Four experiments investigated the impact of the lexical status of memory and processing stimuli on complex memory performance, with the aim of exploring mechanisms of interference in working memory. ...In a complex memory task, participants recalled words or nonwords while either monitoring words or nonwords for phonological content, or suppressing articulation. In groups of 9- and 10-year-old children and adults, word recall was significantly more impaired by monitoring words than nonwords. A converse disturbance of nonword recall by nonword monitoring was consistently found for adults, but was less marked in the child groups. It is proposed that interference in complex memory tasks reflects the operation of two distinct processes: a lexical-semantic process of either interference between memory and processing stimuli or redintegration, and the strategic use of lexical status to discriminate potential target from non-target items. Whereas the former process is invariant with age, the latter strategy is robust in adults but in the early stages of emergence with the younger participants.
Intravascular large B-cell lymphoma (IVLBL) is an uncommon form of non-Hodgkin lymphoma that is also known as malignant angioendotheliosis, intravascular lymphomatosis, and angiotropic large-cell ...lymphoma. The disease is characterized by a bizarre population of neoplastic cells, which are found systemically within vascular lumina. Although originally thought to be a neoplastic process of the endothelial cells, it has since been demonstrated, by molecular techniques and immunohistochemistry, that the neoplastic cells are of lymphoid origin. The differential diagnosis of these lesions includes granulocytic sarcomas that can be distinguished from IVLBL or other lymphomas by the presence of immunohistochemical positivity for myeloperoxidase. We describe a patient with a history of a myelodysplastic syndrome who subsequently developed IVLBL, which demonstrated immunohistochemical positivity for myeloperoxidase. To our knowledge, this represents the first case of a malignant lymphoma to demonstrate such findings.
•Cutaneous metastases are common in women with metastatic breast cancer (MBC).•Tucatinib is an oral, HER2-specific reversible tyrosine kinase inhibitor.•Tucatinib in combination with trastuzumab ...and/or capecitabine shows evidence of efficacy against cutaneous metastases in HER2-positive MBC.
Cutaneous metastases are a common and very morbid development in women with metastatic breast cancer (MBC). Tucatinib, an oral, potent, HER2-specific reversible tyrosine kinase inhibitor, is a new treatment for HER2-positive MBC. Here, we describe a case series of 7 patients who had cutaneous metastases from a phase 1b study of tucatinib. The phase 1b study enrolled women with progressive HER2-positive MBC previously treated with trastuzumab, pertuzumab, and ado-trastuzumab emtansine. Prior lapatinib, neratinib, or afatinib were allowed. Tucatinib was dosed in 2 cohorts of 350 mg (8 patients) and 300 mg (52 patients) orally twice daily with either capecitabine (1000 mg/m2 orally twice daily for 14 days of a 21-day cycle) or trastuzumab (8 mg/kg intravenous load then 6 mg/kg every 21 days) or the triplet. A total of 60 patients were treated, 16 of which (26.7%) had cutaneous metastasis. The experience of seven patients with cutaneous metastasis treated at three participating centers is described here. The seven patients, aged 36 to 58 years, had received a median 6 prior lines of therapy (range: 3-9), including lapatinib (n=6) and pertuzumab (n=6). All patients received tucatinib with an additional therapy (capecitabine or trastuzumab), and 5 patients received triplet therapy. The median time on therapy was 8 cycles (range: 5-12). Complete (n=1) or partial responses (n=3) of skin disease were observed in 4 patients resulting in a cutaneous response rate of 57.1%. An overall response (including all disease sites) was observed in 4 patients (57.1%). Tucatinib shows evidence of efficacy against cutaneous metastasis, which is common and difficult to control for patients with HER2-overexpressing MBC.
Tinnitus: identifying the ominous causes Conlin, Anne Elizabeth; Massoud, Emad; Versnick, Eric
CMAJ. Canadian Medical Association journal,
2011-Dec-13, 2011-12-13, 20111213, Letnik:
183, Številka:
18
Journal Article
Epidermolytic hyperkeratosis (EH) is a unique histopathologic alteration of the skin characterized by hyperkeratosis with perinuclear vacuolization of keratinocytes primarily in the stratum ...granulosum and the stratum malpighii. It is seen as an incidental finding in a variety of conditions, benign and malignant, as well as sporadic and familial. Recently, it has been reported that EH may be associated with dysplastic nevi (nevus with architectural disorder NAD). Cases of melanocytic nevi with epidermolytic hyperkeratosis were retrieved from the files of a referral dermatopathology laboratory over a 6-year period. We present a series of 53 cases of EH in both ordinary nevi and NAD. Epidermolytic hyperkeratosis identified in association with NAD accounted for 46 cases or 86.8% of the total lesions while ordinary nevi represented 7 or 13.2% of total cases. Our study confirms that the incidence of EH is higher in association with dysplastic nevi than in ordinary melanocytic nevi and may serve as a marker for NAD, but with lower sensitivity and only moderate specificity.
Abstract
Background: Cytokines are being explored as a therapeutic strategy to modulate the tumor microenvironment and facilitate immunotherapy benefit in breast cancer. Here, we investigate a ...locoregional therapeutic approach whereby cytokines (IRX-2) are administered into the subcutaneous peri-areolar tissue (in an anatomic distribution similar to sentinel lymph node mapping) to facilitate immune cell recruitment/activation within the draining lymph nodes and tumor in ESBC. IRX-2 is derived from ex vivo phytohemagglutinin-stimulated lymphocytes and contains multiple cytokines including IL-1β, IL-2, TNF-α, IFN-γ, IL-6, IL-8, and GM-CSF, with stable concentrations from lot to lot. Preclinically, IRX-2 activates T-cells and natural killer (NK) cells, facilitates antigen presentation, and enhances activity of anti-PD-1/L1 in a SCC7 model. In a preceding head/neck squamous cell carcinoma phase I trial, perilymphatic IRX-2 was safe and increased TILs. Here, we report the final clinical results of a phase Ib trial evaluating the feasibility and immunologic activity of IRX-2 in ESBC.
Methods: Beginning 21 days prior to surgical resection, enrolled operable patients with stage I-III ESBC (all subtypes) received the pre-operative IRX-2 regimen consisting of a single low-dose cyclophosphamide (300 mg/m2 to facilitate T-regulatory cell depletion), followed by 10 days of subcutaneous peri-areolar IRX-2 injections into the affected breast (1 mL × 2 at tumor axis and at 90°). Endpoints were feasibility (primary endpoint), stromal TIL (sTIL) count (pre-treatment versus post-treatment, blinded average of two pathologist reads using San Antonio H&E sTIL guidelines), PD-L1 expression (Nanostring) and enumeration of peripheral immune cells by flow cytometry.
Results: All patients (n=16/16) completed and tolerated the regimen with no surgical delays or treatment-attributed grade III/IV toxicities. Common adverse events (occurring in >15% subjects) attributed to IRX-2 injections were: injection site reaction (grade 1, n=8/16), bruising (grade 1, n=7/16), and pain (grade 1, n=3/16). Common adverse events attributed to low-dose cyclophosphamide were: fatigue (grade 1, n=5/16) and nausea (grade 1/2, n=3/16). Treatment was associated with an increase in sTIL score (Wilcoxon signed-rank p=.04), with 4/10 sTIL-low tumors (0-10% score) re-categorized to sTIL-moderate (11-50% score). Increases in PD-L1 RNA expression were observed (Wilcoxon signed-rank p=.04) in 12/16 tumors (median 57% increase, range: -53% to 185% increase), as well as increases in Nanostring NK and Th1 cell signatures. In blood, increases in CD4 and CD8 effector T-cell activation (ICOS, HLA-DR, and CD38) and T-reg depletion were observed.
Conclusions: IRX-2 was well tolerated with preliminary evidence of sTIL increase, PD-L1 upregulation, and peripheral lymphocyte activation. Based upon these data and preclinical evaluations demonstrating synergy with checkpoint inhibition, the IRX-2 regimen is being evaluated for clinical efficacy in conjunction with pembrolizumab and neoadjuvant chemotherapy (doxorubicin, cyclophosphamide, paclitaxel) in patients with stage II-III triple negative breast cancer.
Citation Format: Pucilowska J, Egan JE, Berinstein NL, Moxon N, Aliabadi-Wahle S, Imatani JH, Conlin A, Acheson A, Massimino K, Martel M, Campbell M, Wu Y, Sun Z, Redmond W, Shah M, Urba WJ, Page DB. Perilymphatic IRX-2 cytokine therapy to enhance tumor infiltrating lymphocytes (TILs) and PD-L1 expression preceding curative-intent therapy in early stage breast cancer (ESBC) abstract. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-12.
Abstract
Background: In mTNBC, anti-PD-1/L1 monotherapy is most effective when administered early in the course of disease, with recent trials demonstrating overall response rates (ORR) of 23-26% in ...the first-line setting and 5-6% in later lines. This may reflect iatrogenic lymphopenia from preceding cytotoxic chemotherapy. Furthermore, curative-intent chemotherapy is associated with prolonged suppression of naïve CD4+ cells, a T-cell subset that may play a critical role in the generation of de novo anti-tumor immune responses. We present the final clinical results of a pilot study evaluating the safety and efficacy of combining pembrolizumab plus standard-of-care capecitabine in the first/second-line mTNBC setting. We also explore potential associations between clinical benefit and lymphopenia, preceding chemotherapy, and absolute naïve CD4+ counts.
Methods: In a pilot study, we evaluated the tolerability and preliminary efficacy of concurrent pembro (200mg IV q21 day) plus investigator-selected 1st/2nd line paclitaxel (80mg/m2 IV weekly) or oral cape (2,000mg BID, weekly 1 on/1 off). The primary endpoint was tolerability, defined as the proportion of subjects receiving >6 weeks concurrent therapy without dose discontinuation with toxicities reported per CTCAE v4.0. The secondary endpoint was 12-week objective response rate (ORR) by RECIST1.1. Exploratory endpoints included peripheral blood cell enumeration by real-time flow cytometry and routine clinical laboratory. Naïve CD4+ cells were defined as CD45+ CD3+ TCRab+ CD4+ CD45RA+ CCR7+. Here, we report the results of the pilot phase of the cape cohort (NCT02734290).
Results: Twelve of 14 subjects were treated in the first-line setting. All subjects (14/14, 100%) tolerated cape+pembro for >6 weeks, with toxicities consistent with monotherapy cape experience (diarrhea: grade I-II 50%, grade III 7%; hand-foot: grade I-II 71%) that improved with dose-reduction as needed. At 12 weeks, the ORR was 6/14 (42.9%), and the clinical benefit rate (ORR + stable disease) was 8/14 (57.1%). Depressed absolute lymphocyte count at baseline (ALC<1.0/uL: 33% CBR; ALC≥1.0/uL: 75% CBR) and recent exposure to cytotoxic chemotherapy (<6 months: 33% CBR; >6 months: 75% CBR) were associated with reduced clinical benefit. By flow cytometry, subjects experiencing clinical benefit had higher baseline absolute naïve CD4+ counts (average 283 cells/uL v. 93 cells/uL, p=.069).
Conclusions: This study met the primary endpoint of safety for cape plus pembro in mTNBC, with encouraging clinical activity. These data are supportive of further studies evaluating combination chemotherapy plus anti-PD-1/L1 mTNBC. We observed greater clinical benefit in subjects with non-suppressed ALC, less exposure to recent chemo, and higher baseline naïve CD4+ counts, suggesting that iatrogenic immunosuppression can impair response to immune checkpoint therapy in mTNBC. These findings should be confirmed in ongoing randomized trials of immune checkpoint +/- chemotherapy in mTNBC, and should be considered in the design of future clinical trials.
Citation Format: Page DB, Pucilowska J, Bennetts L, Kim I, Sanchez K, Martel M, Conlin A, Moxon N, Mellinger S, Acheson A, Kemmer K, Mitri Z, Vuky J, Ahn J, Abaya C, Manigault T, Basho R, Urba WJ, McArthur HL. Updated efficacy of first or second-line pembrolizumab (pembro) plus capecitabine (cape) in metastatic triple negative breast cancer (mTNBC) and correlations with baseline lymphocyte and naïve CD4+ T-cell count abstract. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-03.
This volume examines human sexuality as an intrinsic element in the interpretation of complex colonial societies. While archaeological studies of the historic past have explored the dynamics of ...European colonialism, such work has largely ignored broader issues of sexuality, embodiment, commemoration, reproduction and sensuality. Recently, however, scholars have begun to recognize these issues as essential components of colonization and imperialism. This book explores a variety of case studies, revealing the multifaceted intersections of colonialism and sexuality. Incorporating work that ranges from Phoenician diasporic communities of the eighth century to Britain's nineteenth-century Australian penal colonies to the contemporary Maroon community of Brazil, this volume changes the way we understand the relationship between sexuality and colonial history.
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