Performing and Processing FNA of Anterior Fat Pad for Amyloid

Historically, heart, liver, and kidney biopsies were performed to demonstrate amyloid deposits in amyloidosis. Since the clinical presentation of this disease is so variable and non-specific, the associated risks of these biopsies are too great for the diagnostic yield. Other sites that have a lower biopsy risk, such as skin or gingival, are also relatively invasive and expensive. In addition, these biopsies may not always have sufficient amyloid deposits to establish a diagnosis. Fat pad aspiration has demonstrated good clinical correlation with low cost and minimal morbidity. However, there are no standardized protocols for performing this procedure or processing the aspirated specimen, which leads to variable and nonreproducible results. The most frequently utilized modality for detecting amyloid in tissue is an apple-green birefringence on Congo red stained sections using a polarizing microscope. This technique requires cell block preparation of aspirated material. Unfortunately, patients presenting in early stage of amyloidosis have minimal amounts of amyloid which greatly reduces the sensitivity of Congo red stained cell block sections of fat pad aspirates. Therefore, ultrastructural evaluation of fat pad aspirates by electron microscopy should be utilized, given its increased sensitivity for amyloid detection. This article demonstrates a simple and reproducible procedure for performing anterior fat pad aspiration for the detection of amyloid utilizing both Congo red staining of cell block sections and electron microscopy for ultrastructural identification

A single center phase II study of ixazomib in patients with relapsed or refractory cutaneous or peripheral T‐cell lymphomas

The transcription factor GATA‐3, highly expressed in many cutaneous T‐cell lymphoma (CTCL) and peripheral T‐cell lymphomas (PTCL), confers resistance to chemotherapy in a cell‐autonomous manner. As GATA‐3 is transcriptionally regulated by NF‐κB, we sought to determine the extent to which proteasomal inhibition impairs NF‐κB activation and GATA‐3 expression and cell viability in malignant T cells. Proteasome inhibition, NF‐κB activity, GATA‐3 expression, and cell viability were examined in patient‐derived cell lines and primary T‐cell lymphoma specimens ex vivo treated with the oral proteasome inhibitor ixazomib. Significant reductions in cell viability, NF‐κB activation, and GATA‐3 expression were observed preclinically in ixazomib‐treated cells. Therefore, an investigator‐initiated, single‐center, phase II study with this agent in patients with relapsed/refractory CTCL/PTCL was conducted. Concordant with our preclinical observations, a significant reduction in NF‐κB activation and GATA‐3 expression was observed in an exceptional responder following one month of treatment with ixazomib. While ixazomib had limited activity in this small and heterogeneous cohort of patients, inhibition of the NF‐κB/GATA‐3 axis in a single exceptional responder suggests that ixazomib may have utility in appropriately selected patients or in combination with other agents.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139920/1/ajh24895.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139920/2/ajh24895_am.pd

Investigating Safety And Preliminary Efficacy Of Afm13 Plus Pembrolizumab In Patients With Relapsed/Refractory Hodgkin Lymphoma After Brentuximab Vedotin Failure

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149522/1/hon134_2629.pd

A phase 1b study of AFM13 in combination with pembrolizumab in patients with relapsed or refractory Hodgkin lymphoma

In relapsed/refractory Hodgkin lymphoma (R/R HL), immunotherapies such as the anti-programmed death-1 inhibitor pembrolizumab have demonstrated efficacy as monotherapy and are playing an increasingly prominent role in treatment. The CD30/CD16A-bispecific antibody AFM13 is an innate immune cell engager, a first-in-class, tetravalent antibody, designed to create a bridge between CD30 on HL cells and the CD16A receptor on natural killer cells and macrophages, to induce tumor cell killing. Early studies of AFM13 have demonstrated signs of efficacy as monotherapy for patients with R/RHL and the combination of AFM13 with pembrolizumab represents a rational new treatment modality. Here, we describe a phase 1b, dose-escalation study to assess the safety and preliminary efficacy of AFM13 in combination with pembrolizumab in patients with R/R HL. The primary objective was estimating the maximum tolerated dose; the secondary objectives were to assess safety, tolerability, antitumor efficacy, pharmacokinetics, and pharmacodynamics. In this heavily pretreated patient population, treatment with the combination of AFM13 and pembrolizumab was generally well tolerated, with similar safety profiles compared to the known profiles of each agent alone. The combination of AFM13 with pembrolizumab demonstrated an objective response rate of 88% at the highest treatment dose, with an 83% overall response rate for the overall population. Pharmacokinetic assessment of AFM13 in the combination setting revealed a half-life of up to 20.6 hours. This proof-of-concept study holds promise as a novel immunotherapy combination worthy of further investigation

Time Trends in the Incidence and Treatment of Extra-Abdominal and Abdominal Aggressive Fibromatosis: A Population-Based Study

BACKGROUND: Aggressive fibromatosis (AF) is a locally infiltrating soft-tissue tumor. In a population-based study in the Netherlands, we evaluated time trends for the incidence and treatment of AF. METHODS: In PALGA: Dutch Pathology Registry, all patients diagnosed between 1993 and 2013 as having extra-abdominal or abdominal wall aggressive fibromatosis were identified and available pathology data of the patients were evaluated. Epidemiological and treatment-related factors were analyzed with χ(2)and regression analysis. RESULTS: During the study period, 1134 patients were identified. The incidence increased from 2.10 to 5.36 per million people per year. Median age at the time of diagnosis increased annually by B 0.285 (P = 0.001). Female gender prevailed and increased over time [annual odds ratio (OR) 1.022; P = 0.058]. All anatomic localizations, but in particular truncal tumors, became more frequent. During the study period diagnostic histological biopsies were performed more often (annual OR 1.096; P < 0.001). The proportion of patients who underwent surgical treatment decreased (annual OR 0.928; P < 0.001). When resection was preceded by biopsy, 49.8 % of the patients had R0-resection versus 30.7 % in patients without biopsy (P < 0.001). CONCLUSIONS: In this population-based study, an increasing incidence of extra-abdominal and abdominal-wall aggressive fibromatosis was observed. The workup of patients improved and a trend towards a nonsurgical treatment policy was observed

Outcomes Following Salvage Therapy in Primary Refractory Peripheral T-Cell Lymphoma (PTCL)

Abstract Background: Resistance to conventional anthracycline-based regimens (CHOP/CHOEP) and the emergence of primary refractory disease remains a clinical challenge in PTCL, and is observed in ≈25% of patients. Outcomes in the setting of primary refractory disease, particularly for those patients who fail to achieve a remission with second-line chemotherapy, are poorly described and the optimal therapeutic strategy for these patients remains uncertain. Patients and Methods: We identified 159 patients with PTCL who received multi-agent, anthracycline-based treatment from 1988 to 2011 in the PTCL database at our institution. Primary refractory disease, defined as disease progression during initial therapy or relapse within 6 months of its completion, was observed in 58 (36%) of patients. Results: The median age at diagnosis with primary refractory PTCL was 49 years (range, 18.8-77.1). Median follow up was 2.7 years among surviving patients (95% CI, 1.2-6.3). Median overall survival (OS) was 1.1 years (95% CI, 0.7-1.9). The median number of lines of therapy underwent by patients was 3 (range, 1-9). PTCL, NOS (n=24), angioimmunoblastic T-cell lymphoma (n=6), and ALK-positive anaplastic large cell lymphoma (n=7) accounted for the majority (63.8%) of these patients. No difference in OS was observed between patients who failed to respond to initial therapy and those who relapsed within 6 months after a first remission (median OS 0.9 [95% CI, 0.6-1.9] vs. 1.3 [95% CI, 0.5-6.3], p=0.6). After developing primary refractory disease, 48.3% of patients received aggressive, multi-agent salvage regimens (ICE, n=16; DHAP, n=3; ESHAP, n=6; other, n=3), 29.3% of patients received other systemic therapies (HDAC inhibitor, n=1; gemcitabine-based therapies, n=5; pralatrexate, n=3; other, n=8), and 22.4% of patients received no systemic therapies. Patients who received no systemic salvage therapy had reduced OS compared to both patients who received aggressive regimens and patients who received other types of systemic therapies (median OS 0.3 [95% CI, 0.2-1.1] vs. 1.7 [95% CI, 0.8-11.7] vs. 1.3 [95% CI, 0.4-8.6], respectively, p&lt;0.001), but the difference in OS observed between patients who received conventional salvage regimens and other systemic therapies was not significant (p=0.3). Patients receiving aggressive, multi-agent salvage regimens were more likely to undergo autologous or allogeneic stem cell transplantation (SCT) compared to those receiving non-traditional regimens or no systemic therapy (53.6% vs. 23.5% vs. 0%, respectively, p=0.0003). Following second-line therapy, 32.8% of patients underwent high dose therapy followed by autologous SCT (ASCT) (n=5) or allogeneic SCT (allo-SCT) (n=15). Not surprisingly, consolidation with either ASCT or allo-SCT was associated with improved OS (median OS 2.3 [95% CI, 0.9-11.4] vs. 0.6 [95% CI, 0.4-1.3], p=0.0012). Among patients who underwent allo-SCT, 26.7% (n=4) relapsed; among those who underwent ASCT, 60% (n=3) relapsed. A median OS of 0.6 years (95% CI, 0.4-1.1) was observed in patients who failed to achieve a remission with first salvage therapy and did not undergo ASCT or allo-SCT (n=25). Overall, 77.6% of patients with primary refractory PTCL failed to achieve a remission following second-line therapy or relapsed within 3 months of transplant. Among patients who did not achieve remission with the first salvage therapy, a median of 1 subsequent line of therapy (range, 0-7) was utilized. Among these patients who did not achieve a remission with initial salvage therapy, 20.6% (n=7) achieved a partial or complete remission with further therapy. Conclusion: Primary refractory PTCL is associated with dismal outcomes. The likelihood of achieving a remission and proceeding to transplant is ≈30% and with transplant, only 11 (19% of patients with primary refractory disease) achieved a durable remission. Improved understanding of resistance mechanisms in PTCL and the development of improved therapeutic strategies are needed. A significant survival benefit was not observed for patients receiving traditional salvage regimens compared to other systemic second-line regimens, with median survival &lt;20 months. Therefore, participation in well-designed clinical trials should be encouraged in these patients. Disclosures No relevant conflicts of interest to declare. </jats:sec