Publications by authors named "Liqiang Xi"

94 Publications

Clinicopathologic Features of Peripheral T-Cell Lymphoma in Sub-Saharan Africa.

Am J Clin Pathol 2021 Feb 2. Epub 2021 Feb 2.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Objectives: Peripheral T-cell lymphomas (PTCLs) are heterogeneous, clinically aggressive, and rare. Subtype distribution varies by geographic location; however, data from sub-Saharan Africa (SSA) are lacking. We sought to elucidate clinicopathologic features of PTCL in SSA.

Methods: We reviewed PTCL consultation cases from three SSA countries. PTCL subtype was determined per 2017 World Health Organization classification. Cases with sufficient material were evaluated by polymerase chain reaction for human T-cell leukemia virus type 1 (HTLV-1) and T-cell receptor γ (TCRG) rearrangement.

Results: Among 32 cases, median age was 45 years and male-to-female ratio was 1.7. Thirty (94%) of 32 cases required additional workup for subclassification. PTCL, not otherwise specified (PTCL-NOS) was the most common subtype (13/32, 41%), followed by PTCL with T-follicular helper phenotype (6/32, 19%) and systemic anaplastic large cell lymphoma (6/32, 19%). Four (16%) of 25 cases were Epstein-Barr virus positive (EBV+) (2/2 extranodal natural killer/T-cell lymphoma, 1/13 PTCL-NOS, and 1/4 angioimmunoblastic T-cell lymphoma with EBV+ immunoblasts). Two (15%) of 13 patients with PTCL-NOS were human immunodeficiency virus positive. No cases with evaluable DNA (0/15) were HTLV-1 positive, and 9 of 10 showed clonal TCRG rearrangements.

Conclusions: In comparison to Western studies, PTCLs from SSA show similar subtype distribution and male predominance but a younger age at diagnosis. Appropriate diagnosis of PTCL requires extensive ancillary testing not readily available in low-income countries, including much of SSA.
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http://dx.doi.org/10.1093/ajcp/aqaa201DOI Listing
February 2021

Genomic Rearrangement as a Secondary Event in High Grade B-Cell Lymphoma.

Hemasphere 2021 Jan 9;5(1):e505. Epub 2020 Dec 9.

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

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http://dx.doi.org/10.1097/HS9.0000000000000505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732336PMC
January 2021

JAK inhibition in early-onset somatic, nonclonal STAT5B gain-of-function disease.

J Allergy Clin Immunol Pract 2021 Feb 5;9(2):1008-1010.e2. Epub 2020 Dec 5.

Division of Allergy, Immunology and Rheumatology, Columbia University Medical Center, New York-Presbyterian Morgan Stanley Children's Hospital, New York, NY.

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http://dx.doi.org/10.1016/j.jaip.2020.11.050DOI Listing
February 2021

The mutational landscape of histiocytic sarcoma associated with lymphoid malignancy.

Mod Pathol 2021 02 14;34(2):336-347. Epub 2020 Sep 14.

Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Histiocytic sarcoma and tumors with dendritic cell differentiation (HDT) are uncommon neoplasms often with an aggressive clinical course that may occur in association with another hematologic malignancy or mediastinal germ cell tumor (secondary HDT, sHDT). Previous studies have shown mutations in the RAS/MAPK pathway in HDT and have demonstrated a clonal relationship between HDT and associated lymphoid malignancies through common translocations or identical immunoglobulin or T-cell receptor gene rearrangements. We performed whole exome sequencing on 16 cases of sHDT to further evaluate the spectrum of mutations that occur in sHDT in the context of an associated lymphoid malignancy, including cases associated with follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma, B- and T-cell acute lymphoblastic leukemia/lymphoma and peripheral T-cell lymphoma, NOS. In addition, we assessed the clonal relationship between the HDT and the associated lymphoid malignancy in three cases for which matched samples were available. We found mutations in RAS/MAPK pathway genes in 14/16 cases of sHDT associated with diverse mature and precursor B-cell and T-cell neoplasms, involving KRAS (8/16), BRAF (2/16), NRAS (2/16), MAP2K1 (1/16), and NF1 (1/16). In addition, we note that FL-associated sHDT frequently shares a similar mutational profile to the associated malignancy, identifying mutations in CREBBP or KMT2D in all cases and "aberrant" somatic hypermutation in 5/6 cases. Our study confirms the role of the RAS/MAPK pathway in the pathogenesis of sHDT, provides further evidence of a common neoplastic precursor and, in the case of FL, gives additional insight into the stage in lymphomagenesis at which transdifferentiation may occur.
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http://dx.doi.org/10.1038/s41379-020-00673-xDOI Listing
February 2021

UHRF1 Is a Novel Druggable Epigenetic Target in Malignant Pleural Mesothelioma.

J Thorac Oncol 2021 Jan 11;16(1):89-103. Epub 2020 Sep 11.

Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

Introduction: Ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) encodes a master regulator of DNA methylation that has emerged as an epigenetic driver in human cancers. To date, no studies have evaluated UHRF1 expression in malignant pleural mesothelioma (MPM). This study was undertaken to explore the therapeutic potential of targeting UHRF1 in MPM.

Methods: Microarray, real-time quantitative reverse transcription-polymerase chain reaction, immunoblot, and immunohistochemistry techniques were used to evaluate UHRF1 expression in normal mesothelial cells (NMCs) cultured with or without asbestos, MPM lines, normal pleura, and primary MPM specimens. The impact of UHRF1 expression on MPM patient survival was evaluated using two independent databases. RNA-sequencing, proliferation, invasion, and colony formation assays, and murine xenograft experiments were performed to evaluate gene expression and growth of MPM cells after biochemical or pharmacologic inhibition of UHRF1 expression.

Results: UHRF1 expression was significantly higher in MPM lines and specimens relative to NMC and normal pleura. Asbestos induced UHRF1 expression in NMC. The overexpression of UHRF1 was associated with decreased overall survival in patients with MPM. UHRF1 knockdown reversed genomewide DNA hypomethylation, and inhibited proliferation, invasion, and clonogenicity of MPM cells, and growth of MPM xenografts. These effects were phenocopied by the repurposed chemotherapeutic agent, mithramycin. Biochemical or pharmacologic up-regulation of p53 significantly reduced UHRF1 expression in MPM cells. RNA-sequencing experiments exhibited the pleiotropic effects of UHRF1 down-regulation and identified novel, clinically relevant biomarkers of UHRF1 expression in MPM.

Conclusions: UHRF1 is an epigenetic driver in MPM. These findings support the efforts to target UHRF1 expression or activity for mesothelioma therapy.
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http://dx.doi.org/10.1016/j.jtho.2020.08.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775915PMC
January 2021

High level MYCN amplification and distinct methylation signature define an aggressive subtype of spinal cord ependymoma.

Acta Neuropathol Commun 2020 07 8;8(1):101. Epub 2020 Jul 8.

Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

We report a novel group of clinically aggressive spinal cord ependymomas characterized by Grade III histology, MYCN amplification, an absence of NF2 alterations or other recurrent pathogenic mutations, and a unique methylation classifier profile. Seven cases were found to have MYCN amplification in the course of routine mutational profiling of 552 patients with central nervous system tumors between December 2016 and July of 2019 and an eighth patient was identified from an unrelated set of cases. Methylation array analysis revealed that none of the 8 cases clustered with any of the nine previously described ependymoma methylation subgroups, and 7 of 8 formed their own tight unique cluster. Histologically all cases showed grade III features, and all demonstrated aggressive clinical behavior. These findings are presented in the context of data from three other studies describing similar cases. Therefore, a combined total of 27 MYCN amplified spinal cord ependymoma cases have now been reported in the literature, warranting their consideration as a distinctive subtype of spinal cord ependymoma (SP-EPN-MYCN) with their unique molecular characteristics and aggressive clinical behavior.
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http://dx.doi.org/10.1186/s40478-020-00973-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346356PMC
July 2020

Epstein-Barr Virus-negative Marginal Zone Lymphoma as an Uncommon Form of Monomorphic Posttransplant Lymphoproliferative Disorder.

Am J Surg Pathol 2020 10;44(10):1340-1352

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD.

Monomorphic posttransplant lymphoproliferative disorders have been defined as lymphoid or plasmacytic proliferations that fulfill criteria for one of the B-cell or T/NK-cell neoplasms recognized in immunocompetent hosts in the current WHO Classification. Low-grade B-cell neoplasms have historically been excluded from this category, although rare reports of marginal zone lymphoma (MZL) have been described. We report 9 cases of posttransplant Epstein-Barr virus-negative MZL, all arising in solid organ transplant recipients (4 renal, 3 liver, 1 cardiac, and 1 liver, pancreas, and small bowel). Seven were extranodal MZL of mucosa-associated lymphoid tissue type, all of which had gastrointestinal involvement (4 colon, 1 duodenum, 1 stomach, and 1 oropharynx/base of tongue). Notably, the preferential involvement of intestine distinguishes posttransplant extranodal MZL from sporadic cases. Immunoglobulin light-chain restriction was seen in all cases, with polymerase chain reaction showing a monoclonal pattern in 7 of 8 cases with successful amplification of polymerase chain reaction products. A clonally unrelated recurrence was seen in one case. Next-generation sequencing identified recurrent mutations previously reported in MZL in 3/5 cases. MZL was diagnosed at least 1 year after solid organ transplant (median time to presentation, 84 mo; range, 13 to 108 mo). The median age was 44 (range, 9 to 73 y); the male: female ratio was 5:4. The mean follow-up was 33.4 months, with an indolent clinical course observed. A subset responded to reduction in immunosuppression and anti-CD20 therapy alone. These data support the designation of Epstein-Barr virus-negative MZL as an uncommon form of monomorphic posttransplant lymphoproliferative disorders.
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http://dx.doi.org/10.1097/PAS.0000000000001514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492423PMC
October 2020

Clonal Evolution and Heterogeneity of Osimertinib Acquired Resistance Mechanisms in EGFR Mutant Lung Cancer.

Cell Rep Med 2020 Apr;1(1)

Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.

Clonal evolution of osimertinib-resistance mechanisms in EGFR mutant lung adenocarcinoma is poorly understood. Using multi-region whole-exome and RNA sequencing of prospectively collected pre- and post-osimertinib-resistant tumors, including at rapid autopsies, we identify a likely mechanism driving osimertinib resistance in all patients analyzed. The majority of patients acquire two or more resistance mechanisms either concurrently or in temporal sequence. Focal copy-number amplifications occur subclonally and are spatially and temporally separated from common resistance mutations such as C797S. amplification occurs in 66% (n = 6/9) of first-line osimertinib-treated patients, albeit spatially heterogeneous, often co-occurs with additional acquired focal copy-number amplifications and is associated with early progression. Noteworthy osimertinib-resistance mechanisms discovered include neuroendocrine differentiation without histologic transformation, amplification, and fusions. The subclonal co-occurrence of acquired genomic alterations upon osimertinib resistance will likely require targeting multiple resistance mechanisms by combination therapies.
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http://dx.doi.org/10.1016/j.xcrm.2020.100007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263628PMC
April 2020

MGMT Status as a Clinical Biomarker in Glioblastoma.

Trends Cancer 2020 05 27;6(5):380-391. Epub 2020 Mar 27.

Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address:

Glioblastoma is the most common primary malignant brain tumor. Although current standard therapy extends median survival to ~15 months, most patients do not have a sustained response to treatment. While O-methylguanine (O-MeG)-DNA methyltransferase (MGMT) promoter methylation status is accepted as a prognostic and promising predictive biomarker in glioblastoma, its value in informing treatment decisions for glioblastoma patients remains debatable. Discrepancies between MGMT promoter methylation status and treatment response in some patients may stem from inconsistencies between MGMT methylation and expression levels in glioblastoma. Here, we discuss MGMT as a biomarker and elucidate the discordance between MGMT methylation, expression, and patient outcome, which currently challenges the implementation of this biomarker in clinical practice.
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http://dx.doi.org/10.1016/j.trecan.2020.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315323PMC
May 2020

The first pancreatic neuroendocrine tumor in Li-Fraumeni syndrome: a case report.

BMC Cancer 2020 Mar 30;20(1):256. Epub 2020 Mar 30.

Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Building 10, Room 4-5952, Bethesda, MD, 20892, USA.

Background: Li-Fraumeni syndrome is a cancer predisposition syndrome caused by germline TP53 tumor suppressor gene mutations, with no previous association with pancreatic neuroendocrine tumors (PNETs). Here we present the first case of PNET associated with Li-Fraumeni syndrome.

Case Presentation: This is a 43-year-old female who underwent laparoscopic distal pancreatectomy at age 39 for a well-differentiated grade 2 cystic PNET. When the patient was 41 years old, her seven-year-old daughter was found to have an astrocytoma and a germline TP53 mutation. While undergoing surveillance with Gallium-DOTATATE positron emission tomography/computed tomography for her PNET, the patient was found to have a large choroid plexus papilloma in her right temporal lobe. She underwent genetic counseling and testing that identified a germline pathogenic variant in TP53, leading to the diagnosis of Li-Fraumeni syndrome. Her PNET had a hemizygous pathogenic TP53 mutation with loss of the wild-type alternate allele, consistent with loss of heterozygosity and the two-hit hypothesis. She was enrolled in a Li-Fraumeni syndrome protocol and continues surveillance screening with our service.

Conclusions: This is the first PNET reported in association with Li-Fraumeni syndrome. Pancreatic cancer risk is elevated in this syndrome, and our case highlights the need for vigilance in screening for pancreatic neoplasms in these patients.
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http://dx.doi.org/10.1186/s12885-020-06723-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106707PMC
March 2020

A Novel Risk Stratification System for Thyroid Nodules With Indeterminate Cytology-A Pilot Cohort Study.

Front Endocrinol (Lausanne) 2020 18;11:53. Epub 2020 Feb 18.

National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK), Bethesda, MD, United States.

Thyroid ultrasound (US), fine needle aspiration biopsy (FNAB), and molecular testing have been widely used to stratify the risk of malignancy in thyroid nodules. The goal of this study was to investigate a novel diagnostic approach for cytologically indeterminate thyroid nodules (ITN) based upon a combination of US features and genetic alterations. We performed a pilot cohort study of patients with ITN (Bethesda III/IV), who underwent surgical treatment. Based on standardized sonographic patterns established by the American Thyroid Association (ATA), each ITN received an US score (X), ranging between 0 and 0.9 according to its risk of thyroid cancer (TC). DNA and RNA were extracted from pathologic material, available for all patients, and subjected to Oncomine™ Comprehensive Assay v2 (OCAv2) next-generation sequencing. Each genetic alteration was annotated based on its strength of association with TC and its sum served as the genomic classifier score (X). The total risk score (TRS) was the sum of X and X. ROC curves were generated to assess the diagnostic accuracy of X, X, and TRS. The study cohort consisted of 50 patients (39 females and 11 males), aged 47.5 ± 14.8 years. Three patients were excluded due to molecular testing failure. Among the remaining 47 patients, 28 (59.6%) were diagnosed with TC. was the most common mutation in papillary TC, fusion was present in NIFTP, pathogenic variants of , and were found in Hürthle cell TC and mutations in medullary TC. The diagnostic accuracy of X and TRS was significantly higher compared with X (88 vs. 62.5%, < 0.001; 85.2 vs. 62.5%, < 0.001, respectively). However, this increased accuracy was due to significantly better sensitivity (80.7 vs. 34.6%, < 0.001; 84.6 vs. 34.6%, < 0.001, respectively) without improved specificity (94.7 vs. 90%, = 0.55; 85.7 vs. 90%, = 0.63, respectively). Molecular testing might not be necessary in ITN with high-risk US pattern (X = 0.9), as specificity of TC diagnosis based on Xus alone is sufficient and not improved with molecular testing. OCAv2 is useful in guiding the management of ITN with low-to-intermediate risk US features (X < 0.9), as it increases the accuracy of TC diagnosis.
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http://dx.doi.org/10.3389/fendo.2020.00053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040241PMC
February 2021

Randomized Phase II Study of First-Line Cladribine With Concurrent or Delayed Rituximab in Patients With Hairy Cell Leukemia.

J Clin Oncol 2020 05 28;38(14):1527-1538. Epub 2020 Feb 28.

Medical Oncology Service, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Purpose: Single-agent purine analog, usually cladribine, has been the standard first-line therapy of hairy cell leukemia (HCL) for 30 years. High complete remission (CR) rates often include minimal residual disease (MRD), leading to relapse and repeated treatments. Rituximab can clear MRD, but long-term results are unknown and optimal timing of rituximab undefined.

Patients And Methods: Patients were randomly assigned to first-line cladribine 0.15 mg/kg intravenously days 1-5 with 8 weekly doses of rituximab 375 mg/m begun either day 1 (concurrent, CDAR) or ≥ 6 months later (delayed) after detection of MRD in blood. MRD tests included blood and bone marrow (BM) flow cytometry, and BM immunohistochemistry.

Results: Sixty-eight patients with purine analog-naïve classic HCL were randomly assigned 1:1 to concurrent versus delayed arms. At 6 months after CDAR versus cladribine monotherapy, CR rates were 100% versus 88% ( = .11), MRD-free CR rates 97% versus 24% ( < .0001, primary end point), and blood MRD-free rates 100% versus 50% ( < .0001), respectively. At 96 months median follow-up, 94% versus 12% remained MRD free. Compared with CDAR, delayed rituximab after cladribine achieved lower rate (67% of 21 evaluable patients; = .0034) and durability ( = .0081, hazard radio favoring CDAR, 0.094) of MRD-free CR. Nevertheless, 12 patients in the delayed arm remained MRD free when restaged 6-104 (median, 78) months after last delayed rituximab treatment. Compared with cladribine monotherapy, CDAR led to brief grade 3/4 thrombocytopenia (59% 9%; < .0001) and platelet transfusions without bleeding (35% 0%; = .0002), but higher neutrophil ( = .017) and platelet ( = .0015) counts at 4 weeks.

Conclusion: Achieving MRD-free CR of HCL after first-line cladribine is greatly enhanced by concurrent rituximab and less so by delayed rituximab. Longer follow-up will determine if MRD-free survival leads to less need for additional therapy or cure of HCL.
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http://dx.doi.org/10.1200/JCO.19.02250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213585PMC
May 2020

Expression of the muscle-associated gene MYF6 in hairy cell leukemia.

PLoS One 2020 10;15(2):e0227586. Epub 2020 Feb 10.

Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD , United States of America.

Hairy cell leukemia (HCL) is a purine analog-responsive B-cell malignancy containing the BRAF V600E mutation, expressing CD22, CD11c, CD103, tartrate resistant acid phosphatase (TRAP) CD25, CD123, and annexin 1A. BRAF V600E and the latter 4 markers are usually absent in the more aggressive and chemoresistant variant HCLv. To evaluate differences between HCL and HCLv, expression microarrays comparing HCL with HCLv were performed for 24694 genes using 47323 probes. Microarray data from 35 HCL and 27 HCLv purified samples showed the greatest HCL-HCLv difference in the muscle-associated gene MYF6, expressed by its 2 probes 18.5- and 10.8-fold higher in HCL than HCLv (p<0.0001). By real-time quantitative PCR (RQ-PCR), 100% of 152 classic HCL samples were MYF6-positive, vs 5 (6%) of 90 blood donors. MYF6-expression was also detected in 18 (35%) of 51 with HCLv, 11 (92%) of 12 with HCL expressing unmutated IGHV4-34, 35 (73%) of 48 with chronic lymphocytic leukemia (CLL), and 1 (8%) of 12 with mantle cell lymphoma. Hypomethylation status of MYF6 supported expression in HCL more than HCLv. Posttreatment blood samples becoming negative by flow cytometry remained MYF6+ by RQ-PCR in 42 (48%) of 87 HCL patients, and MYF6 RQ-PCR could detect 1 HCL in 105 normal cells. MYF6, universally expressed in HCL and in most CLL samples, may be a useful biomarker for these leukemias. Further studies are underway to determine the role of MYF6 in HCL.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227586PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010284PMC
April 2020

Sensitivity of Mesothelioma Cells to PARP Inhibitors Is Not Dependent on BAP1 but Is Enhanced by Temozolomide in Cells With High-Schlafen 11 and Low-O6-methylguanine-DNA Methyltransferase Expression.

J Thorac Oncol 2020 05 28;15(5):843-859. Epub 2020 Jan 28.

Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

Introduction: BRCA1-associated protein-1 (BAP1), a nuclear deubiquitinase thought to be involved in DNA double-strand break repair, is frequently mutated in mesothelioma. Because poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPIs) induce synthetic lethality in BRCA1/2 mutant cancers, we evaluated whether BAP1 inactivating mutations confer sensitivity to PARPIs in mesothelioma and if combination therapy with temozolomide (TMZ) would be beneficial.

Methods: A total of 10 patient-derived mesothelioma cell lines were generated and characterized for BAP1 mutation status, protein expression, nuclear localization, and sensitivity to the PARPIs, olaparib, and talazoparib, alone or in combination with TMZ. BAP1 deubiquitinase (DUB) activity was evaluated by ubiquitin with 7-amido-4-methylcoumarin assay. BAP1 knockout mesothelioma cell lines were generated by CRISPR-Cas9. Because Schlafen 11 (SLFN11) and O-methylguanine-DNA methyltransferase also drive response to TMZ and PARPIs, we tested their expression and relationship with drug response.

Results: BAP1 mutations or copy-number alterations, or both were present in all 10 cell lines. Nonetheless, four cell lines exhibited intact DUB activity and two had nuclear BAP1 localization. Half maximal-inhibitory concentrations of olaparib and talazoparib ranged from 4.8 μM to greater than 50 μM and 0.039 μM to greater than 5 μM, respectively, classifying them into sensitive (two) or resistant (seven) cells, independent of their BAP1 status. Cell lines with BAP1 knockout resulted in the loss of BAP1 DUB activity but did not increase sensitivity to talazoparib. Response to PARPI tended to be associated with high SLFN11 expression, and combination with temozolomide increased sensitivity of cells with low or no MGMT expression.

Conclusions: BAP1 status does not determine sensitivity to PARPIs in patient-derived mesothelioma cell lines. Combination of PARPI with TMZ may be beneficial for patients whose tumors have high SLFN11 and low or no MGMT expression.
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http://dx.doi.org/10.1016/j.jtho.2020.01.012DOI Listing
May 2020

Antigen Experienced T Cells from Peripheral Blood Recognize p53 Neoantigens.

Clin Cancer Res 2020 03 29;26(6):1267-1276. Epub 2020 Jan 29.

Surgery Branch, National Cancer Institute, Bethesda, Maryland.

Purpose: The purpose of this study was to evaluate antigen experienced T cells in peripheral blood lymphocytes (PBL) for responses to p53 neoantigens.

Experimental Design: PBLs from patients with a mutated tumor were sorted for antigen-experienced T cells and stimulation (IVS) was performed with p53 neoantigens. The IVS cultures were stimulated with antigen-presenting cells expressing p53 neoantigens, enriched for 41BB/OX40 and grown with rapid expansion protocol.

Results: T-cell responses were not observed in the PBLs of 4 patients who did not have tumor-infiltrating lymphocyte (TIL) responses to mutated . In contrast, 5 patients with TIL responses to mutated also had similar T-cell responses in their PBLs, indicating that the PBLs and TILs were congruent in p53 neoantigen reactivity. CD4 and CD8 T cells were specific for p53, p53, or p53 neoantigens, including a 78% reactive T-cell culture against p53 and HLA-A*02:01. Tracking clonotypes (clonality, top ranked, and mutation-specific) supported the enrichment of p53 neoantigen-reactive T cells from PBLs. The same T-cell receptor (TCR) from the TIL was found in the IVS cultures in three cases and multiple unique TCRs were found in another patient. mutation-specific T cells also recognized tumor cell lines bearing the appropriate human leukocyte antigen restriction element and mutation, indicating these T cells could recognize processed and presented p53 neoantigens.

Conclusions: PBL was a noninvasive source of T cells targeting mutations for cell therapy and can provide a window into intratumoral p53 neoantigen immune responses..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424598PMC
March 2020

Molecular Analysis of Mutations in the Human HPRT Gene.

Methods Mol Biol 2020 ;2102:349-359

Public Health Program, Nova Southeastern University, Fort Lauderdale, FL, USA.

The HPRT assay uses incorporation of toxic nucleotide analogues to select for cells lacking the purine scavenger enzyme hypoxanthine-guanine phosphoribosyl transferase. A major advantage of this assay is the ability to isolate mutant cells and determine the molecular basis for their functional deficiency. Many types of analyses have been performed at this locus: the current protocol involves generation of a cDNA and multiplex PCR of each exon, including the intron/exon junctions, followed by direct sequencing of the products. This analysis detects point mutations, small deletions and insertions within the gene, mutations affecting RNA splicing, and the products of illegitimate V(D)J recombination within the gene. Establishment of and comparisons with mutational spectra hold the promise of identifying exposures to mutation-inducing genotoxicants from their distinctive pattern of gene-specific DNA damage at this easily analyzed reporter gene.
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http://dx.doi.org/10.1007/978-1-0716-0223-2_20DOI Listing
October 2020

Expansion of PD1-positive T Cells in Nodal Marginal Zone Lymphoma: A Potential Diagnostic Pitfall.

Am J Surg Pathol 2020 05;44(5):657-664

National Institutes of Health, Bethesda, MD.

The diagnosis of nodal marginal zone lymphoma (NMZL) can be challenging, with the differential diagnosis including other low-grade B-cell lymphomas, reactive hyperplasia, and even some cases of peripheral T-cell lymphoma (PTCL). PTCL may have a perifollicular growth pattern mimicking NMZL. We and others have noted an atypical distribution of T-follicular helper (TFH) cells in some cases of NMZL. This study was prompted by the diagnosis of NMZL in several cases in which a marked increase of TFH cells, as determined by staining for programmed death-1 (PD1), had prompted suspicion for a diagnosis of PTCL. We analyzed PD1 staining in 48 cases of NMZL to characterize the extent and pattern of the PD1-positive infiltrate. Three main patterns of PD1 staining were identified: follicular pattern (peripheral, n=16; central, n=9; mixed, n=3), diffuse pattern (n=4), and a reduced or normal staining pattern in residual follicles (n=16). A comprehensive analysis of other TFH markers was undertaken in 14 cases with a high content of PD1-positive cells that were confirmed as B-cell lymphoma by clonality analysis. We describe in detail 5 of these cases in which PTCL was an initial consideration. This study illuminates the diverse immunohistochemical patterns encountered in NMZL and highlights a diagnostic pitfall important for diagnostic accuracy.
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http://dx.doi.org/10.1097/PAS.0000000000001414DOI Listing
May 2020

Langerhans Cell Histiocytosis, Non-Langerhans histiocytosis and concurrent Papillary Thyroid Carcinoma with BRAF V600E mutations: A case report and literature review.

Hum Pathol (N Y) 2019 Sep 15;17. Epub 2019 Jun 15.

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America.

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http://dx.doi.org/10.1016/j.hpcr.2019.200302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779126PMC
September 2019

Genomic profiling of primary histiocytic sarcoma reveals two molecular subgroups.

Haematologica 2020 04 22;105(4):951-960. Epub 2019 Aug 22.

Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD

Histiocytic sarcoma is a rare malignant neoplasm that may occur or in the context of a previous hematologic malignancy or mediastinal germ cell tumor. Here, we performed whole exome sequencing and RNA-sequencing (RNA-Seq) on 21 archival cases of primary histiocytic sarcoma. We identified a high number of genetic alterations within the RAS/RAF/MAPK pathway in 21 of 21 cases, with alterations in (6 of 21), (5 of 21), (4 of 21), (4 of 21), (4 of 21), (1 of 21), and (1 of 21), including single cases with homozygous deletion of , high-level amplification of , and a novel fusion. Concurrent and mutations were present in 3 of 21 cases, and 5 of 7 cases with alterations in and/or had disease involving the gastrointestinal tract. Following unsupervised clustering of gene expression data, cases with and/or abnormalities formed a distinct tumor subgroup. A subset of wild-type cases had frequent mutations in B-cell lymphoma associated genes and/or clonal IG gene rearrangements. Our findings expand the current understanding of the molecular pathogenesis of this rare tumor and suggest the existence of a distinct subtype of primary histiocytic sarcoma characterized by alterations with predilection for the gastrointestinal tract.
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http://dx.doi.org/10.3324/haematol.2019.230375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109753PMC
April 2020

Recurrent somatic mutations in NK-cell enteropathy.

Blood 2019 09 5;134(12):986-991. Epub 2019 Aug 5.

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; and.

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http://dx.doi.org/10.1182/blood.2019001443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753620PMC
September 2019

ALK-positive histiocytosis with fusion in an adult female.

Haematologica 2019 11 1;104(11):e534-e536. Epub 2019 Aug 1.

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD

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http://dx.doi.org/10.3324/haematol.2019.230094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821621PMC
November 2019

Durvalumab in Combination with Olaparib in Patients with Relapsed SCLC: Results from a Phase II Study.

J Thorac Oncol 2019 08 4;14(8):1447-1457. Epub 2019 May 4.

Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.

Purpose: Despite high tumor mutationburden, immune checkpoint blockade has limited efficacy in SCLC. We hypothesized that poly (ADP-ribose) polymerase inhibition could render SCLC more susceptible to immune checkpoint blockade.

Methods: A single-arm, phase II trial (NCT02484404) enrolled patients with relapsed SCLC who received durvalumab, 1500 mg every 4 weeks, and olaparib, 300 mg twice a day. The primary outcome was objective response rate. Correlative studies included mandatory collection of pretreatment and during-treatment biopsy specimens, which were assessed to define SCLC immunephenotypes: desert (CD8-positive T-cell prevalence low), excluded (CD8-positive T cells in stroma immediately adjacent/within tumor), and inflamed (CD8-positive T cells in direct contact with tumor).

Results: A total of 20 patients were enrolled. Their median age was 64 years, and most patients (60%) had platinum-resistant/refractory disease. Of 19 evaluable patients, two were observed to have partial or complete responses (10.5%), including a patient with EGFR-transformed SCLC. Clinical benefit was observed in four patients (21.1% [95% confidence interval: 6.1%-45.6%]) with confirmed responses or prolonged stable disease (≥8 months). The most common treatment-related adverse events were anemia (80%), lymphopenia (60%), and leukopenia (50%). Nine of 14 tumors (64%) exhibited an excluded phenotype; 21% and 14% of tumors exhibited the inflamed and desert phenotypes, respectively. Tumor responses were observed in all instances in which pretreatment tumors showed an inflamed phenotype. Of the five tumors without an inflamed phenotype at baseline, no during-treatment increase in T-cell infiltration or programmed death ligand 1 expression on tumor-infiltrating immune cells was observed.

Conclusions: The study combination did not meet the preset bar for efficacy. Pretreatment and during-treatment biopsy specimens suggested that tumor immune phenotypes may be relevant for SCLC responses to immune checkpoint blockade combinations. The predictive value of preexisting CD8-positive T-cell infiltrates observed in this study needs to be confirmed in larger cohorts.
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http://dx.doi.org/10.1016/j.jtho.2019.04.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660419PMC
August 2019

Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy.

Proc Natl Acad Sci U S A 2019 04 11;116(18):9008-9013. Epub 2019 Apr 11.

Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637.

Survival from malignant mesothelioma, particularly pleural mesothelioma, is very poor. For patients with breast, ovarian, or prostate cancers, overall survival is associated with increased sensitivity to platinum chemotherapy due to loss-of-function mutations in DNA repair genes. The goal of this project was to evaluate, in patients with malignant mesothelioma, the relationship between inherited loss-of-function mutations in DNA repair and other tumor suppressor genes and overall survival following platinum chemotherapy. Patients with histologically confirmed malignant mesothelioma were evaluated for inherited mutations in tumor suppressor genes. Survival was evaluated with respect to genotype and site of mesothelioma. Among 385 patients treated with platinum chemotherapy, median overall survival was significantly longer for patients with loss-of-function mutations in any of the targeted genes compared with patients with no such mutation ( = 0.0006). The effect of genotype was highly significant for patients with pleural mesothelioma (median survival 7.9 y versus 2.4 y, = 0.0012), but not for patients with peritoneal mesothelioma (median survival 8.2 y versus 5.4 y, = 0.47). Effect of patient genotype on overall survival, measured at 3 y, remained independently significant after adjusting for gender and age at diagnosis, two other known prognostic factors. Patients with pleural mesothelioma with inherited mutations in DNA repair and other tumor suppressor genes appear to particularly benefit from platinum chemotherapy compared with patients without inherited mutations. These patients may also benefit from other DNA repair targeted therapies such as poly-ADP ribose polymerase (PARP) inhibitors.
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http://dx.doi.org/10.1073/pnas.1821510116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500142PMC
April 2019

Pilot Trial of Adoptive Transfer of Chimeric Antigen Receptor-transduced T Cells Targeting EGFRvIII in Patients With Glioblastoma.

J Immunother 2019 05;42(4):126-135

Surgery Branch.

A deletion variant of epidermal growth factor receptor (EGFRvIII) is a known driver mutation in a subset of primary and secondary glioblastoma multiforme. Adoptive transfer of genetically modified chimeric antigen receptor (CAR) lymphocytes has demonstrated efficacy in hematologic malignancies but is still early in development for solid cancers. The surface expression of the truncated extracellular ligand domain created by EGFRvIII makes it an attractive target for a CAR-based cancer treatment. Patients with recurrent glioblastoma expressing EGFRvIII were enrolled in a dose escalation phase I trial, using a third-generation CAR construct derived from a human antibody. Transduced cells were administered after lymphodepleting chemotherapy and supported posttransfer with intravenous interleukin-2. The dose escalation proceeded at half-log increments from 10 to >10 cells. Primary endpoints were safety and progression-free survival. Eighteen patients were treated with final infusion products ranging from 6.3×10 to 2.6×10 anti-EGFRvIII CAR T cells. Median progression-free survival was 1.3 months (interquartile range: 1.1-1.9), with a single outlier of 12.5 months. Two patients experienced severe hypoxia, including one treatment-related mortality after cell administration at the highest dose level. All patients developed expected transient hematologic toxicities from preparative chemotherapy. Median overall survival was 6.9 months (interquartile range: 2.8-10). Two patients survived over 1 year, and a third patient was alive at 59 months. Persistence of CAR cells correlated with cell dose, but there were no objective responses. Administration of anti-EGFRvIII CAR-transduced T cells did not demonstrate clinically meaningful effect in patients with glioblastoma multiforme in this phase I pilot trial.
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http://dx.doi.org/10.1097/CJI.0000000000000260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691897PMC
May 2019

Expanding the Spectrum of EBV-positive Marginal Zone Lymphomas: A Lesion Associated With Diverse Immunodeficiency Settings.

Am J Surg Pathol 2018 10;42(10):1306-1316

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda.

Traditionally low-grade B-cell lymphomas have been excluded from the category of monomorphic posttransplant lymphoproliferative disorders. However, recent reports identified Epstein-Barr virus-positive (EBV) extranodal marginal zone lymphomas (MZL), almost exclusively seen in the posttransplant setting. Some reported cases responded to reduced immunosuppression, suggesting that they should be considered as a form of posttransplant lymphoproliferative disorders. We identified 10 cases of EBV MZL, 9 in extranodal sites and 1 presenting in lymph node. Two cases arose following solid organ transplantation, but other settings included iatrogenic immunosuppression for rheumatoid arthritis (2); prior chemotherapy (2); congenital immune deficiency (1); and increased age (3), as the only potential cause of immune dysfunction. There were 4 males and 6 females; age range 18 to 86. The atypical plasmacytoid and/or monocytoid B cells were positive for EBV in all cases, with either latency I or II in all cases tested. Monotypic light chain expression was shown in all with 6 cases positive for IgG, and 2 for IgM, undetermined in 2. Clonal immunoglobulin gene rearrangement was positive in all cases with successful amplification. MYD88 L265P was wild type in the 6 cases tested. We show that EBV MZLs can arise in a variety of clinical settings, and are most often extranodal. Treatment varied, but most patients had clinically indolent disease with response to reduction of immune suppression, or immunochemotherapy.
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http://dx.doi.org/10.1097/PAS.0000000000001113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133753PMC
October 2018

Expression of CD70 (CD27L) Is Associated With Epithelioid and Sarcomatous Features in IDH-Wild-Type Glioblastoma.

J Neuropathol Exp Neurol 2017 Aug;76(8):697-708

Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (DP,SP,MP,PF,LX,MR,MQ); and Neuro-Oncology Branch, CCR, NCI, National Institutes of Health, Bethesda, Maryland (MRG).

Glioblastoma is an aggressive, often recalcitrant disease. In the majority of cases, prognosis is dismal and current therapies only moderately prolong survival. Immunotherapy is increasingly being recognized as an effective treatment modality. CD70 is a transmembrane protein that shows restricted expression in tissue but has been described in various malignancies. Therapeutic targeting of CD70 has demonstrated antitumor efficacy and is in clinical trials. Here, we sought to characterize CD70 expression in a large cohort of gliomas (n = 205) using tissue microarrays. We identified a subset of tumors (n = 18, 8.8% of high-grade gliomas) exhibiting moderate-to-strong immunoreactivity that enriched for the IDH-wild-type glioblastoma variants gliosarcoma (n = 10) and the newly described epithelioid glioblastoma (n = 4). CD70 expression was associated with prolonged survival in gliosarcoma. Analysis of TCGA datasets showed significantly increased CD70 expression in mesenchymal tumors and prolonged survival in recurrent non-G-CIMP high-expressing tumors. In CD70+ gliomas, there was a significant increase in CD68/CD163/HLA-DR+ tumor-associated macrophages, but not CD27+ TIL. These results confirm prior in vitro studies and demonstrate expression in a clinical cohort. The absence of CD70 expression in the post-treatment setting may portend more clinically aggressive disease in gliosarcoma. However, larger-scale studies will be needed to characterize and validate this relationship.
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http://dx.doi.org/10.1093/jnen/nlx051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251514PMC
August 2017

The clinical spectrum of Erdheim-Chester disease: an observational cohort study.

Blood Adv 2017 Feb;1(6):357-366

Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health. 10 Center Dr, Bldg 10, Room 3-2551, Bethesda, Maryland, USA, 20892. Telephone: 301-594-2952.

Erdheim-Chester Disease (ECD) is a rare, potentially fatal, multi-organ myeloid neoplasm occurring mainly in adults. The diagnosis is established by clinical, radiologic, and histologic findings; ECD tumors contain foamy macrophages that are CD68+, CD163+, CD1a-, and frequently S100-. The purpose of this report is to describe the clinical and molecular variability of ECD. Sixty consecutive ECD patients (45 males, 15 females) were prospectively evaluated at the NIH Clinical Center between 2011 and 2015. Comprehensive imaging and laboratory studies were performed, and tissues were examined for V600E and MAPK pathway mutations. Mean age at first manifestations of ECD was 46 years; a diagnosis was established, on average, 4.2 years after initial presentation. Bone was the most common tissue affected, with osteosclerosis in 95% of patients. Other manifestations observed in one-third to two-thirds of patients include cardiac mass and periaortic involvement, diabetes insipidus, retro-orbital infiltration, retroperitoneal, lung, CNS, skin and xanthelasma, usually in combination. Methods of detection included imaging studies of various modalities. Mutation in V600E was detected in 51% of 57 biopsies. One patient had an D228V mutation, and one had an activating fusion. Treatments included interferon alpha, imatinib, anakinra, cladribine, vemurafenib and dabrafenib with trametinib; eleven patients received no therapy. The diagnosis of ECD is elusive because of the rarity and varied presentations of the disorder. Identification of BRAF and other MAPK pathway mutations in biopsies improves ECD diagnosis, allows for development of targeted treatments, and demonstrates that ECD is a neoplastic disorder.
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http://dx.doi.org/10.1182/bloodadvances.2016001784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446206PMC
February 2017

Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-centre, two-stage, single-arm, phase 2 study.

Lancet Oncol 2017 06 7;18(6):792-802. Epub 2017 Apr 7.

Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Background: Uveal melanoma is a rare tumour with no established treatments once metastases develop. Although a variety of immune-based therapies have shown efficacy in metastatic cutaneous melanoma, their use in ocular variants has been disappointing. Recently, adoptive T-cell therapy has shown salvage responses in multiple refractory solid tumours. Thus, we sought to determine if adoptive transfer of autologous tumour-infiltrating lymphocytes (TILs) could mediate regression of metastatic uveal melanoma.

Methods: In this ongoing single-centre, two-stage, phase 2, single-arm trial, patients (aged ≥16 years) with histologically confirmed metastatic ocular melanoma were enrolled. Key eligibility criteria were an Eastern Cooperative Oncology Group performance status of 0 or 1, progressive metastatic disease, and adequate haematological, renal, and hepatic function. Metastasectomies were done to procure tumour tissue to generate autologous TIL cultures, which then underwent large scale ex-vivo expansion. Patients were treated with lymphodepleting conditioning chemotherapy (intravenous cyclophosphamide [60 mg/kg] daily for 2 days followed by fludarabine [25 mg/m] daily for 5 days, followed by a single intravenous infusion of autologous TILs and high-dose interleukin-2 [720 000 IU/kg] every 8 h). The primary endpoint was objective tumour response in evaluable patients per protocol using Response to Evaluation Criteria in Solid Tumors, version 1.0. An interim analysis of this trial is reported here. The trial is registered at ClinicalTrials.gov, number NCT01814046.

Findings: From the completed first stage and ongoing expansion stage of this trial, a total of 21 consecutive patients with metastatic uveal melanoma were enrolled between June 7, 2013, and Sept 9, 2016, and received TIL therapy. Seven (35%, 95% CI 16-59) of 20 evaluable patients had objective tumour regression. Among the responders, six patients achieved a partial response, two of which are ongoing and have not reached maximum response. One patient achieved complete response of numerous hepatic metastases, currently ongoing at 21 months post therapy. Three of the responders were refractory to previous immune checkpoint blockade. Common grade 3 or worse toxic effects were related to the lymphodepleting chemotherapy regimen and included lymphopenia, neutropenia, and thrombocytopenia (21 [100%] patients for each toxicity); anaemia (14 [67%] patients); and infection (six [29%] patients). There was one treatment-related death secondary to sepsis-induced multiorgan failure.

Interpretation: To our knowledge, this is the first report describing adoptive transfer of autologous TILs to mediate objective tumour regression in patients with metastatic uveal melanoma. These initial results challenge the belief that metastatic uveal melanoma is immunotherapy resistant and support the further investigation of immune-based therapies for this cancer. Refinement of this T-cell therapy is crucial to improve the frequency of clinical responses and the general applicability of this treatment modality.

Funding: Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.
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http://dx.doi.org/10.1016/S1470-2045(17)30251-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490083PMC
June 2017

KSHV-associated and EBV-associated Germinotropic Lymphoproliferative Disorder: New Findings and Review of the Literature.

Am J Surg Pathol 2017 Jun;41(6):795-800

*Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD †Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA ‡Department of Pathology, University of Witwatersrand, Johannesburg, South Africa.

We report 2 cases of Kaposi sarcoma-associated herpesvirus (KSHV)-and Epstein-Barr Virus (EBV) associated germinotropic lymphoproliferative disorder. Both cases arose in patients from regions endemic for KSHV, Cape Verde, and the Democratic Republic of the Congo, presenting as localized lymphadenopathy. The affected lymph nodes showed colonization of the follicles by clusters of large atypical plasmablasts, but also showed regressive changes with vascular proliferation and interfollicular plasmacytosis, both reminiscent of human herpesvirus 8 (HHV-8) positive multicentric Castleman disease. The atypical plasmablasts showed dual positivity for HHV-8 and EBV, being positive for LANA and viral interleukin 6, as well as Epstein-Barr virus-encoded small RNA by in situ hybridization. They showed a latency I phenotype, being negative for LMP1, EBNA2, and BZLF-1. The plasmablasts were negative for immunoglobulin light chains, and in 1 case with successful DNA amplification had a polyclonal immunoglobulin rearrangement pattern. Germinotropic lymphoproliferative disorder is a rare disorder, with only 6 cases reported in the literature. We demonstrate for the first time the expression of HHV-8 viral interleukin 6 and provide evidence for latency I phenotype for EBV. In addition, 1 case progressed to an EBV-positive diffuse large B-cell lymphoma, but interestingly was negative for KSHV/HHV-8, likely indicative of tumor derived from an independent clone.
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http://dx.doi.org/10.1097/PAS.0000000000000823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423846PMC
June 2017

The Genetic Basis of Hepatosplenic T-cell Lymphoma.

Cancer Discov 2017 04 25;7(4):369-379. Epub 2017 Jan 25.

Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.

Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including , and , were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in (31%), (9%), and (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in , and was the most frequently silenced gene in HSTL. We experimentally demonstrated that acts as a tumor suppressor gene. In addition, we found that mutations in and activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets. We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines as a tumor suppressor gene in HSTL and implicates genes including and in the disease. .
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http://dx.doi.org/10.1158/2159-8290.CD-16-0330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402251PMC
April 2017