Proliferative Disorders Research Articles

Two branchial pathological conditions, nuclear hypertrophy and abnormal epithelial proliferation, in Mya arenaria from northwest Russian coasts.

Histopathological analysis of soft-shell clams Mya arenaria collected from 2 northwest Russian locations disclosed high prevalence of 2 pathological gill conditions. One involved the occurrence of more or less extended gill areas in which the branchial filaments showed hyperchromatic (basophilic) epithelium with some hypertrophied nuclei, which were considered presumptive signs of viral infection. Another pathological condition involved abnormal proliferation of the branchial epithelium, which lost the main differential features of the normal branchial epithelium (ciliated and simple cell layer structure), becoming non-ciliated, pseudostratified or stratified hyperchromatic epithelium with abundant mitotic figures and frequent apoptotic cells. The most complex cases involved loss of the normal branchial filament architecture, which was replaced with tumour-like growths consisting of branching, convoluted epithelial projections with a connective stroma. Images suggesting migration (invasion) of cells from the abnormally proliferating epithelium to the subjacent connective tissue, which would involve malignancy, were observed in one individual. The occurrence of both pathological conditions in clams from both locations and their co-occurrence in one clam suggest the possibility of a common, possibly viral, aetiology. Furthermore, the high prevalence of the abnormal proliferative disorder in non-polluted areas suggests an infectious aetiology. Additional studies are needed to assess a viral aetiology for the nuclear hypertrophy and/or the abnormal epithelial proliferation as well as the malignancy of the latter condition.

Immunophenotypic Characterization by Flow Cytometry of Chronic Lymphoid Leukemia

Chronic lymphoid leukemia (CLL) is a malignant proliferative disorder of incompetent mature-looking lymphocytes that accumulate in peripheral blood (PB), bone marrow (BM) and lymphoid tissues. Currently, the flow cytometry (FC) technique has demonstrated its great utility in the immunophenotypic classification of this entity.

A Case of POEMS Syndrome Previously Diagnosed with Extramedullary Plasmacytoma

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) syndrome is a rare multisystem disorder associated with osteosclerotic myeloma. It is characterized by peripheral polyneuropathy, presence of monoclonal plasma cell proliferative disorder, and one or more of the following features – sclerotic bone lesions, Castleman disease, elevated levels of vascular endothelial growth factor, organomegaly, extravascular volume overload, endocrinopathy, skin changes, papilledema, and thrombocytosis. Extramedullary plasmacytoma (EMP) is a rare plasma cell neoplasm that arises in isolated tissues without bone marrow involvement or systemic characteristics of multiple myeloma. Herein, we report a male patient who was previously diagnosed with EMP and later developed POEMS.

Rosai-Dorfman Disease of Bone and Soft Tissue.

Rosai-Dorfman disease is a rare histiocytic proliferative disorder of unknown pathogenesis that may be diagnostically difficult in extranodal sites. It is commonly an unsuspected diagnosis when arising in bone and soft tissue, especially when it presents without associated lymphadenopathy. Its variable clinical presentation and nonspecific imaging findings make the diagnosis quite challenging, particularly in small biopsies. The problem is compounded by its less-characteristic histomorphologic features in comparison with nodal disease. Awareness of the potential diagnostic pitfalls in Rosai-Dorfman disease of bone and soft tissue should raise the degree of diagnostic accuracy. To review the clinical manifestations, imaging characteristics, and histomorphologic features of Rosai-Dorfman disease of bone and soft tissue along with a brief discussion of its differential diagnosis, pathogenesis, and current management. Thorough review of the literature with focus on clinical manifestations, imaging findings, key histomorphologic features, pathogenesis, and treatment. The diagnosis of Rosai-Dorfman disease of bone and soft tissue may be quite challenging because of its variable clinical presentation and nonspecific imaging findings. It may be asymptomatic without systemic manifestations or associated lymphadenopathy. The definitive diagnosis relies on histopathologic identification of the characteristic S-100-positive histiocytes demonstrating emperipolesis. Bone and soft tissue lesions tend to have lower numbers of characteristic histiocytes and less conspicuous emperipolesis and often demonstrate areas of fibrosis or storiform spindle cell areas resembling fibrohistiocytic lesions. Awareness of these unusual features is necessary in order to consider Rosai-Dorfman disease in the differential diagnosis when confronting these rare and often misleading lesions.

An Analysis of M-protein in Plasma cell Dyscrasia Patients Identifies that IgG Lambda Subtype is More Commonly Associated with Normal Serum Free Light Chain (SFLC) Ratio.

The determination of monoclonal protein (M-protein) by SPE, IFE and SFLC assay is fundamental in the diagnosis of Plasma cell proliferative disorder (PCPD). In the present study, we seek to assess the diagnostic performance and concordance of these three techniques in un-treated PCPD patients. All new patients with dysproteinemia and/or suspected PCPD were included in this retrospective observational study. The baseline parameters were retrieved from electronic medical records. SPE was performed on gel electrophoresis system; monoclonal component was identified by IFE. SFLC assays were performed by nephelometry using a latex-enhanced immunoassay. Total 402 patients of PCPD were included (10.9% of MGUS/SMM and 89.1% of multiple myeloma). The combination of SPE + rSFLC (ratio of kappa/lambda light chain) and SPE + IFE + rSFLC was able to detect M-protein across all subgroups of patients. In 61 patients, rSFLC values were within normal range (54.5% of MGUS/SMM and 10.3% of MM) and was more commonly seen with IgG lambda M-protein (57.4% vs. all-others). The median dFLC value, among these patients, was higher for MM than MGUS/SMM patients (23.8 vs. 14.4mg/L, respectively). The combination of SPE and rSFLC can be reliably used to detect M-protein in PCPD patients. In a small subgroup of MM patients, despite the presence of an intact immunoglobulin (M-protein), the rSFLC is not abnormal. Historically, these patients should respond better to treatment. However, a further follow-up analysis with more number of such patients would be advantageous for better understanding.

Serotype-dependent recombinant adeno-associated vector (AAV) infection of Epstein\u2013Barr virus-positive B-cells, towards recombinant AAV-based therapy of focal EBV\u2009+\u2009lymphoproliferative disorders

BackgroundB-cell proliferative disorders, such as post-transplant lymphoproliferative disease (PTLD), are increased among persons afflicted by T-cell compromise. Most are Epstein–Barr virus (EBV) + and can first present with a focal lesion. Direct introduction of oncolytic viruses into localized tumors provides theoretical advantages over chemotherapy, immunotherapy and radiation therapy by reducing systemic toxicity. Despite extensive study as a vehicle for gene therapy, adeno-associated viruses (AAV) have rarely been applied to human cancer research due to technical and theoretical obstacles. Moreover, human B-cells have historically been described as resistant to AAV infection. Nonetheless, advances using different recombinant (r)AAV serotypes with unique tropisms to deliver cytotoxic therapy suggested a localized anti-tumor approach was feasible.MethodsAs a prelude to the development of a therapeutic vehicle, the ability of fifteen distinct EGFP-bearing rAAV serotypes to transduce human B-cells, including primary, immortalized, and B-cell tumor lines ± EBV was assessed by confocal microscopy, flow cytometry and subsequently cell viability assay.ResultsRank order analysis revealed augmented transduction by rAAV6.2 and closely related virions. EBV infection of EBV-negative B-cell tumor lines and EBV immortalization of primary B-cells increased susceptibility to rAAV6.2 transduction. As a proof of concept, transduction by rAAV6.2 encoding herpes simplex virus type 1 (HSV1)-thymidine kinase (TK) eliminated TK-negative rhabdomyosarcoma cells and diminished viability of transduced B-cell lines upon incubation with ganciclovir.ConclusionsrAAV serotypes differentially transduce human B-cell lines reversing the dogma that human B-cells are refractory to AAV infection. EBV + B-cells display increased susceptibility to rAAV6.2 infection, uncovering a new method for improved nucleic acid transfer into transfection-resistant B-cell lines. The introduction of a functional suicide gene into the rAAV6.2 genome identifies a candidate vector for the development of rAAV-based oncolytic therapy targeting focal EBV-bearing B-lymphoproliferative disorders.

Is intra-articular infliximab therapy a good alternative to radionuclide synovectomy for a patient with refractory pigmented villonodular synovitis?

Pigmented villonodular synovitis (PVNS) is a rare disease that has clinical and histopathological characteristics of both benign proliferative disorder and a chronic inflammatory process of the synovial tissue. The primary mode of treatment is surgery followed by an adjuvant radiotherapy; however, the risk of recurrence is a significant (40–70%). Several publications suggest that the TNF-α inhibitors might be a treatment option. We present a case of a 29-year-old female diagnosed with PVNS of the knee joint, refractory to surgery and 3 radionuclide synovectomies. Because the possibilities of conventional therapy were exhausted, treatment with an intra-articular anti-TNF-α monoclonal antibody (infliximab) was performed. Despite a high safety profile and a good tolerance of that therapy we did not observe significant clinical and radiological improvement. To assess the effectiveness of intra-articular TNF-α inhibitors as an adjuvant treatment in PVNS, prospective studies are needed.

Dabrafenib, Alone or in Combination with Trametinib, in Pediatric Patients with BRAF V600 Mutation-Positive Langerhans Cell Histiocytosis

▪Introduction: Langerhans cell histiocytosis (LCH) is a rare proliferative disorder associated with varied clinical presentations. Patients (pts) with advanced disease have frequent recurrences despite standard chemotherapy and a significant proportion experience long-term complications, including orthopaedic, endocrine, auditory, or neurodegenerative complications. BRAF V600 mutations have been reported in over 50% of LCH cases. The BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib is approved for BRAF V600-mutation positive melanoma, NSCLC, and anaplastic thyroid cancer. Here we describe the pooled analysis of pts with LCH from two open-label phase I/II studies in pediatric pts with recurrent/refractory malignancies, treated with dabrafenib monotherapy (CDRB436A2102; NCT01677741) or dabrafenib plus trametinib (CTMT212X2101; NCT02124772).Results: At the data cut-off date of January 19, 2021, 13 pts with LCH had received dabrafenib monotherapy (n=2, escalation; n=11, expansion). Median age was 3 years (range, 1-11) and all pts had received prior chemotherapy (100%); one patient received prior immunoglobulin and prior anti-CD52 monoclonal antibody (8%). Median duration of exposure to dabrafenib was 51 months (range, 7-65); 7 pts continued treatment on a rollover study and 6 discontinued, due to adverse events (AE; n=2), investigator decision (n=3), or switch to combination therapy via compassionate use (n=1). All pts experienced AEs, regardless of relationship to treatment; 11 pts (85%) had grade ≥3 AEs. All pts experienced AEs, suspected to be related to treatment, most commonly vomiting (46%), increased creatinine (38%), dry skin, rash, and melanocytic naevus (each 30%). AEs led to treatment discontinuation in 2 pts (increased blood creatinine; Epstein-Barr virus associated lymphoma, not related to treatment); there were no on-treatment deaths. The overall response rate (ORR) was 77% (6 complete response [CR]; 4 regressive disease [RD]); median duration of response (DOR) was not reached (NR), the estimated 24-month DOR rate was 90% (95% CI, 40-100). Median PFS was NR; the estimated 24-month PFS rate was 90% (95% CI, 50-100).At the data cut-off date of February 10, 2021, 12 pts with LCH had received dabrafenib + trametinib combination (2, escalation; 10, expansion). Median age was 4 years (range, 2-13) and all pts had received prior chemotherapy (100%). Median duration of exposure to treatment was 22 months (range 1.8-35.9); 8 patients continued therapy on a rollover study and 4 discontinued, due to AEs (n=2), lack of efficacy (n=1), or long term CR (n=1). All pts experienced AEs; 9 pts (75%) had grade ≥3 AEs. All pts experienced AEs, suspected to be related to treatment, most commonly pyrexia (58%), diarrhoea, dry skin, decreased neutrophil count, and vomiting (each 42%). AEs led to treatment discontinuation in 2 pts (AST increased; ALT increased); there were no on-treatment deaths. The ORR was 58% (4 CR; 3 RD); median DOR was NR, the estimated 24-month DOR rate was 100% (95% CI, NR-NR). Median PFS was NR; the estimated 24-month PFS rate was 100% (95% CI, NR-NR).Conclusions: Dabrafenib, with or without trametinib, demonstrated durable efficacy in pediatric pts with relapsed/refractory BRAF V600E mutation-positive LCH, with 90-100% of responses ongoing at 24 months. Treatment was associated with acceptable tolerability and manageable toxicities; the safety profile was consistent with what has been seen in other pediatric indications and in adult studies. DisclosuresWhitlock: Sobi Pharmaceuticals: Consultancy; Novartis: Research Funding; Amgen; Jazz Pharmaceuticals: Honoraria. Roughton: Novartis Pharma AG: Current Employment. Choi: Novartis Pharmaceuticals: Current Employment. Osterloh: Novartis Farmacéutica S.A. Spain: Current Employment. Russo: Novartis: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Hargrave: AstraZeneca; Bayer; DayOne; Janssen; Novartis; Roche: Consultancy; AstraZeneca: Research Funding; AstraZeneca; Bayer; Novartis; Roche: Honoraria; Bayer: Speakers Bureau. OffLabel Disclosure:Trametinib in combination with dabrafenib is approved for the treatment of unresectable/metastatic melanoma with BRAF V600E or V600K mutations; adjuvant treatment for melanoma with BRAF V600E or V600K mutations; metastatic non-small cell lung cancer with BRAF V600E mutation; locally advanced/metastatic anaplastic thyroid cancer with BRAF V600E mutation.

Purine Nucleoside Analogs Plus Rituximab Is an Effective Treatment Choice for Hairy Cell Leukemia-Variant: Results from a Single Center in China

Background: Hairy cell leukemia-variant (HCL-v) is one type of chronic lymphocytic proliferative disorders which was classified into splenic B-cell lymphoma/leukemia, unclassifiable. Both clinical and laboratory characteristics and treatment strategy remain elusive due to the rarity of the disease. Here, we firstly presented the diseases features and efficacy of a variety of treatment options in a large cohort from China.Methods: Thirty-three patients were diagnosed with HCL-v in Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College from June 1990 to February 2021. We analyzed the disease characteristics and treatment outcome, especially in terms of clinical manifestation, immunophenotypic and molecular evaluation and efficacy of multiple first-line treatment.Results: The median age of this cohort was 59 years (range, 34-79 years) at diagnosis, with 23 males and 10 females. Abdominal mass and relative signs (n=22) and abnormal complete blood count (n=9) were the most common chief complaints. Splenomegaly was present in 32 (97.0%) cases, among whom 26 (78.8%) cases were massive. Leukocytosis and leukopenia were presented in 23 (69.7%) patients and 5 (15.2%) patients, with a median white blood cell count of 21.58×10 9/L (range, 1.34-224.59×10 9/L). The median percentage of the leukemic cells in bone marrow tested by flow cytometry was 33% (range, 6.2%-96%), and immunophenotyping showed monoclonal B-cells positive for pan B-cell antigens (CD19, CD20, CD22, CD79b) in almost all patients (Table). CD11c was positive in all patients, and CD103 was positive in 20/26 (76.9%) patients. CD25 was negative in 30/33 (90.9%) patients, and CD23 was negative in 20/26 (76.9%) cases. CD200 was frequently expressed among patients (15/21, 71.4%). For the pathological pattern of bone marrow involvement, 20/27 (74.1%) patients showed a predominantly interstitial pattern. Moreover, Annexin A1 was negative in all (n=12) patients detected by immunohistochemistry. Conventional cytogenetic analysis showed abnormal karyotype in 10/24 (41.7%) patients, including 6 patients with complex karyotype. Fluorescence in situ hybridization analysis showed deletion of TP53 in 4/20 (20.0%) patients and IGH translocation in 5/16 (31.3%) patients. The BRAF V600E mutation was negative in all the patients (n=20). In 2 of 14 (16.7%) patients, TP53 mutation was detected by next-generation sequencing. Sixteen of nineteen (84.2%) patients showed monoclonal IGHV rearrangements, and the most common rearrangement fragment was VH4-34 (n=3, 18.8%). Six of seventeen (35.3%) patients presented with unmutated IGHV and patients with VH4-34 were all unmutated. 31 patients needed treatment finally. Treatment choices included interferon-α (IFN-α) in 11 patients, chlorambucil (CLB) in 5 patients, single purine nucleoside analogs (PNA) in 3 patients and PNA plus rituximab in 9 patients. Four patients who received IFN-α or CLB treatment also underwent splenectomy. The objective response rate was 100% for patients receiving PNA plus rituximab and 77% for cases receiving others. And people treated with PNA plus rituximab had a higher complete response rate compared to the other regimen (75% versus 12%, P = 0.004). During a median follow-up of 32 months (range, 3-207) for 29 patients, 14 (48.3%) patients experienced at least one relapse or progression, and 7 (24.1%) patients had 2 or more relapses. Of note, one case also underwent a diffuse large B-cell lymphoma transformation. The median PFS and OS were 31 months (95% CI 25.5-36.5) and 70 months (95% CI 50.5-89.5), respectively. PNA plus rituximab prolong PFS compared to the others (3-year PFS rate 80% [95%CI 20-97] versus 10% [95%CI 1-35], P = 0.012, Figure A). But no significant difference in 3-year OS rate was observed between two groups (100% [95%CI 100-100] versus 43% [95%CI 10-73], P = 0.128, Figure B).Conclusion: HCL-v is a rare disease with specific clinical and immunophenotypic features but may overlap with classic hairy cell leukemia or other splenic B-cell neoplasms. Overall, it is an indolent lymphoma with recurrent progression, and the use of PNA plus rituximab in first-line treatment can result in a deeper and longer remission. [Display omitted] DisclosuresWang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.

Heavy Chain Disease Reviewed on MALDI-TOF

Abstract Heavy Chain Disease (HCD) is a group of rare B-cell proliferative disorders. Diagnosis depends on the detection of a truncated heavy chain with no associated light chain, often done by serum or urine immunofixation. This approach has been reported to have low specificity, since associated light chain bands are sometimes not visible and heavy chain bands can be mistaken for polyclonal bands. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) offers improved sensitivity in detecting monoclonal immunoglobulins. Truncation is thought to happen in the constant heavy chain (CH1) region, detected as a fragment of mass 27,000 Da on MALDI-TOF. Other mass patterns have not been reported in the literature. In this study, frozen serum samples from 8 heavy chain disease patients were analyzed by MALDI-TOF mass spectrometry. Spectra were reviewed on Mass-Fix software and visually inspected for monoclonal peaks. We detected two types of patterns for the IgG heavy chain disease. One pattern shows an IgG heavy chain with truncated mass (27,000 Da vs. 50,000 Da) and another in which the mass of the IgG heavy chain is greater than normal (65,000 Da). Follow-up work demonstrates that these are most likely dimers of truncated heavy chains. Thus, mass spectrometry-based immunofixation can provide new insights into heavy chain disease biology, mechanism, and progression, which are not identified by traditional diagnostic methods.

Sequence complementarity between human noncoding RNAs and SARS-CoV-2 genes: What are the implications for human health?

ObjectivesTo investigate in silico the presence of nucleotide sequence complementarity between the RNA genome of Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) and human non-coding (nc)RNA genes. MethodsThe FASTA sequence (NC_045512.2) of each of the 11 SARS-CoV-2 isolate Wuhan-Hu-1 genes was retrieved from NCBI.nlm.nih.gov/gene and the Ensembl.org library interrogated for any base-pair match with human ncRNA genes. SARS-CoV-2 gene-matched human ncRNAs were screened for functional activity using bioinformatic analysis. Finally, associations between identified ncRNAs and human diseases were searched in GWAS databases. ResultsA total of 252 matches were found between the nucleotide sequence of SARS-CoV-2 genes and human ncRNAs. With the exception of two small nuclear RNAs, all of them were long non-coding (lnc)RNAs expressed mainly in testis and central nervous system under physiological conditions. The percentage of alignment ranged from 91.30% to 100% with a mean nucleotide alignment length of 17.5 ± 2.4. Thirty-three (13.09%) of them contained predicted R-loop forming sequences, but none of these intersected the complementary sequences of SARS-CoV-2. However, in 31 cases matches fell on ncRNA regulatory sites, whose adjacent coding genes are mostly involved in cancer, immunological and neurological pathways. Similarly, several polymorphic variants of detected non-coding genes have been associated with neuropsychiatric and proliferative disorders. ConclusionThis pivotal in silico study shows that SARS-CoV-2 genes have Watson-Crick nucleotide complementarity to human ncRNA sequences, potentially disrupting ncRNA epigenetic control of target genes. It remains to be elucidated whether this could result in the development of human disease in the long term.

Histiocytosis in Nigerian children: A report of two variants


 
 
 Histiocytoses are a rare group of proliferative disorders with very similar clinical and histological pictures. We present a case report of two variants seen in an eight-month-old female and five-month-old male in a tertiary hospital in southern Nigeria. They both presented with painless neck swellings and fever, leucocytosis, neutrophilia and lymphopenia. Initial histologic examinations of the cervical lymph nodes biopsy posed a diagnostic conundrum. However, Immuno-histochemical analysis done on both sample showed CD1a, positive S100 in keeping with Langerhans cell histiocytosis in the former. While, that of the latter showed strongly positive CD68, positive S-100 in 30% cells in keeping with Sinus histiocytosis with massive lymphadenopathy (SLMH) in the latter. Clinicians should have a high index of suspicion for histiocytosis in children presenting with generalised lymphadenopathy. Also, apart from the routine histology, immunohistochemistry analysis is recommended for all cases
 
 

P-100: Serum protein electrophoresis screening as a part of health-check program in Korea

<h3>Background</h3> Plasma cell myeloma and monoclonal gammopathy of undetermined significance (MGUS) have markedly increased in Korean population, especially in older age group. Serum protein electrophoresis (sPEP) with total protein level, can provide information about the overall distribution of serum protein and enables screening of plasma cell neoplasms. In this study, we analysed the results of sPEP screening in the hospital health-check program. <h3>Methods</h3> The sPEP was performed for 1405+2490 individuals, aged 23-83 years, who had visited in the health-check program of Pusan National University Yangsan Hospital for 10 years since 2010. The sPEP tests were performed using kit reagent (Protein 6 assay, Sebia, France) with automated multi-capillary electrophoresis system (Capillary 2, Sebia). According to the patterns of sPEP, we classified the whole data for 7 different groups. <h3>Results</h3> Among total of 3895 cases, 76.5% showed normal pattern including 164 cases which have only mildly decreased early alpha-2 fraction consisted with haptoglobin. Thirty cases (0.8%) showed acute inflammatory disease pattern with increase of alpha fractions. 11.0% of cases had mildly increased gamma fractions and 2.0% have more than 1.5 g/dL of the calculated quantity of gamma fraction. Three male patients were newly diagnosed as plasma cell myeloma and 36 cases were diagnosed as MGUS. The prevalence of plasma cell proliferative disorders in this study, 1.0% was lower than the previous report of Korea and similar that of large previous reports of large China population. <h3>Conclusion</h3> sPEP provides information about overall protein abnormalities in serum and is considered as the single most useful test for the detection of plasma cell neoplasm. As the prevalence of plasma cell proliferative disorders has been increasing, we suggest that sPEP may useful and cost-effective for screening in the health-check program.

Tenosynovial giant cell tumor-diffuse type, treated with a novel colony-stimulating factor inhibitor, pexidartinib: initial experience with MRI findings in three patients.

Tenosynovial giant cell tumor-diffuse type (diffuse TSGCT) is a benign but locally aggressive proliferative disorder of the synovium. Treatment is usually surgical, although in cases of extensive disease complete synovectomy is not possible and local recurrence rates are high. Pexidartinib (trade name Turalio®), a colony-stimulating factor-1 (CSF-1) inhibitor, was shown in a recent phase III trial to effectively treat diffuse TSGCT and is FDA approved for the treatment of adult patients with symptomatic diffuse TSGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Pexidartinib is available only through a restricted program under a risk evaluation and mitigation strategy (REMS) because of the risk of hepatotoxicity. Magnetic resonance imaging (MRI) is the preferred imaging modality for the diagnosis and surveillance of TSGCT. Here we present three patients with diffuse TSGCT of the knee who underwent multiple MRIs over several years while on pexidartinib. We describe the disease burden and signal characteristics on MRI and correlate with the response reported in the patients' medical records. Given that the use of pexidartinib and other CSF inhibitors is likely to increase, musculoskeletal radiologists should be aware of this novel non-operative treatment and the MRI appearance of diffuse TSGCT during therapy.

Diffuse vertebral marrow changes at MRI: Multiple myeloma or normal?

Five MRI patterns of marrow involvement (diffuse, focal, combined diffuse and focal, variegated, and normal) are observed in patients with a marrow proliferative disorder including MM. The wide range of marrow involvement patterns in monoclonal plasma cell proliferative disorders mirrors that of their natural histories that can vary from indolent to rapidly lethal. MRI of the axial bone marrow contributes to stage these disorders, but it should not be obtained for disease detection and characterization because of its limited specificity and sensitivity. At MRI, diffuse benign hematopoietic marrow hyperplasia and marrow heterogeneities in elderly patients mimic the diffuse and variegated patterns observed in MM patients. Careful analysis of fat- and fluid-sensitive MR images and quantitative marrow assessment by using MRI and FDG-PET can contribute in differentiating these changes from those associated with neoplastic marrow infiltration, with some residual overlapping findings.

MM-359: Pattern-Based Identification of Normal and Aberrant Plasma Cell Compartment across a Spectrum of Plasma Cell Proliferative Disorders Using Multiparametric Flow Cytometry

Context The discriminative power of various antigens for delineating normal plasma cells (NPC) from aberrant plasma cells (APC) is variable; thus, understanding of the multiparametric flow cytometry (MFC)-based PC compartment is crucial for reliable PC characterization across various PC proliferative disorders (PCPD). Objective The expression profile and patterns of currently used immunophenotypic (IPT) markers were assessed for their ability to differentiate NPC from APC across the spectrum of PCPDs. Design This is a prospective analysis of patients diagnosed with PCPD (per standard IMWG criteria). Setting Tertiary care cancer center. Patients A total of 900 patients with diagnosis of PCPD were evaluated (MM: 724, PCL: 15, SMM: 12, MGUS: 42, Plasmacytoma: 54, Amyloidosis: 31, POEMS: 22). Interventions Bone marrow aspirate from cases (n=900) and controls (n=30) were processed per consensus guidelines from the Euro-flow protocol. An aberrant PC cluster was defined by >30 plasma cells with light chain expression beyond the range of control samples (0.26 to 3.08) and/or aberrant immunophenotypes (≥3). Main Outcomes Measures 1. Utility of cytoplasmic light chain restriction and 2. Most useful combination of markers to discriminate NPC from APC. Results All cases were segregated into three groups: cases with 1. only APC (n=181); 2. with both NPC and APC (n=574); or 3. only NPC (n=145). The PC compartment was solely characterized by light chain expression and IPT aberrancy in 36.22% (n=326) and 21.88% cases (n=197), respectively (p Conclusions Assessment of cytoplasmic light chain expression by MFC is essential for demonstrating clonality in cases with all normal or all aberrant PC. Pattern-based recognition is a useful parameter that identifies aberrant PC reliably in the majority of cases with co-existing NPC and APC, especially in setting of smaller clones of APC, which are likely to be missed by light chain assessment alone.

Poster: MM-359: Pattern-Based Identification of Normal and Aberrant Plasma Cell Compartment across a Spectrum of Plasma Cell Proliferative Disorders Using Multiparametric Flow Cytometry

Poster: MM-359: Pattern-Based Identification of Normal and Aberrant Plasma Cell Compartment across a Spectrum of Plasma Cell Proliferative Disorders Using Multiparametric Flow Cytometry

How to Recognize and Treat MGRS

AbstractMonoclonal gammopathy of renal significance (MGRS) represents a group of B-cell or plasma cell proliferative disorders that causes kidney injury via a monoclonal immunoglobulin they produce. The need for this new category of hematologic disorders came from a lack of renal definition in the current diagnostic criteria for plasma cell disorders, Waldenstrom macroglobulinemia and chronic lymphocytic leukemia (CLL). By definition, the hematologic conditions considered to be MGRS do not meet standard consensus criteria for malignancy or treatment, but they cannot be diagnosed as monoclonal gammopathy of undetermined significance (MGUS) because of the end-organ damage. Although generally not life threatening except in the cases of immunoglobulin (AIg) amyloidosis and monoclonal immunoglobulin deposition disease (MIDD) with extrarenal manifestations, the kidney diseases secondary to MGRS are progressive and are associated with significant morbidity. The MGUS designation is also problematic because treatment is not recommended for the MGUS stage of these hematologic disorders. The clone directed therapy required for preservation of kidney function would not be available when these conditions were classified as MGUS, IgM MGUS or low-grade CLL. MGRS clearly separates these conditions from MGUS and allows for the use of clone directed therapy without contradicting current diagnostic criteria and guidelines.

Fuzhenghefuzhiyang Formula (FZHFZY) Improves Epidermal Differentiation via Suppression of the Akt/mTORC1/S6K1 Signalling Pathway in Psoriatic Models.

Psoriasis is a chronic proliferative skin disorder characterised by abnormal epidermal differentiation. The Fuzhenghefuzhiyang (FZHFZY) formula created by Chuanjian Lu, a master of Chinese medicine in dermatology, has been external used in the Guangdong Provincial Hospital of Chinese Medicine for the treatment of psoriasis, but its mechanisms of action against psoriasis remain poorly understood. This study involved an exploration of the effects of FZHFZY on epidermal differentiation and its underlying mechanisms in interleukin (IL)-17A/IL-22/interferon (IFN)-γ/tumour necrosis factor (TNF)-α–stimulated HaCaT cells and in a mouse model of imiquimod (IMQ)-induced psoriasis. Cell viability was assessed by MTT assay. Epidermal differentiation was detected by reverse-transcription polymerase chain reaction and western blotting. Histological evaluation of the skin tissue was performed via haematoxylin and eosin staining, and the Akt/mTORC1/S6K1 pathway was analysed by western blotting. FZHFZY inhibited proliferation and improved epidermal differentiation in IL-17A/IL-22/IFN-γ/TNF-α–induced HaCaT cells. FZHFZY ameliorated symptoms of psoriasis, regulated epidermal differentiation and inhibited phosphorylation of the Akt/mTORC1/S6K1 pathway in the skin of mice with imiquimod-induced psoriasis. Our results suggest that FZHFZY may exhibit therapeutic action against psoriasis by regulating epidermal differentiation via inhibition of the Akt/mTORC1/S6K1 pathway.

Targeting KIT by frameshifting mRNA transcripts as a therapeutic strategy for aggressive mast cell neoplasms

Activating mutations in c-KIT are associated with the mast cell (MC) clonal disorders cutaneous mastocytosis and systemic mastocytosis and its variants, including aggressive systemic mastocytosis, MC leukemia, and MC sarcoma. Currently, therapies inhibiting KIT signaling are a leading strategy to treat MC proliferative disorders. However, these approaches may have off-target effects, and in some patients, complete remission or improved survival time cannot be achieved. These limitations led us to develop an approach using chemically stable exon skipping oligonucleotides (ESOs) that induce exon skipping of precursor (pre-)mRNA to alter gene splicing and introduce a frameshift into mature KIT mRNA transcripts. The result of this alternate approach results in marked downregulation of KIT expression, diminished KIT signaling, inhibition ofMC proliferation, and rapid induction of apoptosis in neoplastic HMC-1.2 MCs. We demonstrate that invivo administration of KIT targeting ESOs significantly inhibits tumor growth and systemic organ infiltration using both an allograft mastocytosis model and a humanized xenograft MC tumor model. We propose that our innovative approach, which employs well-tolerated, chemically stable oligonucleotides to target KIT expression through unconventional pathways, has potential as a KIT-targeted therapeutic alone, or in combination with agents that target KIT signaling, in the treatment of KIT-associated malignancies.