Citations

Aims Prognostication and treatment selection for cardiac amyloidosis requires accurate amyloid typing. The aim of this study was to investigate the utility of histomorphology for predicting type. Methods and results Autopsy cases with cardiac amyloidosis (1998–2010) were typed by the use of mass spectrometry‐based proteomics. Deposition patterns were correlated with amyloid type. Among 108 decedents (mean age 75 years; 69% men), 107 had a single type, including transthyretin (ATTR) (60 cases), amyloid light chain (AL) (32 λ; 12 κ), amyloid A (AA) (two), and apolipoprotein AIV (AApoAIV) (one). Interstitial deposition was more extensive in AL amyloidosis cases than in ATTR cases [odds ratio (OR) 6.8, P = 0.0004]. Histomorphological patterns of interstitial deposition were mixed in 61% of AL amyloidosis cases and in 61% of ATTR cases, but diffuse pericellular deposits favoured AL amyloidosis (OR 10.7, P = 0.0001), nodular deposits favoured ATTR (OR 3.1, P = 0.0229), and discrete pericellular deposits tended to partially favour ATTR (OR 1.7, P = 0.1970). Arterial and venous deposits each favoured AL amyloidosis (OR ranging from 9.3 to 192.0, P‐value ranging from 0.0022 to <0.0001), and were severe in AL amyloidosis. Endocardial deposits favoured AL amyloidosis (OR 46.3, P < 0.0001) and were also more severe in AL amyloidosis. Conclusions The extent and distribution of cardiac amyloidosis strongly correlate with amyloid type, suggesting fundamental differences in the pathobiology of deposition. The tendency for mixed patterns to occur limits the practicality and accuracy of using histopathology for amyloid typing.

SummaryPatients with early stage diffuse large B‐cell lymphoma (DLBCL) receive RCHOP (rituximab cyclophosphamide, doxorubicin, vincristine, prednisone) alone or with involved field radiotherapy (IFRT). Anti‐CD20 radioimmunotherapy (RIT) delivers radiation to microscopic sites outside of known disease. This phase II study aimed to achieve a functional complete response (CR) rate of ≥75% to RCHOP and 90Yttrium‐ibritumomab tiuxetan RIT. Patients with stages I/II DLBCL received 4–6 cycles of RCHOP followed by RIT [14·8 MBq/kg (0·4 mCi/kg)]; patients with positron emission tomographypositive sites of disease after RCHOP/RIT received 30 Gy IFRT. Of the 62 patients enrolled; 53 were eligible. 42% (22/53) had stage I/IE; 58% (31/53) stage II/IIE. After RCHOP, 79% (42/53) were in CR/unconfirmed CR. Forty‐eight patients proceeded to RIT. One partial responder after RIT received IFRT and achieved a CR. The best response after RCHOP + RIT in all 53 patients was a functional CR rate of 89% (47/53; 95% confidence interval: 77–96%). With a median follow‐up of 5·9 years, 7 (13%) patients have progressed and 4 (8%) have died (2 with DLBCL). At 5 years, 78% of patients remain in remission and 94% are alive. Chemoimmunotherapy and RIT is an active regimen for early stage DLBCL patients. Eighty‐nine percent of patients achieved functional CR without the requirement of IFRT. This regimen is worthy of further study for early stage DLBCL in a phase III trial.

Key PointsThe NF-κB subunits p52 and RelB increase IRF4 promoter activity and expression in PTCL cells. A positive feedback loop involving CD30, NF-κB, and IRF4 drives PTCL cell proliferation and can be blocked by NF-κB inhibitors.

Amyloidosis is caused by deposition in tissues of abnormal protein in a characteristic fibrillar form. There are many types of amyloidosis, classified according to the soluble protein precursor from which the amyloid fibrils are derived. Accurate identification of amyloid type is critical in every case since therapy for systemic amyloidosis is type specific. In ∼20–25% cases, however, immunohistochemistry (IHC) fails to prove the amyloid type and further tests are required. Laser microdissection and mass spectrometry (LDMS) is a powerful tool for identifying proteins from formalin-fixed paraffin-embedded tissues. We undertook a blinded comparison of IHC, performed at the UK National Amyloidosis Centre, and LDMS, performed at the Mayo Clinic, in 142 consecutive biopsy specimens from 38 different tissue types. There was 100% concordance between positive IHC and LDMS, and the latter increased diagnostic accuracy from 76% to 94%. LDMS in expert hands is a valuable tool for amyloid diagnosis.

Objective Takayasu arteritis is a rare large vessel vasculitis with incompletely understood etiology. This study was undertaken to perform the first unbiased genome‐wide association analysis of Takayasu arteritis. Methods Two independent cohorts of patients with Takayasu arteritis from Turkey and North America were included in our study. The Turkish cohort consisted of 559 patients and 489 controls, and the North American cohort consisted of 134 patients and 1,047 controls of European ancestry. Genotyping was performed using the Omni1‐Quad and Omni2.5 genotyping arrays. Genotyping data were subjected to rigorous quality control measures and subsequently analyzed to discover genetic susceptibility loci for Takayasu arteritis. Results We identified genetic susceptibility loci for Takayasu arteritis with a genome‐wide level of significance in IL6 (rs2069837) (odds ratio [OR] 2.07, P = 6.70 × 10 −9 ), RPS9 / LILRB3 (rs11666543) (OR 1.65, P = 2.34 × 10 −8 ), and an intergenic locus on chromosome 21q22 (rs2836878) (OR 1.79, P = 3.62 × 10 −10 ). The genetic susceptibility locus in RPS9 / LILRB3 lies within the leukocyte receptor complex gene cluster on chromosome 19q13.4, and the disease risk variant in this locus correlates with reduced expression of multiple genes including the inhibitory leukocyte immunoglobulin‐like receptor gene LILRB3 ( P = 2.29 × 10 −8 ). In addition, we identified candidate susceptibility genes with suggestive levels of association ( P < 1 × 10 −5 ) with Takayasu arteritis, including PCSK5, LILRA3, PPM1G/NRBP1 , and PTK2B . Conclusion Our findings indicate novel genetic susceptibility loci for Takayasu arteritis and uncover potentially important aspects of the pathophysiology of this form of vasculitis.

Key Points BCL2 mutations in FL correlate with activation-induced cytidine deaminase expression and frequently alter the amino acid sequence of the protein. Mutations in the BCL2 coding sequence at diagnosis are associated with shortened time to transformation and earlier death due to lymphoma.

Abstract Background: Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of generally aggressive malignancies, with 5-year overall survival (OS) rates of ∼35%. Only ALK translocations, which define ALK-positive anaplastic large T-cell lymphoma (ALCL), have emerged as a genetic biomarker predicting favorable outcome following conventional chemotherapy (e.g. CHOP). Using next-generation sequencing, we discovered additional recurrent chromosomal translocations in PTCLs involving either the DUSP22 locus on 6p25.3 or TP63 on 3q28. The purpose of this study was to evaluate the prognostic utility of combined testing for both these events in PTCL patients. Methods: We examined the clinicopathologic features of 134 systemic PTCLs using WHO criteria, including 49 ALCLs, 23 angioimmunoblastic PTCLs, 50 PTCLs of “not otherwise specified” type, and 12 PTCLs of other subtypes. Immunohistochemistry was used to determine ALK expression, an established surrogate for ALK translocations in ALCL. Fluorescent in situ hybridization (FISH) was performed to detect translocations of DUSP22 or TP63 in all cases. OS was plotted using the Kaplan-Meier method. Comparisons were made using the log-rank test. Results: There were 83 males and 51 females, with a mean age of 58 years (range, 6 to 90 years). Median OS for all patients was 22 months (5-year OS, 36%) with a median follow-up of 24 months (range, 0.1 to 354 months). Translocations of DUSP22, TP63, and ALK were mutually exclusive. Patients with ALK-positive ALCL (n=17) had a median OS of 176 months (median follow-up, 68 months; 5-year OS, 69%). Despite being ALK-negative, cases with translocations of DUSP22 or TP63 shared pathologic features with ALCL. Median OS was not reached in patients with DUSP22 translocations (n=7; median follow-up, 88 months; 5-year OS, 100%). Patients with tumors harboring TP63 translocations (n=9) had a median OS of 13 months (all dead at 76 months; 5-year OS, 11%). Patients with none of these abnormalities (n=101) had a median OS of 17 months (median follow-up, 13 months; 5-year OS, 29%). Differences in OS among these groups were highly significant (p=0.0002). Conclusions: PTCLs with DUSP22 translocations had a favorable prognosis similar to ALK-positive ALCLs. In contrast, TP63 were associated with very poor prognosis. FISH for these biomarkers is a promising tool for risk stratification, particularly since both translocations occurred in cases with overlapping pathologic features. PTCLs with DUSP22 translocations may represent a genetically defined subset of ALK-negative ALCLs. Like patients with ALK-positive ALCLs, these patients may not derive additional benefit from intensified up-front strategies such as early transplantation. Patients with none of these abnormalities comprised 75% of patients studied and had an intermediate prognosis, indicating the need for additional biomarkers in this group to improve risk stratification. Citation Format: Edgardo R. Parrilla Castellar, George Vasmatzis, Ryan A. Knudson, Rhett P. Ketterling, Karen L. Grogg, William R. Macon, Mark E. Law, Stephen M. Ansell, Ahmet Dogan, Andrew L. Feldman. Genetic biomarkers for risk stratification of patients with peripheral T-cell lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3538. doi:10.1158/1538-7445.AM2013-3538

Key Points ALK-negative ALCLs have chromosomal rearrangements of DUSP22 or TP63 in 30% and 8% of cases, respectively. DUSP22-rearranged cases have favorable outcomes similar to ALK-positive ALCLs, whereas other genetic subtypes have inferior outcomes.