paclitaxel With or Without Everolimus in Patients with Stage II/III Triple-Negative Breast Cancer (TNBC): Responses and Long-term Outcome Correlated with Increased Frequency of DNA Damage Response Gene Mutations, TNBC Subtype, AR Status, and Ki67.

Purpose: Because of inherent disease heterogeneity, targeted therapies have eluded triple-negative breast cancer (TNBC), and biomarkers predictive of treatment response have not yet been identified. This study was designed to determine whether the mTOR inhibitor everolimus with cisplatin and paclitaxel would provide synergistic antitumor effects in TNBC.Methods: Patients with stage II/III TNBC were enrolled in a randomized phase II trial of preoperative weekly cisplatin, paclitaxel and daily everolimus or placebo for 12 weeks, until definitive surgery. Tumor specimens were obtained at baseline, cycle 1, and surgery. Primary endpoint was pathologic complete response (pCR); secondary endpoints included clinical responses, breast conservation rate, safety, and discovery of molecular features associated with outcome.Results: Between 2009 and 2013, 145 patients were accrued; 36% of patients in the everolimus arm and 49% of patients in the placebo arm achieved pCR; in each arm, 50% of patients achieved complete responses by imaging. Higher rates of neutropenia, mucositis, and transaminase elevation were seen with everolimus. Clinical response to therapy and long-term outcome correlated with increased frequency of DNA damage response (DDR) gene mutations, Basal-like1 and Mesenchymal TNBC-subtypes, AR-negative status, and high Ki67, but not with tumor-infiltrating lymphocytes.Conclusions: The paclitaxel/cisplatin combination was well tolerated and active, but addition of everolimus was associated with more adverse events without improvement in pCR or clinical response. However, discoveries made from correlative studies could lead to predictive TNBC biomarkers that may impact clinical decision-making and provide new avenues for mechanistic exploration that could lead to clinical utility. Clin Cancer Res; 23(15); 4035-45. ©2017 AACR.

Bioinspired locomotion and grasping in water: the soft eight-arm OCTOPUS robot.

The octopus is an interesting model for the development of soft robotics, due to its high deformability, dexterity and rich behavioural repertoire. To investigate the principles of octopus dexterity, we designed an eight-arm soft robot and evaluated its performance with focused experiments. The OCTOPUS robot presented here is a completely soft robot, which integrates eight arms extending in radial direction and a central body which contains the main processing units. The front arms are mainly used for elongation and grasping, while the others are mainly used for locomotion. The robotic octopus works in water and its buoyancy is close to neutral. The experimental results show that the octopus-inspired robot can walk in water using the same strategy as the animal model, with good performance over different surfaces, including walking through physical constraints. It can grasp objects of different sizes and shapes, thanks to its soft arm materials and conical shape.

Gender impact on electrophysiological activity of the brain.

Gender is presumed to be one of the factors causing interindividual variability in the brain's electrophysiological parameters. Our aim was to characterize the role of gender in visual evoked potentials (VEPs), event-related potentials (ERPs), visual mismatch negativity (vMMN) and the spectral characteristics of the EEG. We examined 42 healthy volunteers (21 women and 21 men, aged 20-29 years). We measured VEPs in response to pattern-reversal and motion-onset stimulation, ERPs in an oddball paradigm and vMMN in response to a combination of motion directions presented in the visual periphery. P100 peak latency for 40' reversal VEPs was significantly shorter in women than in men as determined using a non-parametric Wilcoxon signed-rank test. In addition, women showed higher relative EEG spectral power in the alpha band (p=0.023) and lower power in the theta band (p=0.004). Our results in this small but homogeneous group of subjects confirm previously reported gender influences on pattern-reversal VEPs and the EEG frequency spectrum. Gender should be taken into consideration in establishing norms on these measures. We found no statistically significant differences between women and men for any of the other stimuli presented.

Efficacy and safety of voriconazole in the treatment of chronic pulmonary aspergillosis: experience in Japan.

BACKGROUND: Though various clinical conditions of aspergillosis can occur, depending essentially on the host's immunological status, the focus of research in North American and European countries has mainly been on invasive pulmonary aspergillosis in immunocompromised patients. There are, however, also many problems to overcome in chronic forms of aspergillosis. One of those problems is that there are no codified treatment guidelines for chronic pulmonary aspergillosis (CPA). Especially in Japan, this issue is more serious, because there are more cases with CPA due to the many aged people with past history of tuberculosis. Several clinical cases and case series have reported the usefulness of the various antifungal agents that are available. The new triazole, voriconazole, in particular, seems to be effective in the treatment of CPA. The aim of the present study is to evaluate the efficacy and safety of voriconazole in the treatment of CPA in non-immunocompromised patients. PATIENTS AND METHODS: We conducted a prospective, open-label, non-comparative, multicenter study over a 2-year period. For inclusion in the study, patients with confirmed or probable CPA were recruited in 11 hospitals of the National Hospital Organization in Japan. Clinical, radiological, serological, and mycological data were collected at baseline and 12 weeks after treatment or at the end of treatment. RESULTS: Among 77 patients enrolled in the study, 71 patients (mean age 65.9 years, 56 males and 15 females) were eligible for the study. All of the eligible patients presented with underlying lung diseases, including sequelae of tuberculosis (n = 35), non-tuberculous mycobacterial lung disease (n = 8), chronic obstructive pulmonary disease (COPD) (n = 8), interstitial pneumonia (n = 7), cystic lung disease (n = 4), pneumothorax (n = 3), bronchial cancer (n = 1), and others (n = 5). Voriconazole was indicated in 48 cases (68 %) as the first-line treatment for CPA and 23 patients previously received other antifungal therapies. Based on a composite of clinical, radiologic, serological, and mycologic criteria, good response was seen in 43 patients (60.6 %), no response was observed in 19 patients (26.8 %), and 4 cases (5.6 %) got worse. Five patients (7.0 %) were unassessable for efficacy. The common adverse events were visual disturbances (17 patients, 23.9 %), abnormal liver function test results (12 patients, 16.9 %), adverse psychological effects (3 patients, 4.2 %), and others (10 patients, 14.0 %). Treatment with voriconazole had to be stopped in 2 cases (2.8 %) because of serious adverse events (abnormal liver function test results). There was no association between adverse effects and trough voriconazole levels in serum. CONCLUSIONS: In Japan, voriconazole provides effective therapy of CPA in non-immunocompromised patients with an acceptable level of toxicity.

Pattern and motion-related visual-evoked potentials in neuroborreliosis: follow-up study.

Visual-evoked potentials (VEPs) were used for objective testing of visual functions during treatment courses of Lyme neuroborreliosis (LNB) in adult patients in the Czech Republic. In 30 LNB patients with originally delayed VEP latencies, pattern-reversal (R-VEP) and motion onset (M-VEP) VEPs were repeatedly examined within 1 to 8 years. Six patients had Lyme optic neuritis (ON), five of them displayed prolonged latencies in both R-VEPs and M-VEPs, and one had only abnormal R-VEPs. The VEP recovery to normal latency values was in three of them. In the group of 24 LNB patients without ON, 14 patients displayed prolonged latencies only to motion stimuli, and 10 patients had abnormal latencies in both R-VEPs and M-VEPs. During the follow-up period, 7 patients displayed shortening to normal latencies. In 5 patients, VEPs latencies improved only partially, and in the remaining 12 patients, VEPs did not improve at all. This study provides objective evidence that in LNB, most of the patients without clinically manifesting ON display optic pathway involvement-predominantly magnocellular system/dorsal stream function changes. In patients with ON, however, mainly the parvocellular system is affected. About half of the patients without ON improved with a relatively long-time course of latency shortening.