Cytomegalovirus-Induced Hemophagocytic Lymphohistiocytosis in an Immunocompromised Patient with Inflammatory Bowel Disease.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and often fatal syndrome of immune hyperactivation, cytokine dysregulation, and severe inflammation. This severe syndrome is commonly triggered by infection, malignancy, autoimmunity, or immunosuppression. We present herein the case of a 56-year-old-female diagnosed with HLH triggered by an acute cytomegalovirus (CMV) infection with viremia in the context of immunosuppression for inflammatory bowel disease. This case highlights the importance of utilizing multiple diagnostic tools, prompt initiation of anti-hemophagocytic treatment, and management of the underlying etiology, to prevent significant morbidity and mortality.

Alpha-Band Lateralization and Microsaccades Elicited by Exogenous Cues Do Not Track Attentional Orienting.

We explore the world by constantly shifting our focus of attention toward salient stimuli and then disengaging from them in search of new ones. The alpha rhythm (8-13 Hz) has been suggested as a pivotal neural substrate of these attentional shifts, due to its local synchronization and desynchronization that suppress irrelevant cortical areas and facilitate relevant areas, a phenomenon called alpha lateralization. Whether alpha lateralization tracks the focus of attention from orienting toward a salient stimulus to disengaging from it is still an open question. We addressed it by leveraging the phenomenon of inhibition of return (IOR), consisting of an initial facilitation in response times (RTs) for stimuli appearing at an exogenously cued location, followed by a suppression of that location. Our behavioral data from human participants showed a typical IOR effect with both early facilitation and subsequent inhibition. In contrast, alpha lateralized in the cued direction after the behavioral facilitation effect and never re-lateralized compatibly with the behavioral inhibition. Furthermore, we analyzed the interaction between alpha lateralization and microsaccades: while alpha was lateralized toward the cued location, microsaccades were mostly oriented away from it. Crucially, the two phenomena showed a significant positive correlation. These results indicate that alpha lateralization reflects primarily the processing of salient stimuli, challenging the view that alpha lateralization is directly involved in exogenous attentional orienting per se. We discuss the relevance of the present findings for an oculomotor account of alpha lateralization as a modulator of cortical excitability in preparation of a saccade.

Discovery and Evaluation of C6-Substituted Pyrazolopyrimidine-Based Bisphosphonate Inhibitors of the Human Geranylgeranyl Pyrophosphate Synthase and Evaluation of Their Antitumor Efficacy in Multiple Myeloma, Pancreatic Ductal Adenocarcinoma, and Colorectal Cancer.

Novel C6-substituted pyrazolo[3,4-d]pyrimidine- and C2-substituted purine-based bisphosphonate (C6-PyraP-BP and C2-Pur-BP, respectively) inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS) were designed and evaluated for their ability to block the proliferation of multiple myeloma (MM), pancreatic ductal adenocarcinoma (PDAC), and colorectal cancer (CRC) cells. Pyrazolo[3,4-d]pyrimidine analogs were identified that induce selective intracellular target engagement leading to apoptosis and downregulate the prenylation of Rap-1A in MM, PDAC, and CRC cells. The C6-PyraP-BP inhibitor RB-07-16 was found to exhibit antitumor efficacy in xenograft mouse models of MM and PDAC, significantly reducing tumor growth without substantially increasing liver enzymes or causing significant histopathologic damage, usually associated with hepatotoxicity. RB-07-16 is a metabolically stable compound in cross-species liver microsomes, does not inhibit key CYP 450 enzymes, and exhibits good systemic circulation in rat. Collectively, the current studies provide encouraging support for further optimization of the pyrazolo[3,4-d]pyrimidine-based GGPPS inhibitors as potential human therapeutics for various cancers.

No evidence for rhythmic sampling in inhibition of return.

When exogenously cued, attention reflexively reorients towards the cued position. After a brief dwelling time, attention is released and then persistently inhibited from returning to this position for up to three seconds, a phenomenon coined 'inhibition of return' (IOR). This inhibitory interpretation has shaped our understanding of the spatio-temporal dynamics of the attentional spotlight after an exogenous visual cue for more than three decades. However, a recent theory refines this traditional view and predicts that attention rhythmically alternates between possible target locations at a theta frequency, implying occasional returns of attention to the cued position. Unfortunately, previous IOR studies have only probed performance at a few, temporally wide-spread cue-target onset asynchronies (CTOAs) rendering a comparison of these contradictory predictions impossible. We therefore used a temporally fine-grained adaptation of the Posner paradigm with 25 equally and densely spaced CTOAs, which yielded a robust IOR effect in the reaction time difference between valid and invalidly cued trials. We modelled the time course of this effect across CTOAs as a linear or exponential decay (traditional IOR model), sinusoidal rhythm (rhythmic model) and a combination of both (hybrid model). Model comparison by means of goodness-of-fit indices provided strong evidence in favor of traditional IOR models, and against theta-rhythmic attentional sampling contributing to IOR. This finding was supported by an FFT analysis, which also revealed no significant theta rhythm. We therefore conclude that the spatio-temporal dynamics of attention following an exogenous cue cannot be explained by rhythmic attentional sampling.

Cutaneous T-cell lymphoma developing in surgical scars post cardiac surgery: A case study.

Cutaneous T-cell lymphomas are a class of non-Hodgkin lymphomas characterized by the infiltration of malignant T cells into the skin. Their precise pathogenesis remains incompletely understood, but persistent and specific antigen stimulation of skin-homing CD4+ memory T cells by external or internal factors, combined with an inflammatory cytokine-rich tissue microenvironment, may be critical in the development of cutaneous T-cell lymphomas. We present herein a case of primary cutaneous T-cell lymphoma arising in two surgical scars that developed 6 months post-operatively and were successfully treated with external beam radiotherapy. This case highlights the notion that primary cutaneous T-cell lymphoma can develop locally at the site of injury/foreign body within a relatively short time post trauma/surgery. This work contributes to the literature of cutaneous T-cell lymphomas arising after a trauma, surgery, or a foreign body.

Breast Implanted-Associated Anaplastic Large Cell Lymphoma: A Case of Advanced Disease with Flow Cytometric Findings.

Breast implant-associated anaplastic large cell lymphoma (breast implant-associated ALCL) is a recently described, distinct clinicopathological entity associated with macrotextured breast implants. The diagnostic workup of a patient suspected to have breast implant-associated ALCL includes cytological assessment of effusions and tissue biopsies of any masses or enlarged lymph nodes, with morphologic and immunophenotypic evaluation and possible flow cytometric and molecular testing. We report the case of a woman found to have breast implant-associated ALCL on fine needle aspirate and core biopsy, who on surgical resection, had extensive local disease with involvement of the resection margins and lymph nodes, requiring systemic treatment. We focus on the flow cytometric findings that identified a population of large cells on the CD30/side scatter dot plot and whose immunophenotype was consistent with breast implant-associated ALCL, highlighting the value of flow cytometry as an adjunct to morphological and immunophenotypic evaluation.

The extent and specificity of visual exploration determines the formation of recollected memories in complex scenes.

Our visual memories of complex scenes often appear as robust, detailed records of the past. Several studies have demonstrated that active exploration with eye movements improves recognition memory for scenes, but it is unclear whether this improvement is due to stronger feelings of familiarity or more detailed recollection. We related the extent and specificity of fixation patterns at encoding and retrieval to different recognition decisions in an incidental memory paradigm. After incidental encoding of 240 real-world scene photographs, participants (N = 44) answered a surprise memory test by reporting whether an image was new, remembered (indicating recollection), or just known to be old (indicating familiarity). To assess the specificity of their visual memories, we devised a novel report procedure in which participants selected the scene region that they specifically recollected, that appeared most familiar, or that was particularly new to them. At encoding, when considering the entire scene,subsequently recollected compared to familiar or forgotten scenes showed a larger number of fixations that were more broadly distributed, suggesting that more extensive visual exploration determines stronger and more detailed memories. However, when considering only the memory-relevant image areas, fixations were more dense and more clustered for subsequently recollected compared to subsequently familiar scenes. At retrieval, the extent of visual exploration was more restricted for recollected compared to new or forgotten scenes, with a smaller number of fixations. Importantly, fixation density and clustering was greater in memory-relevant areas for recollected versus familiar or falsely recognized images. Our findings suggest that more extensive visual exploration across the entire scene, with a subset of more focal and dense fixations in specific image areas, leads to increased potential for recollecting specific image aspects.

Distinct contributions of alpha and theta rhythms to perceptual and attentional sampling.

Accumulating evidence suggests that visual perception operates in an oscillatory fashion at an alpha frequency (around 10 Hz). Moreover, visual attention also seems to operate rhythmically, albeit at a theta frequency (around 5 Hz). Both rhythms are often associated to "perceptual snapshots" taken at the favorable phases of these rhythms. However, less is known about the unfavorable phases: do they constitute "blind gaps," requiring the observer to guess, or is information sampled with reduced precision insufficient for the task demands? As simple detection or discrimination tasks cannot distinguish these options, we applied a continuous report task by asking for the exact orientation of a Landolt ring's gap to estimate separate model parameters for precision and the amount of guessing. We embedded this task in a well-established psychophysical protocol by densely sampling such reports across 20 cue-target stimulus onset asynchronies in a Posner-like cueing paradigm manipulating involuntary spatial attention. Testing the resulting time courses of the guessing and precision parameters for rhythmicities using a fast Fourier transform, we found an alpha rhythm (9.6 Hz) in precision for invalidly cued trials and a theta rhythm (4.8 Hz) in the guess rate across validity conditions. These results suggest distinct roles of the perceptual alpha and the attentional theta rhythm. We speculate that both rhythms result in environmental sampling characterized by fluctuating spatial resolution, speaking against a strict succession of blind gaps and perceptual snapshots.

In-situ follicular neoplasia: a clinicopathological spectrum.

AIMS: In-situ follicular neoplasia (ISFN) occurs in approximately 2-3% of reactive lymph nodes, and is currently set apart from 'partial involvement by follicular lymphoma' (PFL). ISFN can progress to overt lymphoma, but precise parameters with which to assess this risk and its association with related diseases remain incompletely understood. The aim of this study was to explore these parameters. METHODS AND RESULTS: We reviewed 11 cases of ISFN and one of PFL between 2003 and 2018. Ten patients had ISFN in the lymph nodes, and one had ISFN in the spleen. Haematoxylin and eosin and immunohistochemical stains were reviewed. Involvement of follicles by ISFN was scored with a three-tier scheme. Of five patients with low ISFN scores, one had chronic myelomonocytic leukaemia, one had mycosis fungoides, and three were free of haematopoietic disease. Among them, four are alive and one was lost to follow-up. Of the six ISFN patients with high scores, two had concurrent marginal zone lymphomas, one had concurrent diffuse large B-cell lymphoma (DLBCL), one had Castleman-like disease, one had progressive transformation of germinal centres with IgG4-related disease, and one had no haematopoietic disease; all are alive except for one who died of concurrent DLBCL. The patient with PFL developed DLBCL 7 years after diagnosis. CONCLUSIONS: On the basis of this limited series, we conclude that only cases with high scores are associated with an overt lymphoma or an abnormal lymphoid process, and that scoring may be a useful parameter with which to assess the risk of associated lymphoma, and deserves further study. We also performed a comprehensive review of the literature.

Case report: multimodality imaging to diagnose cardiac diffuse large B-cell lymphoma.

BACKGROUND: Primary cardiac lymphoma (PCL) is rare and can present with a wide variety of clinical symptoms, frequently leading to a delay in diagnosis. CASE SUMMARY: We report a case of a PCL in an 81-year-old man. Cardiac magnetic resonance imaging showed multiple masses in the right atrium and a mass in the right ventricular outflow tract extending to the pulmonary artery. Biopsy revealed a diffuse large B-cell lymphoma. The patient also had metastases to the liver and lung on the positron emission tomography-computed tomography (PET-CT) scan. He was treated with R-CHOP chemotherapy, with complete remission documented PET-CT scans. CONCLUSION: Although most patients with PCL die before chemotherapy can be initiated, a timely diagnosis can result in a favourable outcome.

Imprint cytology: Invaluable technique to evaluate fresh specimens received in the pathology department for lymphoma workup.

At the time of intraoperative consultation, cytologic preparations including smears and imprints can be used in combination with frozen sections to increase diagnostic yield; however, these simple and rapid techniques are not adopted by all pathologists and their use varies considerably between institutions. In patients under investigation for suspected lymphoma, optimal triaging of tissue received fresh in pathology for lymphoma workup is paramount to maximize the odds of obtaining an accurate and clinically meaningful diagnosis and to avoid the need for additional procedures and delays in management, particularly in the current context in which core biopsies have become common practice as a first attempt to attain this goal. Imprint cytology is invaluable in this regard, also as these patients may not have a lymphoma but rather one of its clinical mimics. Herein, imprint cytology is used to approach fresh specimens received intraoperatively for lymphoma workup. More specifically, how these specimens are triaged for ancillary studies, such as flow cytometry, florescence in situ hybridization, or molecular analyses based on an interpretation of the touch imprints, is described. Detailed imprint cytological findings of typical benign and malignant lymphoid and nonlymphoid lesions are discussed and illustrated.

Extranodal NK/T cell lymphoma and lymphomatoid granulomatosis in a patient with chronic lymphocytic leukaemia: Case report for a new perspective on Richter syndrome.

RATIONALE: Richter syndrome (RS) defines the transformation of chronic lymphocytic leukemia (CLL) into a more aggressive lymphoma. Although the term RS is most often reserved for transformation of CLL into diffuse large B-cell lymphoma (DLBCL), and less frequently Hodgkin lymphoma , the list of cases with more variable presentations in the literature is growing. PATIENT CONCERNS: A 71-year-old Caucasian man initially consulted an otolaryngologist for a 1-year history of nasal congestion. DIAGNOSES: The asynchronous occurrence of 2 rare angiocentric Epstein-Barr virus (EBV)-related lymphoproliferative disorders in a patient with CLL, specifically clonally related lymphomatoid granulomatosis (LYG), and an extranodal NK/T-cell lymphoma, nasal type, are described herein. INTERVENTIONS: Radiation therapy and a regimen of cis-platinum were administered for the NK/T cell lymphoma, and ibrutinib for LYG. OUTCOMES: The patient remains in complete clinical remission 8 years after the diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma and recurrent extranodal NK/T cell lymphoma, and 2 years after the diagnosis of clonally related LYG. LESSONS: Although the precise pathogenesis of RS remains incompletely understood, various molecular alterations, in particular long-term immunosuppression, may lead to RS, similar to the causal link existing between non-Hodgkin lymphomas and HIV infection, and post-transplantation lymphoproliferative disorders. EBV infection is linked to the pathogenesis of several types of lymphomas and found in a subset of patients with RS; immunosuppression, in the context of CLL or other pathological conditions or pharmacological agents, can disrupt the fine balance between virus and the host immune system, and result in EBV-driven lymphoproliferations of B-, T-, or NK-cell origin. The findings of our literature review thus suggest that such non-diffuse large B-cell lymphoma , non-Hodgkin lymphoma CLL transformations, may be considered as rare variants of RS.

Breast implant-associated anaplastic large cell lymphoma and effusions: A review with emphasis on the role of cytopathology.

Breast implants are surgically implanted by the hundreds of thousands every year worldwide for reconstructive or aesthetic purposes. Complications related to breast implants include early and late effusions that are often submitted for cytopathological analysis, particularly to exclude the possibility of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), a rare disease that generally follows an indolent clinical course, although it is becoming clearer that a subset of patients with adverse features have a poorer prognosis. Since a late-onset breast implant-associated effusion is the most common initial presentation of BIA-ALCL, cytopathological analysis of these effusions is considered the cornerstone and gold standard for rapid, efficient, reliable diagnosis and is critical for appropriate management and treatment. The National Comprehensive Cancer Network recently published clinical guidelines for the diagnosis and management of BIA-ALCL and stresses the essential role of cytopathological analysis, although it remains a matter of debate if all seromas should undergo immunocytochemistry or flow cytometry, particularly for assessment of expression of CD30 irrespective of morphological appearance on cytology. Herein, we review the current knowledge on BIA-ALCL, review the key cytological findings of reactive and malignant effusions related to breast implants, and present a comprehensive cytopathological workup with the presence of atypical cells as the key and pivotal element triggering further ancillary studies. We believe this approach will ensure appropriate and cost-effective management of effusion specimens from breast implants.

Pathology of Gastrointestinal and Liver Complications of Hematopoietic Stem Cell Transplantation.

CONTEXT.­: Despite advances in therapeutic and preventive measures, hematopoietic stem cell transplant recipients remain at risk for a variety of gastrointestinal and liver complications. OBJECTIVE.­: To detail the pathologic features of the various gastrointestinal and liver complications occurring after hematopoietic stem cell transplantation in relation to their clinical context. The specific complications covered include graft-versus-host disease, mycophenolate mofetil-induced injury, timeline of infections, neutropenic enterocolitis, gastrointestinal thrombotic microangiopathy, sinusoidal obstruction syndrome, hepatic iron overload, and the controversy around cord colitis syndrome. DATA SOURCES.­: The content of this article is based on pertinent peer-reviewed articles in PubMed, relevant textbooks, and on the authors' personal experiences. CONCLUSIONS.­: The final histopathologic diagnosis requires the integration of clinical and histologic findings and the exclusion of other competing causes of injury. Review of the clinical data, including the original disease pretransplant, the type of transplant, the timing of the gastrointestinal and/or liver manifestations, the timing of the biopsy after transplant, the presence of graft-versus-host disease in other organs and sites, the list of drug regimens, and the clinical and laboratory evidence of infection, is the key to reaching the proper histologic diagnosis.

Revitalising an academic pathology department: lessons learnt.

Pathology is a specialty that bridges basic medical science and clinical practice. In the era of personalised medicine, this specialty is facing unprecedented challenges. Some of these challenges are institution-specific, while many are shared worldwide at different magnitude. This review shares our team efforts in the past 5 years, 2012-2017, to revitalise a century-old academic pathology department in three aspects: administration, clinical service and academic development. The lessons learnt and insights gained from our experience may provide guidance to leaders in pathology or in other related specialties.

When a Social Experimenter Overwrites Effects of Salient Objects in an Individual Go/No-Go Simon Task - An ERP Study.

When two persons share a Simon task, a joint Simon effect occurs. The task co-representation account assumes that the joint Simon effect is the product of a vicarious representation of the co-actor's task. In contrast, recent studies show that even (non-human) event-producing objects could elicit a Simon effect in an individual go/no-go Simon task arguing in favor of the referential coding account. For the human-induced Simon effect, a modulation of the P300 component in Electroencephalography (EEG) is typically considered as a neural indicator of the joint Simon effect and task co-representation. Showing that the object-induced Simon effects also modulates the P300 would lead to a re-evaluation of the interpretation of the P300 in individual go/no-go and joint Simon task contexts. To do so, the present study conceptually replicated Experiment 1 from Dolk et al. (2013a) adding EEG recordings and an experimenter controlling the EEG computer to test whether a modulation of the P300 can also be elicited by adding a Japanese waving cat to the task context. Subjects performed an individual go/no-go Simon task with or without a cat placed next to them. Results show an overall Simon effect regardless of the cat's presence and no modulatory influence of the cat on the P300 (Experiment 1), even when conceivably interfering context factors are diminished (Experiment 2). These findings may suggest that the presence of a spatially aligned experimenter in the laboratory may produce an overall Simon effect overwriting a possible modulation of the Japanese waving cat.

Acute hemodialysis in a young man with severe symptomatic hyponatremia and kidney injury.

A 35-year-old man presented with severe hypo-osmolar hyponatremia (serum sodium 99 mmol/L), profound nonoliguric renal failure (serum creatinine 1240 µmol/L), and nephrotic range proteinuria. Computed tomography of the abdomen revealed nephromegaly and no obstruction. The patient was admitted to the intensive care unit (ICU) and conventional hemodialysis was initiated. To avoid rapid sodium correction, we prescribed concurrent dialysate flow, a low dialysate sodium concentration, a small surface area dialyzer, and a low blood flow rate. We infused dextrose 5% water into the venous return line and adjusted the infusion rate according to hourly sodium concentration. The rate of sodium correction was 7.7 mmol/day over the first 3 days of admission. A subsequent renal biopsy revealed focal segmental glomerulosclerosis and interstitial infiltration with extranodal NK/T-cell lymphoma nasal type. The patient died of massive lower gastrointestinal bleeding secondary to lymphomatous involvement day 19 in the ICU. In the setting of acute kidney injury requiring renal replacement therapy and concomitant severe hyponatremia, it is challenging to avoid overcorrection of serum sodium. We describe several key prescription modifications to conventional hemodialysis, factors that affect sodium diffusion at the level of the dialyzer membrane, and the importance of frequent laboratory monitoring.