Background: Fluorescence labeled DNA probes and in situ hybridization methods had shorter turn round time for results revolutionized their clinical application. Signals obtained from these probes are highly specific, yet they can produce fusion signals not necessarily representing fusion of actual genes due to other genes included in the probe design. In this study we evaluated discordance between cytogenetic, FISH and RNAseq results in 3 different patients with hematologic malignancies and illustrated the need to perform next generation sequencing (NGS) or RNASeq to accurately interpret FISH results. Methods: Bone marrow or peripheral blood karyotypes and FISH were performed to detect recurring translocations associated with hematologic malignancies in clinical samples routinely referred to our clinical cytogenetics laboratory. When required, NGS was performed on DNA and RNA libraries to detect somatic alterations and gene fusions in some of these specimens. Discordance in results between these methods is further evaluated. Results: For a patient with plasma cell leukemia standard FGFR3 / IGH dual fusion FISH assay detected fusion that was interpreted as FGFR3-positive leukemia, whereas NGS/RNASeq detected NSD2::IGH. For a pediatric acute lymphoblastic leukemia patient, a genetic diagnosis of PDGFRB-positive ALL was rendered because the PDGFRB break-apart probe detected clonal rearrangement, whereas NGS detected MEF2D::CSF1R. A MYC-positive B-prolymphocytic leukemia was rendered for another patient with a cytogenetically identified t(8;14) and MYC::IGH by FISH, whereas NGS detected a novel PVT1::RCOR1 not previously reported. Conclusions: These are 3 cases in a series of several other concordant results, nevertheless, elucidate limitations when interpreting FISH results in clinical applications, particularly when other genes are included in probe design. In addition, when the observed FISH signals are atypical, this study illustrates the necessity to perform complementary laboratory assays, such as NGS and/or RNASeq, to accurately identify fusion genes in tumorigenic translocations.
e19070 Background: Peripheral T-cell lymphomas (PTCL) are a rare heterogenous group of lymphomas and modern studies on incidence patterns of PTCL are lacking. Methods: Using the National Program of Cancer registries (NPCR) database, which covers 99% of the US population, we aim to evaluate the incidence of PTCL according to age, race-ethnicity, and gender; and examine trends over time. We identified PTCL using ICD-O-3 codes and evaluated incidence trends from 2001 to 2015. Results: A total of 78722 PTCL cases were identified, the most common were Mycoses fungoides/Sezary syndrome (MF-SS), PTCL Not Otherwise Specified (NOS), and ALK+ Anaplastic Large Cell Lymphoma (ALK+ ALCL). The age-adjusted incidence rate was 2.1 per 100,000. Incidence of PTCL increased with age (6.7/100,000 in 80+years). PTCL was more common in males than females (incidence rate ratio [IRR] of 0.6, p<0.05). Most PTCL were more common in Non-Hispanic Blacks (NHB). Incidence rates of MF-SS, PTCL NOS, Hepatosplenic TCL (HSL) in NHB were 0.8, 0.8, and 0.02 per 100,000 [IRR 1.7, 1.8, 2.2, p<0.05] respectively which is approximately twice that of Non-Hispanic whites (NHW). Viral related PTCL like Adult T-cell Leukemia Lymphoma (HTLV), Angio-Immunoblastic T-cell Lymphoma [AITL] (EBV), Extranodal NK-TCL nasal type [ENK TCL] (EBV), NK cell leukemia (EBV) are higher in groups at highest predisposition such as NHB and Non-Hispanic Asian Pacific Islanders (NHAPI). Primary cutaneous (PC) gamma-delta TCL occurs exclusively in NHW at an incidence rate of 0.03 per 100,000. There was no increase in overall yearly incidence of PTCL over the study period (0.1%, p=NS) but the incidence increased in NHB (Annual Percent Change [APC] 1.4%, p <0.05). Incidence of ENK TCL and AITL increased in NHAPI (2.2% and 3.7%, respectively [p <0.05]). The incidence of ALK + ALCL, PC CD30+ TCL decreased (APC -4.2%, -2% [p≤0.05] respectively). Conclusions: This is the first study to show unique incidence patterns of PTCL namely higher incidence in males, African Americans (esp. MF, PTCL-NOS and HSL unaccounted for viral etiologies) and exclusivity of primary cutaneous gamma delta TCL in NHW. Further research is needed to understand these differences.
ABSTRACT AL amyloidosis is a systemic disease caused by the aggregation of free antibody light chains (LC) secreted by aberrant plasma cell clones into the bloodstream. These LC aggregates form amyloid fibrils that deposit in multiple organs, leading to organ failure and, ultimately, death. Investigating the structural basis of LC aggregation is a critical avenue for understanding the biopathology of AL amyloidosis. Structural insights into AL fibril formation may reveal mechanisms driving amyloid deposition and inspire novel therapeutic strategies. Previous studies using cryo-electron microscopy have uncovered diverse AL fibril structures extracted from multiple patients, highlighting variability in fibril architecture. Here, we present a novel cryo-EM structure of AL cardiac fibrils from a patient with AL amyloidosis. This structure reveals a unique fibril fold and the coexistence of multiple morphologies, including single- and double-protofilament forms. Notably, some of these double-protofilament fibrils exhibit an uncommon rotational symmetry, raising intriguing questions about the mechanisms governing fibril formation and evolution over time.
Current treatment guidelines of myeloma cast nephropathy (MCN) recommend the institution of plasma cell-directed therapy and consideration of therapeutic plasma exchange (TPE), with the goal of rapid reduction of the serum free light chain (sFLC). However, the role of TPE continues to remain a subject of debate. The goal of this retrospective bi-institutional study was to evaluate the clinical outcomes of TPE in combination with systemic therapy. Eighty patients were included in this analysis, of whom 72.5% had ≥50% drop in their initial involved sFLC. At 3 months from TPE initiation, the overall hematologic response rate (ORR) was 67.5% with a very good partial response or better (≥VGPR) rate of 40%. At 6 months, ORR was 57.5%, with ≥VGPR rate of 49%. The renal response rate at 3 and 6 months was 47.5% and 43.75%, respectively; the overall renal response rate was 48.75%. On multivariable analysis, every one unit increase in baseline creatinine (odds ratio [OR] 0.76, p = 0.006), and achievement of ≥VGPR (OR 21.7 p < 0.0001) were significantly associated with renal response. Also, a ≥50% drop in sFLC was favorably associated with renal response (OR 3.39, p = 0.09). With a median follow-up of 36.4 months, the median overall survival (OS) was 11 months. On multivariable analysis, achievement of renal response (hazard ratio [HR] 0.3, p < 0.0001) and newly diagnosed disease (NDMM; HR 0.43, p = 0.0055) were associated with improved OS. Among NDMM patients, those treated with daratumumab-based regimens had a trend for better OS (p = 0.15), compared to other regimens, but the difference was not significant. At the end of follow-up, an estimated 40.4% of patients who were on dialysis were able to become dialysis independent. In conclusion, our study highlights the poor survival of patients with MCN. Achievement of early renal response is crucial for prolonged OS, with daratumumab-based therapies showing promise.
Pancreatic cancer is ranked as the fourth leading cause of cancer-related deaths in the United States despite intensive basic and clinical research over the last decade. In this paper we summarize the Abstracts #176, #234, and #206 presented at the 2014 ASCO Gastrointestinal Cancers Symposium focussing on BRCA 1 and 2 mutations, PABL gene mutations and expression of microRNAs to matrix metalloproteinase. There is an intense need for new findings in the translational research field with prognostic, predictive and therapeutic value.
