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Systemic amyloidosis is a rare protein misfolding and deposition disorder leading to progressive organ failure. There are over 15 types of systemic amyloidosis, each caused by a different precursor protein which promotes amyloid formation and tissue deposition. Amyloidosis can be acquired or hereditary and can affect various organs, including the heart, kidneys, liver, nerves, gastrointestinal tract, lungs, muscles, skin and soft tissues. Symptoms are usually insidious and nonspecific resulting in diagnostic delay. The field of amyloidosis has seen significant improvements over the past decade in diagnostic accuracy, prognosis prediction and management. The advent of mass spectrometry‐based shotgun proteomics has revolutionized amyloid typing and has led to the discovery of new amyloid types. Accurate typing of the precursor protein is of paramount importance as the type dictates a specific management approach. In this article, we review each type of systemic amyloidosis to provide the practitioner with practical tools to improve diagnosis and management of these rare disorders. [ABSTRACT FROM AUTHOR]

Study Type - Diagnostic (case series) Level of Evidence 4 What's known on the subject? and What does the study add? It is known that magnetic resonance imaging (MRI) is safe and effective for imaging patients with inflatable penile prostheses (IPPs). Previous series have reported results of MRI for imaging series of patients with IPPs. The impact on management in particular with regard to salvage procedures is not well defined. This study represents the largest known experience with MRI evaluation of IPPs. This also provides an algorithm that assists with decisions regarding utilization of MRI and treatment planning based on results. OBJECTIVE In some patients who undergo placement of an inflatable penile prosthesis (IPP) the device may function inadequately. We describe the use of magnetic resonance imaging (MRI) for anatomical localization and detection of prosthesis malrotation, angulation, displacement and erosion in IPPs with equivocal clinical examination., PATIENTS AND METHODS We prospectively performed MRI by a defined protocol including T1-weighted imaging, and transaxial, sagittal and coronal fat-saturated fast spin-echo T2-weighted imaging in both deflated and inflated states to evaluate patients seen at our referral centre for IPP-related complaints., We retrospectively reviewed 32 such MRI studies performed as a supplement to clinical examination between 2000 and 2008., RESULTS Of 32 cases, 75% (24/32) underwent surgical intervention. Of these, 45% (11/24) underwent device salvage procedures including cylinder revision in 33% (8/24), cylinder replacement in 8% (2/24) and pump replacement in 4% (1/24)., MRI was most useful for determination of surgical approach in those with abnormal physical examination, and for justification of either surgical or expectant management in those with indeterminate physical examination., CONCLUSIONS MRI is safe and effective for imaging genitourinary prostheses., We found MRI to be a valuable adjunct for evaluation of IPP-related complaints when clinical examination is equivocal as it detected a variety of prosthetic and corporal abnormalities and impacted management decisions regarding observation, replacement or device salvage procedures., We provide technique, results and an algorithm that can be beneficial in this complex subset of patients. [ABSTRACT FROM AUTHOR]

Using a battery of simple tests, psychomotor performance was assessed in 11 healthy subjects, 14 untreated epileptic patients and 66 epileptics on chronic anticonvulsant medication. Significant differences were found between controls and untreated patients for choice reaction time, card sorting and Simple Simon memory game. Treated patients performed less well than both untreated epileptics and controls in choice reaction time ( p<0.05; p<0.001), card sorting ( p<0.01; p<0.001), Simple Simon ( p<0.05; p<0.001) and finger tapping ( p<0.05; p<0.001). Patients with centrencephalic epilepsy were slower than those with discrete focal EEG abnormalities in reaction time and card sorting. Patients receiving treatment with carbamazepine, phenytoin or sodium valproate alone all performed similarly to each other and to those patients taking anticonvulsant polypharmacy. Monotherapy patients with potentially 'toxic' plasma anticonvulsant concentrations did no worse than those within or below the 'therapeutic' range. Both the disease and its treatment reduce psychomotor performance. All major anticonvulsants appear to cause a similar degree of impairment across a wide range of concentrations. The effect of chronic anticonvulsant medication on 'quality of life' should not be neglected in the pursuit of perfect seizure control. [ABSTRACT FROM AUTHOR]

The mechanisms of tissue damage in kidney amyloidosis are not well described. To investigate this further, we used laser microdissection-mass spectrometry to identify proteins deposited in amyloid plaques (expanded proteome) and proteins overexpressed in plaques compared to controls (plaque-specific proteome). This study encompassed 2650 cases of amyloidosis due to light chain (AL), heavy chain (AH), leukocyte chemotactic factor-2-type (ALECT2), secondary (AA), fibrinogen (AFib), apo AIV (AApoAIV), apo CII (AApoCII) and 14 normal/disease controls. We found that AFib, AA, and AApoCII have the most distinct proteomes predominantly driven by increased complement pathway proteins. Clustering of cases based on the expanded proteome identified two ALECT2 and seven AL subtypes. The main differences within the AL and ALECT2 subtypes were driven by complement proteins and, for AL only, 14-3-3 family proteins (a family of structurally similar phospho-binding proteins that regulate major cellular functions) widely implicated in kidney tissue dysfunction. The kidney AL plaque-specific proteome consisted of 24 proteins, including those implicated in kidney damage (α1 antitrypsin and heat shock protein β1). Hierarchical clustering of AL cases based on their plaque-specific proteome identified four clusters, of which one was associated with improved kidney survival and was characterized by higher overall proteomic content and 14-3-3 proteins but lower levels of light chains and most signature proteins. Thus, our results suggest that there is significant heterogeneity across and within amyloid types, driven predominantly by complement proteins, and that the plaque protein burden does not correlate with amyloid toxicity., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Objective: To describe a 41-year-old woman with a history of neonatal onset multisystem inflammatory disease, on treatment with daily subcutaneous injections of 600 mg of recombinant interleukin-1 receptor antagonist (IL-1Ra) protein, anakinra, since the age of 28, who presented with golf-ball size nodules at the anakinra injection sites, early satiety, new onset nephrotic syndrome in the context of normal markers of systemic inflammation., Methods: Clinical history and histologic evaluation of biopsies of skin, gastric mucosa, and kidney with Congo-red staining and proteomic evaluation of microdissected Congo red-positive amyloid deposits by liquid chromatography-tandem mass spectrometry., Results: The skin, stomach, and kidney biopsies all showed the presence of Congo red-positive amyloid deposits. Mass spectrometry-based proteomics demonstrated that the amyloid deposits in all sites were of AIL1RAP (IL-1Ra protein)-type. These were characterized by high spectral counts of the amyloid signature proteins (apolipoprotein AIV, apolipoprotein E, and serum amyloid P-component) and the amyloidogenic IL-1Ra protein, which were present in Congo red-positive areas and absent in Congo red-negative areas. The amino acid sequence identified by mass spectrometry confirmed that the amyloid precursor protein was recombinant IL-1Ra (anakinra) and not endogenous wild-type IL-1Ra., Conclusion: This is the first report of iatrogenic systemic amyloidosis due to an injectable protein drug, which was caused by recombinant IL1Ra (anakinra)., (© 2023 American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Focus Echocardiography has routinely been used to offer quick diagnosis in critical care environments, predominantly by clinicians with limited training. During the COVID-19 pandemic, international guidance recommended all echocardiography scans were performed as focus studies to limit operator viral exposure in both inpatient and outpatient settings. The aim of this study was to assess the effectiveness of eFoCUS, a focus scan performed by fully trained echocardiographers following a minimum dataset plus full interrogation of any pathology found., Methods: All diagnostic echocardiograms, performed by fully trained echocardiographers during an 8-week period during the first UK COVID-19 wave, were included. The number of images acquired was compared in the following categories: admission status, COVID status, image quality, indication, invasive ventilation, pathology found, echocardiographer experience, and whether eFoCUS was deemed adequate to answer the clinical question., Results: In 87.4% of the 698 scans included, the operator considered that the eFOCUS echo protocol, with additional images when needed, was sufficient to answer the clinical question on the request. Echocardiographer experience did not affect the number of images acquired. Less images were acquired in COVID-19 positive patients compared to negative/asymptomatic (38 ± 12 vs. 42 ± 12, p = .001), and more images were required when a valve pathology was identified., Conclusion: eFoCUS echocardiography is an effective protocol for use during the COVID-19 pandemic. It provides sufficient diagnostic information to answer the clinical question but differs from standard focus/limited protocols by enabling the identification and interrogation of significant pathology and incidental findings, preventing unnecessary repeat scans and viral exposure of operators., (© 2022 Wiley Periodicals LLC.)

Patients in medium secure hospitals may be at particularly increased risk of coronavirus disease 2019 (COVID-19) infection and complications. We undertook a service evaluation involving all current in-patients within a single, English medium secure hospital to describe the uptake of the COVID-19 vaccine among this population. Data regarding capacity to consent to the vaccine, acceptance/refusal of this (and reasons for refusal) and demographics was retrospectively collected from the patients' clinical records and analysed. In total, 85 patients (92.4% of eligible patients) had capacity to decide if they wanted the COVID-19 vaccine. Of these 68 (80.0%) consented and 17 (20.0%) declined to consent. A similar proportion of patients aged under and over 40 years old consented to have the vaccine. Those from a Black Asian minority ethnic background were more likely to decline the vaccine than White British patients. The reasons for capacitous refusal appeared similar to those seen in the general population.

Background: requires training and validation to standards expected of humans. We developed an online platform and established the Unity Collaborative to build a dataset of expertise from 17 hospitals for training, validation, and standardization of such techniques., Methods: The training dataset consisted of 2056 individual frames drawn at random from 1265 parasternal long-axis video-loops of patients undergoing clinical echocardiography in 2015 to 2016. Nine experts labeled these images using our online platform. From this, we trained a convolutional neural network to identify keypoints. Subsequently, 13 experts labeled a validation dataset of the end-systolic and end-diastolic frame from 100 new video-loops, twice each. The 26-opinion consensus was used as the reference standard. The primary outcome was precision SD, the SD of the differences between AI measurement and expert consensus., Results: In the validation dataset, the AI's precision SD for left ventricular internal dimension was 3.5 mm. For context, precision SD of individual expert measurements against the expert consensus was 4.4 mm. Intraclass correlation coefficient between AI and expert consensus was 0.926 (95% CI, 0.904-0.944), compared with 0.817 (0.778-0.954) between individual experts and expert consensus. For interventricular septum thickness, precision SD was 1.8 mm for AI (intraclass correlation coefficient, 0.809; 0.729-0.967), versus 2.0 mm for individuals (intraclass correlation coefficient, 0.641; 0.568-0.716). For posterior wall thickness, precision SD was 1.4 mm for AI (intraclass correlation coefficient, 0.535 [95% CI, 0.379-0.661]), versus 2.2 mm for individuals (0.366 [0.288-0.462]). We present all images and annotations. This highlights challenging cases, including poor image quality and tapered ventricles., Conclusions: Experts at multiple institutions successfully cooperated to build a collaborative AI. This performed as well as individual experts. Future echocardiographic AI research should use a consensus of experts as a reference. Our collaborative welcomes new partners who share our commitment to publish all methods, code, annotations, and results openly.

Cerebral amyloidomas, characterized by localized amyloid deposits in the nervous system in the absence of systemic disease, are rare. These typically consist of immunoglobulin light chain (AL)-type, predominantly lambda. Trigeminal nerve involvement is exceptionally rare with only 21 previously reported cases, three with bilateral disease. We report two additional cases of amyloid localized to Meckel's cave with secondary involvement of the trigeminal nerves bilaterally, with protein characterization by mass spectrometry. The patients, both females, 39 and 49-years-old, respectively, presented with the insidious onset of progressive trigeminal neuropathy, including pain and numbness with sensory loss, refractory to medical therapy. One patient experienced bilateral symptoms. Magnetic resonance imaging demonstrated abnormal thickening and contrast enhancement along Meckel's cave bilaterally in both cases. The clinical differential diagnosis included benign neoplasms and inflammatory disorders. At the time of biopsy, the trigeminal nerve was noted to be enlarged and multinodular in one case and associated with abnormal soft tan tissue in the other case. Microscopically, the nerve biopsies showed extensive Congo red-positive amyloid deposits. Liquid chromatography tandem mass spectrometry demonstrated that the amyloid was of (AL)-type in both cases (AL [kappa] in one case and AL [lambda] in the other). After extensive evaluation, there was no evidence of systemic involvement. Both patients received localized radiotherapy for their refractory symptoms. One patient has stable symptomatology and imaging. No follow-up is available for the other patient., Competing Interests: Conflict of Interest None., (Thieme. All rights reserved.)

Double/triple hit lymphoma (DH/TH), known as high-grade B-cell lymphoma (HGBL), is an aggressive diffuse large B cell lymphoma (DLBCL), defined as having concurrent MYC, BCL2, and/or BCL6 gene rearrangements. While gene rearrangements represent significant genetic events in cancer, copy number alterations (CNAs) also play an important role, and their contributions to rearrangements have yet to be fully elucidated. Using FISH and high-resolution CNA data, we defined the landscape of concurrent gene rearrangements and copy gains in MYC, BCL2, and BCL6, in a cohort of 479 newly diagnosed DLBCL. We also show that concurrent translocations and copy number alterations, in combinations similar to DH/TH, identify a unique subset of DLBCL, alternative DH/TH, that have survival outcomes similar to DH/TH DLBCL patients.

Background: The PI3K-mTORC pathway is upregulated in diffuse large B-cell lymphoma (DLBCL) and can be targeted with the mTOR complex 1 (mTORC1) inhibitor everolimus. Everolimus has activity in relapsed DLBCL. These data provide the rationale to combine everolimus with standard treatment for DLBCL of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone delivered in a 21-day cycle (R-CHOP-21) for six cycles., Methods: We did a phase 1 and feasibility study (NCCTG 1085) of oral everolimus 10 mg/day plus R-CHOP-21 in patients aged at least 18 years with new, untreated, CD20-positive DLBCL (stages II-IV) in the NCCTG (Alliance) National Cancer Institute Cooperative Group (USA). Patients received standard R-CHOP-21 (intravenous rituximab 375 mg/m(2), intravenous cyclophosphamide 750 mg/m(2), intravenous doxorubicin 50 mg/m(2), and intravenous vincristine 1·4 mg/m(2) [maximum 2·0 mg] all on day 1 of the 21-day cycle; and oral prednisone 100 mg/m(2) each day on days 1-5 of the cycle) for six cycles with scheduled subcutaneous pegfilgrastim 6 mg on day 2 of each cycle. We tested two schedules: everolimus given in the fasting state either on days 1-10 or days 1-14 of the R-CHOP cycle. The primary endpoint of the phase 1 portion of this study was to establish the maximum tolerated dose of everolimus that could be combined with R-CHOP-21. The primary endpoint of the feasibility portion of the study was to determine the feasibility of the regimen, which was assessed by determining the rate of significant toxicity. Secondary endpoints were the proportion of patients who achieved an overall response, a complete response, event-free survival at 12 months and 24 months from enrolment, progression-free survival, and overall survival; relapse of DLBCL; and duration of response. We deemed patients as assessable for the primary endpoint in the phase 1 portion if they completed the first cycle as planned. In the feasibility portion, all patients who received at least one dose of everolimus were included. This trial is registered with ClinicalTrials.gov, number NCT01334502., Findings: Between March 21, 2012, and Sept 15, 2014, we enrolled 26 patients into the study. Two were ineligible, therefore results are presented for 24 eligible patients. Nine patients were enrolled into the phase 1 portion of the trial (three given everolimus on days 1-10, and six given everolimus on days 1-14) without any dose-limiting toxicities; therefore, everolimus 10 mg/day given on days 1-14 with R-CHOP-21 was tested in 15 additional patients for a total of 24. One (5%, 95% CI 0-24%) of 21 patients had a toxicity during the feasibility phase-a treatment delay of 12 days due to grade 3 hypokalaemia possibly related to everolimus. The median follow-up was 21·5 months (IQR 17-29). 23 (96%, 95% CI 79-100%) of 24 patients achieved an overall response, and all 23 (96%, 79-100%) also attained a complete metabolic response by PET. The remaining patient withdrew consent after in cycle 1 and attained a complete response with R-CHOP alone. All 24 (100%) patients met 12-month event-free survival, and nine had sufficient follow-up data to be event-free at 24 months. None of the 24 patients had died by the last follow-up (March 30, 2016), and none had had a relapse with DLBCL. Because no events occurred during the study or follow-up, we were unable to assess the duration of response or progression-free survival. The most common grade 3-4 adverse events were haematological; the most common of these was grade 4 neutropenia in 18 (75%) of 24 patients. Five (21%) of 24 had grade 3 febrile neutropenia., Interpretation: The mTORC1 inhibitor everolimus given for 14 days in combination with R-CHOP-21 for patients with DLBCL is safe. These findings suggest that drugs that target the PI3K-mTORC pathway add benefit when combined with standard R-CHOP. The everolimus with R-CHOP regimen should be tested against standard R-CHOP alone in a randomised trial, to support the benefits of this novel combination noted in this study., Funding: National Cancer Institute of the US National Institutes of Health., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Amyloid is a characteristic histologic feature in medullary thyroid carcinomas (MTC). We utilized a novel mass spectrometry-based proteomic analysis to determine if we could identify specific proteins associated with amyloid in MTC. We studied 9 MTC (1 multiple endocrine neoplasia type 2A, 1 familial MTC, and 7 sporadic). Laser microdissection was utilized to sample the amyloid which was then trypsin digested and evaluated by liquid chromatography electrospray tandem MS (LC-MS/MS) which identified the presence of amyloidogenic proteins in all cases of MTC. High levels of calcitonin were identified in all 9 cases of MTC. Secretogranin-1 was identified in 6 of 9 MTC. Calcitonin gene-related peptide was identified in 4 of 9 cases of MTC. LC-MS/MS proteomic analysis provides a rapid, highly specific, and sensitive method for identification of the specific type of amyloid in these endocrine tumors. This approach may allow classification of different forms of endocrine amyloid present in neuroendocrine tumors.

Purpose: Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma confined to the central nervous system. Whether there is a PCNSL-specific genomic signature and, if so, how it differs from systemic diffuse large B-cell lymphoma (DLBCL) is uncertain., Experimental Design: We performed a comprehensive genomic study of tumor samples from 19 immunocompetent PCNSL patients. Testing comprised array-comparative genomic hybridization and whole exome sequencing., Results: Biallelic inactivation of TOX and PRKCD was recurrently found in PCNSL but not in systemic DLBCL, suggesting a specific role in PCNSL pathogenesis. In addition, we found a high prevalence of MYD88 mutations (79%) and CDKN2A biallelic loss (60%). Several genes recurrently affected in PCNSL were common with systemic DLBCL, including loss of TNFAIP3, PRDM1, GNA13, TMEM30A, TBL1XR1, B2M, CD58, activating mutations of CD79B, CARD11, and translocations IgH-BCL6. Overall, B-cell receptor/Toll-like receptor/NF-κB pathways were altered in >90% of PNCSL, highlighting its value for targeted therapeutic approaches. Furthermore, integrated analysis showed enrichment of pathways associated with immune response, proliferation, apoptosis, and lymphocyte differentiation., Conclusions: In summary, genome-wide analysis uncovered novel recurrent alterations, including TOX and PRKCD, helping to differentiate PCNSL from systemic DLBCL and related lymphomas., (©2015 American Association for Cancer Research.)

Genetic aberrations, including trisomies 3 and 18, and well-defined IGH translocations, have been described in marginal zone lymphomas (MZLs); however, these known genetic events are present in only a subset of cases. Here, we report the cloning of an IGH translocation partner on chromosome X, t(X;14)(p11.4;q32) that deregulates expression of an poorly characterized orphan G-protein-coupled receptor, GPR34. Elevated GPR34 gene expression was detected independent of the translocation in multiple subtypes of non-Hodgkin lymphoma and distinguished a unique molecular subtype of MZL. Increased expression of GPR34 was also detected in tissue from brain tumors and surface expression of GPR34 was detected on human MZL tumor cells and normal immune cells. Overexpression of GPR34 in lymphoma and HeLa cells resulted in phosphorylation of ERK, PKC, and CREB; induced CRE, AP1, and NF-κB-mediated gene transcription; and increased cell proliferation. In summary, these results are the first to identify a role for a GPR34 in lymphoma cell growth, provide insight into GPR34-mediated signaling, identify a genetically unique subset of MZLs that express high levels of GPR34, and suggest that MEK inhibitors may be useful for treatment of GPR34-expressing tumors.