To map the occurrence of amyloid types in a large clinical cohort using mass spectrometry-based shotgun proteomics, an unbiased method that unambiguously identifies all amyloid types in a single ...assay.
A mass spectrometry-based shotgun proteomics assay was implemented in a central reference laboratory. We documented our experience of typing 16,175 amyloidosis specimens over an 11-year period from January 1, 2008, to December 31, 2018.
We identified 21 established amyloid types, including AL (n=9542; 59.0%), ATTR (n=4600; 28.4%), ALECT2 (n=511; 3.2%), AA (n=463; 2.9%), AH (n=367; 2.3%), AIns (n=182; 1.2%), KRT5-14 (n=94; <1%), AFib (n=71; <1%), AApoAIV (n=57; <1%), AApoA1 (n=56; <1%), AANF (n=47; <1%), Aβ2M (n=38; <1%), ASem1 (n=34; <1%), AGel (n=29; <1%), TGFB1 (n=29; <1%), ALys (n=15; <1%), AIAPP (n=13; <1%), AApoCII (n=11; <1%), APro (n=8; <1%), AEnf (n=6; <1%), and ACal (n=2; <1%). We developed the first comprehensive organ-by-type map showing the relative frequency of 21 amyloid types in 31 different organs, and the first type-by-organ map showing organ tropism of 18 rare types. Using a modified bioinformatics pipeline, we detected amino acid substitutions in cases of hereditary amyloidosis with 100% specificity.
Amyloid typing by proteomics, which effectively recognizes all amyloid types in a single assay, optimally supports the diagnosis and treatment of amyloidosis patients in routine clinical practice.
Lymphocyte enhancer–binding factor 1 (LEF1) and SRY-Box 11 (SOX11) are highly sensitive and specific for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and mantle cell lymphoma ...(MCL) including the cyclin D1–negative subtype, respectively. We assessed the utility of these markers in a large cohort of small B-cell lymphomas (SBCLs) on varied sample types. Immunohistochemistry (IHC) was performed for LEF1 and SOX11 on 354 SBCLs (129 CLL/SLLs, 33 MCLs, 142 marginal zone lymphomas MZLs—nodal MZL NMZL: 40, extranodal MZL ENMZL: 28, splenic MZL SMZL: 74 cases—and 50 lymphoplasmacytic lymphomas LPLs/Waldenstrom macroglobulinemias WMs). Ninety-eight percent of CLL/SLLs were LEF1 positive. SOX11 showed good sensitivity (82%) and excellent specificity for MCL (99%), with only 2 of 142 MZLs (both SMZLs) showing SOX11 expression. The low sensitivity for SOX11 was on account of inclusion of 4 non-nodal cases. All 50 LPL/WMs were negative for both LEF1 and SOX11. The expression of SOX11 and LEF1 was not always mutually exclusive, as 2 confirmed MCLs expressed both markers. LEF1 and SOX11 have excellent utility as diagnostic markers especially for atypical CD5-positive SBCLs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Anaplastic large cell lymphomas (ALCLs) are broadly classified into ALK-positive and ALK-negative. ALK-negative ALCL is composed of DUSP22-rearranged, TP63-rearranged, and triple-negative cases. ...While lymphoid enhancer–binding factor (LEF1) plays a crucial role in T-cell maturation, limited data exist on its expression in T-cell lymphomas, including ALCL. We characterized the expression of LEF1 in ALCL by immunohistochemistry. LEF1 nuclear expression in the neoplastic cells was graded as negative (0), weak (1+), intermediate (2+), or strong (3+), with the percentage of LEF1-positive neoplastic cells recorded. A total of 45 ALCL cases were evaluated, of which 16 were DUSP22-rearranged. About 93.8% (15/16) DUSP22-rearranged cases showed strong expression of LEF1 in >75% tumor cells, compared with 3.4% (1/29) non–DUSP22-rearranged ALCL (P<0.0001). The striking association of LEF1 protein overexpression with DUPS22 rearrangement in ALCL was further confirmed by a gene expression profiling study which revealed significantly higher LEF1 expression in DUSP22-rearranged ALCL compared with other ALCL subtypes (P=0.0001). Although LEF1 is a nuclear mediator of the Wnt/β-catenin pathway, CTNNB1 RNA and protein levels were not overexpressed in LEF1-positive cases, suggesting the LEF1 overexpression in ALCL may not be involved in the Wnt/β-catenin pathway. The strong and uniform LEF1 expression pattern has a high positive predictive value (93.8%) and high negative predictive value (96%) for DUSP22 rearrangement in ALK-negative ALCL. The combination of characteristic morphologic and molecular features of DUSP22-rearranged cases with the high LEF1 expression further emphasizes that DUSP22-rearranged ALCL represents a distinct clinicopathologic subset of ALCL.
Large B-cell lymphoma (LBL) with interferon regulatory factor 4 (IRF4) rearrangement (LBL-IRF4), a provisional entity in the 2017 WHO classification, primarily arises in children and young adults and ...has a favorable prognosis. However, few studies have addressed the clinicopathologic and cytogenetic features of older adults with IRF4-rearranged B-cell lymphomas. From a database of all internal and external cases (08/01/2015 to 12/01/2020) on which interphase fluorescence in situ hybridization was performed at the Mayo Clinic, we identified 43 patients with B-cell lymphoma and IRF4 rearrangements. Consistent features included large cell morphology, expression of CD20, BCL6, and MUM1, and absence of MYC-R. All pediatric cases (n = 12) arose in Waldeyer's ring (WR), cervical lymph node (CLN), or bowel, and lacked BCL6-R and BCL2-R, and all but one showed classic morphology. Adults with WR, CLN, or bowel involvement (n = 22) were younger (median 32 years). Their lymphomas resembled pediatric cases morphologically and lacked BCL2-R, although 30% harbored BCL6-R (P = 0.043). Lymphomas that involved other anatomic sites (n = 9) arose in older adults (median 68 years; P = 0.002) and often showed atypical morphology (P < 0.001). All lacked BCL6-R and 2 of 4 harbored BCL2-R (P < 0.001). LBL-IRF4 - arising in WR, CLN, or bowel may represent a distinct clinicopathologic entity characterized by pediatric/younger adult age, classic morphology, and lack of BCL2-R. In contrast, B-cell lymphomas with IRF4-R that arise in other sites usually involve older adults, are often morphologically atypical and/or harbor BCL2-R, and may be more akin to diffuse LBL, not otherwise specified.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This case report describes 2 patients with iatrogenic amyloidosis secondary to subcutaneous injections of anakinra to manage neonatal-onset multisystem inflammatory disease.
Introduction
Although peripheral neuropathy and cardiomyopathy are well‐recognized manifestations of transthyretin (ATTR) amyloidosis, myopathy has been rarely reported.
Methods
In this study we ...reviewed our muscle biopsy database (January 1998 to June 2018) to identify patients with ATTR amyloid myopathy confirmed by molecular or proteomic analysis. Clinical and laboratory findings were reviewed.
Results
We identified eight ATTR amyloid myopathy patients (5 hereditary ATTR ATTRv and 3 wild‐type ATTR ATTRwt). Myopathy was the initial manifestation in all ATTRwt patients and followed peripheral neuropathy (4 patients) or cardiomyopathy (1 patient) in ATTRv patients. One ATTRv patient developed myopathy after liver transplant. Peripheral neuropathy and cardiac amyloidosis occurred in seven and six patients, respectively. Muscle biopsy showed interstitial amyloid deposition in all patients, rare necrotic/regenerating fibers in six, and vacuoles in four.
Discussion
Myopathy can be the initial manifestation of ATTRwt amyloidosis and can precede the peripheral neuropathy or occur after liver transplant in ATTRv amyloidosis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
High-grade B-cell lymphomas with
and
and/or
rearrangements (double-/triple-hit lymphoma) have an aggressive clinical course. We investigated the prognostic value of transformation from low-grade ...lymphoma, cytological features (high grade
large cell),
rearrangement partners (immunoglobulin
nonimmunoglobulin gene), and treatment. We evaluated 100 adults with double-/triple-hit lymphoma, reviewing cytological features; cell of origin; and rearrangements of
,
, and
using
,
, and
break-apart and
,
,
, and
dual-fusion interphase fluorescence
hybridization probes. Outcome analysis was restricted to patients with lymphoma,
or at transformation, who received anthracycline-based chemotherapy. Among them, 60% had high-grade cytological features; 91% had a germinal center B-cell phenotype, and 60% had a
rearrangement. Germinal center B-cell phenotype was associated with
rearrangements (
<0.001). Mean (95% confidence interval) 5-year overall survival was 49% (37%-64%). Transformation from previously treated and untreated low-grade lymphoma was associated with inferior overall survival (hazard ratio, 2.99;
=0.008). Patients with high-grade cytological features showed a non-significant tendency to inferior outcome (hazard ratio, 2.32;
=0.09). No association was observed between
rearrangement partner and overall survival (hazard ratio, 1.00;
=0.99). Compared with patients receiving rituximab, cyclophosphamide, doxorubicin, and vincristine (R-CHOP) and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R), patients receiving rituximab, cyclophosphamide, vincristine, doxorubicin, methotrexate/ifosfamide, etoposide, and cytarabine (R-CODOX-M/IVAC) had a non-significant tendency to better overall survival (hazard ratio, 0.37;
=0.10). In conclusion, high-grade B-cell lymphomas with
and
and/or
rearrangements had heterogeneous outcomes and
rearrangements were not associated with inferior overall survival.
Cardiac amyloidosis is increasingly recognized as a treatable form of heart failure. Highly effective specific therapies have recently become available for the 2 most frequent forms of cardiac ...amyloidosis: immunoglobulin light chain amyloidosis and transthyretin (ATTR) amyloidosis. Nevertheless, initiation of specific therapies requires recognition of cardiac amyloidosis and appropriate characterization of the amyloid type. Although noninvasive diagnosis is possible for ATTR cardiac amyloidosis, histological demonstration and typing of amyloid deposits is still required for a substantial number of patients with ATTR and in all patients with light chain amyloidosis and other rarer forms of cardiac amyloidosis. Amyloid histological typing can be performed using different techniques: mass spectrometry, immunohistochemistry, and immunoelectron microscopy. This review describes which patients require histological confirmation of cardiac amyloidosis along with when and how to type amyloid deposits in histologic specimens. Furthermore, it covers the characteristics and limitations of the different typing methods that are available in clinical practice.
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