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author:("Li, shisong")
1.  Breast Implant–Associated Anaplastic Large-Cell Lymphoma: Long-Term Follow-Up of 60 Patients 
Journal of Clinical Oncology  2013;32(2):114-120.
Breast implant–associated anaplastic large-cell lymphoma (ALCL) is a recently described clinicopathologic entity that usually presents as an effusion-associated fibrous capsule surrounding an implant. Less frequently, it presents as a mass. The natural history of this disease and long-term outcomes are unknown.
Patients and Methods
We reviewed the literature for all published cases of breast implant–associated ALCL from 1997 to December 2012 and contacted corresponding authors to update clinical follow-up.
The median overall survival (OS) for 60 patients was 12 years (median follow-up, 2 years; range, 0-14 years). Capsulectomy and implant removal was performed on 56 of 60 patients (93%). Therapeutic data were available for 55 patients: 39 patients (78%) received systemic chemotherapy, and of the 16 patients (28%) who did not receive chemotherapy, 12 patients opted for watchful waiting and four patients received radiation therapy alone. Thirty-nine (93%) of 42 patients with disease confined by the fibrous capsule achieved complete remission, compared with complete remission in 13 (72%) of 18 patients with a tumor mass. Patients with a breast mass had worse OS and progression-free survival (PFS; P = .052 and P = .03, respectively). The OS or PFS were similar between patients who received and did not receive chemotherapy (P = .44 and P = .28, respectively).
Most patients with breast implant–associated ALCL who had disease confined within the fibrous capsule achieved complete remission. Proper management for these patients may be limited to capsulectomy and implant removal. Patients who present with a mass have a more aggressive clinical course that may be fatal, justifying cytotoxic chemotherapy in addition to removal of implants.
PMCID: PMC4062709  PMID: 24323027
2.  Improved Detection and Characterization of Paroxysmal Nocturnal Hemoglobinuria Using Fluorescent Aerolysin 
Paroxysmal nocturnal hemoglobinuria (PNH) is caused by a somatic mutation in the gene PIGA, which encodes an enzyme essential for the synthesis of glycosylphosphatidylinositol (GPI) anchors. The PIGA mutation results in absence or marked deficiency of more than a dozen proteins on PNH blood cells. Current flow cytometric assays for PNH rely on the use of labeled antibodies to detect deficiencies of specific GPI anchor proteins, such as CD59. However, because no single GPI anchor protein is always expressed in all cell lineages, no one monoclonal antibody can be used with confidence to diagnose PNH. We describe a new diagnostic test for PNH, based on the ability of a fluorescently labeled inactive variant of the protein aerolysin (FLAER) to bind selectively to GPI anchors. We compared GPI anchor protein expression in 8 patients with PNH using FLAER and anti-CD59. In all cases, FLAER detected similar or higher proportions of PNH monocytes and granulocytes compared with anti-CD59. Because of the increased sensitivity of detection, FLAER could detect small abnormal granulocyte populations in patients to a level of about 0.5%; samples from healthy control subjects contained substantially fewer FLAER-negative cells. FLAER gives a more accurate assessment of the GPI anchor deficit in PNH.
PMCID: PMC4124633  PMID: 10989647
Paroxysmal nocturnal hemoglobinuria; Aerolysin; GPI anchor proteins; CD59; Aplastic anemia
3.  Nodal involvement by marginal zone B-cell lymphoma harboring t(14;22)(q32;q11) involving immunoglobulin heavy chain and light chain lambda as the sole karyotypically recognizable abnormality in a patient with systemic lupus erythematosus 
Recurrent non-random balanced chromosomal translocation, usually involving the immunoglobulin heavy chain (IgH) gene or an immunoglobulin light chain gene and a proto-oncogene, which results in the overexpression of the latter under the control of an enhancer or promoter of the former, is a hallmark of many types of non-Hodgkin lymphoma (NHL) of B-cell origin. However, translocations between IgH and the immunoglobulin (Ig) light chain lambda gene (IgL), namely, a t(14;22)(q32;q11), have rarely been described in B-cell NHL. Herein we report the first case of marginal zone B-cell lymphoma harboring a t(14;22)(q32;q11) as its sole genetic abnormality in a patient with a 12-year history of systemic lupus erythematosus (SLE). Other interesting findings of this case include: 1) the neoplastic B-cells lack expression of both surface and cytoplasmic Ig light chain as revealed by flow cytometry and 2) monoclonal rearrangement of Ig light chain kappa (IgK) only due to k-deleting element (kde) recombination event. This case illustrates the necessity of utilizing a multi-modality approach in the diagnosis of B-cell NHL.
PMCID: PMC4152091  PMID: 25197401
t(14;22)(q32;q11); K-deleting element; marginal zone B-cell lymphoma; systemic lupus erythematosus
4.  Systemic mastocytosis with associated myeloproliferative neoplasm with t(8;19)(p12;q13.1) and abnormality of FGFR1: report of a unique case 
Systemic mastocytosis is a neoplastic proliferation of mast cells that frequently presents with associated clonal hematological non-mast cell lineage disease. Myeloid and lymphoid neoplasms with abnormalities of the FGFR1 gene are a heterogenous group of rare and aggressive hematopoietic stem cell disorders. About a dozen of chromosome changes involving the FGFR1 gene, presenting as myeloid or lymphoid neoplasms, have been described in the literature. To date, only 2 cases of myeloid and lymphoid neoplasms with abnormalities of the FGFR1 gene have been reported in association with systemic mastocytosis, one with t(8;13) and one with t(8;17) involving the FGFR1 gene. Here we describe another case of myeloproliferative neoplasm with chromosome translocation t(8;19) involving FGFR1 gene associated with systemic mastocytosis.
PMCID: PMC3925931  PMID: 24551307
Myeloproliferative neoplasm; systemic mastocytosis associated with clonal hematological non-mast cell lineage disease; FGFR1; eosinophilia
5.  HER2-associated radiation resistance of breast cancer stem cells isolated from HER2-negative breast cancer cells 
To understand the role of HER2-associated signaling network in breast cancer stem cells (BCSCs); using radiation-resistant breast cancer cells and clinical recurrent breast cancers to evaluate HER2-targeted therapy as a tumor eliminating strategy for recurrent HER2−/low breast cancers.
Experimental Design
HER2-expressing BCSCs (HER2+/CD44+/CD24−/low) were isolated from radiation-treated breast cancer MCF7 cells and in vivo irradiated MCF7 xenograft tumors. Tumor aggressiveness and radiation resistance were analyzed by gap filling, Matrigel invasion, tumor-sphere formation, and clonogenic survival assays. The HER2/CD44 feature was analyzed in 40 primary and recurrent breast cancer specimens. Protein expression profiling in HER2+/CD44+/CD24−/low versus HER2−/CD44+/CD24−/low BCSCs was conducted with 2-D DIGE and HPLC-MS/MS analysis and HER2-mediated signaling network was generated by MetaCore™ program.
Compared to HER2-negative BCSCs, HER2+/CD44+/CD24−/low cells showed elevated aldehyde dehydrogenase (ALDH) activity and aggressiveness tested by matrigel invasion, tumor sphere formation and in vivo tumorigenesis. The enhanced aggressive phenotype and radioresistance of the HER2+/CD44+/CD24−/low cells were markedly reduced by inhibition of HER2 via siRNA or Herceptin treatments. Clinical breast cancer specimens revealed that cells co-expressing HER2 and CD44 were more frequently detected in recurrent (84.6%) than primary tumors (57.1%). In addition, 2-D DIGE and HPLC-MS/MS of HER2+/CD44+/CD24−/low versus HER2−/CD44+/CD24−/low BCSCs reported a unique HER2-associated protein profile including effectors involved in tumor metastasis, apoptosis, mitochondrial function and DNA repair. A specific feature of HER2-STAT3 network was identified.
This study provides the evidence that HER2-mediated pro-survival signaling network is responsible for the aggressive phenotype of breast cancer stem cells that could be targeted to control the therapy-resistant HER2−/low breast cancer.
PMCID: PMC3593096  PMID: 23091114
6.  Synergistic suppression of noscapine and conventional chemotherapeutics on human glioblastoma cell growth 
Acta Pharmacologica Sinica  2013;34(7):930-938.
Noscapine (NOS) is a non-narcotic opium alkaloid with anti-tumor activity. The aim of this study was to investigate the effects of the combination of NOS with conventional chemotherapeutics temozolamide (TMZ), bis-chloroethylnitrosourea (BCNU), or cisplatin (CIS)on human glioblastoma cells.
U87MG human glioblastoma cells were examined. Cell proliferation was quantified using MTT assay. Western blotting and flow cytometry were used to examine apoptosis and the expression of active caspase-3 and cleaved PARP. Mouse tumor xenograft model bearing U87MG cells was treated with TMZ (2 mg·kg−1·d−1, ip) or CIS (2 mg/kg, ip 3 times a week) alone or in combination with NOS (200 mg·kg−1·d−1, ig) for 3 weeks. Immunohistochemistry was used to investigate the expression of active caspase-3 and Ki67 following treatment in vivo. The safety of the combined treatments was evaluated based on the body weight and histological studies of the animal's organs.
NOS (10 or 20 mol/L) markedly increased the anti-proliferation effects of TMZ, BCNU, and CIS on U87MG cells in vitro. The calculated combination index (CI) values of NOS-CIS, NOS-TMZ, and NOS-BCNU (20 μmol/L) were 0.45, 0.51, and 0.57, respectively, demonstrating synergistic inhibition of the drug combinations. In tumor xenograft models, combined treatment with NOS robustly augmented the anti-cancer actions of TMZ and CIS, and showed no detectable toxicity. The combined treatments significantly enhanced the apoptosis, the activated caspase-3 and PARP levels in U87MG cells in vitro, and reduced Ki67 staining and increased the activated caspase-3 level in the shrinking xenografts in vivo.
NOS synergistically potentiated the efficacy of FDA-approved anti-cancer drugs against human glioblastoma cells, thereby allowing them to be used at lower doses and hence minimizing their toxic side effects.
PMCID: PMC4002615  PMID: 23708557
glioblastoma; noscapine; temozolamide; bis-chloroethylnitrosourea; cisplatin; apoptosis; caspase-3; tumor xenograft model; drug synergism
7.  Erythroblastic Sarcoma Presenting as Bilateral Ovarian Masses in an Infant with Pure Erythroid Leukemia 
Human pathology  2011;42(5):749-758.
Pure erythroid leukemia is a rare subtype of acute erythroid leukemia that is characterized by a predominant erythroid population, and erythroblastic sarcoma has not yet been described in the English literature. Here we report a first case of erythroblastic sarcoma which presented as bilateral ovarian masses in a three and half month old baby girl with pure erythroid leukemia. Bone marrow aspirate and biopsy showed the marrow was completely replaced by large-sized blasts consistent with erythroblasts. Immunophenotypically, both the tumor cells from the ovarian mass and bone marrow blasts were positive for CD117, glycophorin A, and hemoglobin A, demonstrating erythroid differentiation. Reverse transcriptase polymerase chain reaction showed the tumor cells from ovarian mass expressed hemoglobin F and α1 spectrin, confirming their erythroid lineage. Conventional karyotype of the bone marrow aspirates revealed del(6) (q23q25) and trisomy 7 in all 21 cells examined. Fluorescence in situ hybridization of the ovarian mass demonstrated loss of C-MYB at 6q23 locus in 41% of the cells, and deletion of chromosome 7 and 7q in 37% and 66% of cells, respectively. Taken together, we showed, for the first time, that pure erythroid leukemia presented as a myeloid sarcoma in the form of ovarian masses.
PMCID: PMC3078188  PMID: 21237494
Pure erythroid leukemia; Acute erythroid leukemia; Myeloid sarcoma; C-MYB
8.  Sphincter-preserving surgery after preoperative radiochemotherapy for T3 low rectal cancers 
Oncology Letters  2012;3(6):1336-1340.
The aim of this study was to evaluate the feasibility and the effectiveness of preoperative radiochemotherapy followed by total mesorectal excision (TME) and sphincter-preserving procedures for T3 low rectal cancer. Patients with rectal cancer and T3 tumors located within 1–6 cm of the dentate line received preoperative radiochemotherapy. Concurrent 5-fluorouracil-based radiochemotherapy was used. Radical resection with TME and sphincter-preserving procedures were performed during the six to eight weeks following radiotherapy. Survival was analyzed using the Kaplan-Meier method. The anal function was evaluated using the Wexner score. The clinical response rate was 83.5%, overall downstaging of T classification was 75.3% and pathological complete response was 15.3%. The anastomotic fistula rate was 4.7%. A median follow-up of 30 months showed the local recurrence rate to be 4.7% and the distant metastasis rate to be 5.9%. The three-year overall survival rate was 87%. The degree of anal incontinence as measured using the Wexner score decreased over time, and the anal sphincter function in the majority of patients gradually improved. Preoperative radiochemotherapy was found to improve tumor downstaging, reduces local recurrence, increase the sphincter preservation rate, and is therefore of benefit to patients with T3 low rectal cancer.
PMCID: PMC3392564  PMID: 22783445
rectal cancer; preoperative radiochemotherapy; sphincter preservation
9.  Peripheral blood polyclonal plasmacytosis mimicking plasma cell leukemia in patients with angioimmunoblastic T-cell lymphoma: report of 3 cases and review of the literature 
Angioimmunoblastic T-cell lymphoma (AITL) is a unique type of peripheral T-cell lymphoma. Patients with AITL may have occasional reactive plasma cells present in the peripheral circulation. Prominent peripheral blood polyclonal plasmacytosis mimicking plasma cell leukemia, however, is distinctly uncommon. Here we describe 3 such cases from two large tertiary medical centers and discuss the role of ancillary studies in the differential diagnosis of peripheral blood plasmacytosis.
PMCID: PMC3093066  PMID: 21577327
Angioimmunoblastic T-cell lymphoma; peripheral blood; plasmacytosis; flow cytometric immunopheno-typing
11.  SAROTUP: Scanner and Reporter of Target-Unrelated Peptides 
As epitope mimics, mimotopes have been widely utilized in the study of epitope prediction and the development of new diagnostics, therapeutics, and vaccines. Screening the random peptide libraries constructed with phage display or any other surface display technologies provides an efficient and convenient approach to acquire mimotopes. However, target-unrelated peptides creep into mimotopes from time to time through binding to contaminants or other components of the screening system. In this study, we present SAROTUP, a free web tool for scanning, reporting and excluding possible target-unrelated peptides from real mimotopes. Preliminary tests show that SAROTUP is efficient and capable of improving the accuracy of mimotope-based epitope mapping. It is also helpful for the development of mimotope-based diagnostics, therapeutics, and vaccines.
PMCID: PMC2842971  PMID: 20339521
12.  An uncommon case of de novo CD10+ CD5− mantle cell lymphoma mimics follicle center B cell lymphoma 
Mantle cell lymphoma (MCL) is a mature B-cell lymphoma characterized by expression of CD5, overexpres-sion of Cyclin D1 as a result of chromosomal translocation t(11;14)(q13;q32), and poor prognosis. Cases of MCL lacking CD5 expression as well as cases with coexpression of CD5 and CD10 have also been reported. Here we describe an uncommon case of de novo MCL with expression of CD10, but not CD5, mimicking lymphoma of germinal center-derived B cells. The lymphoma cells in this case demonstrated a diffuse pattern of proliferation, and were strongly positive for Cyclin D1 by immunohistochemical stain. Fluorescence in situ hybridization studies demonstrated the presence of t(11;14)(q13;q32) involving BCL1, but not chromosomal translocations involving C-MYC or BCL2, confirming the diagnosis of MCL. This case further highlights the importance of comprehensive immunopheno-typic and genetic characterization in the diagnosis and classification of B-cell lymphomas.
PMCID: PMC2872749  PMID: 20490333
Mantle cell lymphoma; follicular lymphoma; germinal center B cell; CD10; CD5; BCL1; Cyclin D1; fluorescence in situ hybridization
13.  NF-κB-Mediated HER2 Overexpression in Radiation-Adaptive Resistance 
Radiation research  2009;171(1):9-21.
The molecular mechanisms governing acquired tumor resistance during radiotherapy remain to be elucidated. In breast cancer patients, overexpression of HER2 (human epidermal growth factor receptor 2) is correlated with aggressive tumor growth and increased recurrence. In the present study, we demonstrate that HER2 expression can be induced by radiation in breast cancer cells with a low basal level of HER2. Furthermore, HER2-postive tumors occur at a much higher frequency in recurrent invasive breast cancer (59%) compared to the primary tumors (41%). Interestingly, NF-κB is required for radiation-induced HER2 transactivation. HER2 was found to be co-activated with basal and radiation-induced NF-κB activity in radioresistant but not radiosensitive breast cancer cell lines after long-term radiation exposure, indicating that NF-κB-mediated HER2 overexpression is involved in radiation-induced repopulation in heterogeneous tumors. Finally, we found that inhibition of HER2 resensitizes the resistant cell lines to radiation. Since HER2 is shown to activate NF-κB, our data suggest a loop-like HER2-NF-κB-HER2 pathway in radiation-induced adaptive resistance in breast cancer cells.
PMCID: PMC2659759  PMID: 19138055
14.  Silicone implant and primary breast ALK1-negative anaplastic large cell lymphoma, fact or fiction? 
The safety of silicone-based implant for mammoplasty has been debated for decades. A series of anecdotal case reports and a recent epidemiological case-control study have suggested a possible association between silicone implant and the development of primary breast ALK1-negative anaplastic large cell lymphoma (ALCL), a rare type of peripheral T-cell lymphoma. In this report, we describe an additional case of primary breast ALK1-negative ALCL in the fibrous capsule and cystic fluid of silicone breast implant in a 58 year old woman who underwent breast reconstructive surgery after lumpectomy for her infiltrating breast adenocarcinoma. Morphologically and immunohistochemically, the lymphoma cells may be confused with recurrent infiltrating breast adenocarcinoma or other non-hematolymphoid malignancies. Molecular studies were needed to determine T-lineage differentiation of the malignant lymphoma cells. We will also review the case reports and case series published in the English literature and discuss our current understanding of silicone implant in primary breast ALK1-negative ALCL.
PMCID: PMC2776268  PMID: 19918336
Breast implant; silicone; anaplastic large cell lymphoma; ALK1; ALCL
15.  Anaplastic Lymphoma Kinase-Positive Large B-Cell Lymphoma: A Distinct Clinicopathological Entity 
Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) represents a distinct subtype of mature B-cell neoplasms in the most recent WHO classification of hematolymphoid neoplasms. It has a characteristic immunoblastic/plasmablastic morphology, a distinct immunophenotypic profile and recurrent cytogenetic/molecular genetic abnormalities, and has been reported in both the adult and pediatric populations. With the advent of new ALK inhibitors for possible targeted therapy clinical trials, it is important to recognize this new entity, particularly in the pediatric population because the prognosis is worse than the more common ALK+ anaplastic large cell lymphoma. Though rare, awareness of its existence will avoid potential misdiagnosis and facilitate appropriate management.
PMCID: PMC2713458  PMID: 19636398
Anaplastic lymphoma kinase; ALK; diffuse large B-cell lymphoma; t(2;17); CLTC/ALK
16.  Prognostic Significance of Flow Cytometric Immunophenotyping in Acute Myeloid Leukemia 
The prognostic significance of flow cytometric immunophenotyping (FCI) in acute myeloid leukemia (AML) has been controversial. In this study, we re-investigated the possible role of FCI in the prediction of AML relapse following standard chemotherapy. A total of 209 AML cases with follow-up information were analyzed. Among those, 78 cases were in remission (M:F=44/34; mean age of 48.9 years) and 131 had relapse (M:F=71/60; mean age of 51.3 years). The expression of CD34, HLA-DR or a combination of both was significantly different between the remission and relapse groups for all AML as well as AML without t(15;17). None of the pammyeloid markers or their combinations analyzed was found to correlate with treatment outcomes. Complex cytogenetic abnormalities were more likely associated with relapse group than with remission group, but were not statistically significant after excluding AML with t(15;17). In conclusion, FCI is useful in predicting treatment outcome and disease relapse in AML.
PMCID: PMC2480555  PMID: 18784805
Flow cytometric immunophenotyping; acute myeloid leukemia; acute promyelocytic leukemia; chromosome translocation; cytogenetics; prognosis
17.  Composite Small Lymphocytic Lymphoma and Extra-medullary Myeloid Tumor: A Potential Diagnostic Pitfall 
Reported herein is a case of composite small lymphocytic lymphoma (SLL) and extramedullary myeloid tumor (EMT) occurring in the same lymph node. Routine morphologic examination revealed a diffuse proliferation of small mature lymphocytes with numerous irregularly dispersed nodules, closely resembling SLL with prominent proliferation centers or Richter's transformation. Flow cytometric immunophenotyping and immunohistochemical stains demonstrated the presence of SLL cells as well as myeloblasts, confirming the diagnosis of a composite SLL and EMT. Conventional cytogenetics and fluorescence in situ hybridization studies revealed inversion 16 chromosome involving the core binding factor beta and myosin heavy chain 11 genes, characteristic of acute myeloid leukemia with abnormal bone marrow eosinophils and inv(16) or t(16;16) [CBFbeta/MYH11]. In conclusion, the occurrence of SLL and EMT in the same lymph node is rare and multiparameter approach is essential for a definitive diagnosis.
PMCID: PMC2480536  PMID: 18784827
Extramedullary myeloid tumor; small lymphocytic lymphoma; flow cytometric immunophenotyping; immunohistochemistry; karyotype; fluorescence in situ hybridization
19.  Regulated Expression of Human Histocompatibility Leukocyte Antigen (HLA)-DO During Antigen-dependent and Antigen-independent Phases of B Cell Development 
The Journal of Experimental Medicine  2002;195(8):1053-1062.
Human histocompatibility leukocyte antigen (HLA)-DO, a lysosomal resident major histocompatibility complex class II molecule expressed in B cells, has previously been shown to be a negative regulator of HLA-DM peptide loading function. We analyze the expression of DO in human peripheral blood, lymph node, tonsil, and bone marrow to determine if DO expression is modulated in the physiological setting. B cells, but not monocytes or monocyte-derived dendritic cells, are observed to express this protein. Preclearing experiments demonstrate that ∼50% of HLA-DM is bound to DO in peripheral blood B cells. HLA-DM and HLA-DR expression is demonstrated early in B cell development, beginning at the pro-B stage in adult human bone marrow. In contrast, DO expression is initiated only after B cell development is complete. In all situations, there is a striking correlation between intracellular DO expression and cell surface class II–associated invariant chain peptide expression, which suggests that DO substantially inhibits DM function in primary human B cells. We report that the expression of DO is markedly downmodulated in human germinal center B cells. Modulation of DO expression may provide a mechanism to regulate peptide loading activity and antigen presentation by B cells during the development of humoral immune responses.
PMCID: PMC2193689  PMID: 11956296
antigen presentation; B cell development; germinal center; HLA-DM; HLA-DO

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