Soon-Thye Lim

The relationship of hepatitis B virus infection and non‐Hodgkin’s lymphoma and its impact on clinical characteristics and prognosis

Aim of the study:  This study aims to evaluate the association between hepatitis B virus (HBV) and lymphoma and to characterize HBV‐related lymphomas. The efficacy of prophylactic lamivudine on HBV reactivation was also evaluated.

Type II enteropathy-associated T-cell lymphoma: a multicenter analysis from the Asia Lymphoma Study Group.

Enteropathy‐associated T‐cell lymphoma (EATL) is a rare primary gastrointestinal T‐cell lymphoma. A multicenter study from the Asia Lymphoma Study Group identified 38 EATL patients within a 19‐year period. All cases were type II EATL. Men were affected twice as common as women, at a median age of 59 (23–89) years. None had a history of celiac disease. The sites of involvement were small bowel and stomach (5%), small bowel (63%), small and large bowel (16%), and large bowel (18%). Common presenting features were bowel perforation (34%), pain (32%), and obstruction (21%). Lymphomas showed monomorphic neoplastic lymphoid infiltrates that were CD3+ (100%), CD56+ (91%), TIA‐1+ (96%), CD4–CD8+ (63%), CD4+CD8+ (19%), CD4–CD8– (16%), and CD4+CD8– (3%). Epstein Barr virus was demonstrable in three cases. Despite chemotherapy and/or surgical resection, the overall response and complete response rates were poor at 46% and 38%. The median overall survival (OS) was 7 months and progression‐free‐survival (PFS) 1 month. Five patients underwent hematopoietic stem cell transplantation all were alive. Age and the prognostic index for peripheral T‐cell lymphoma were not prognostically significant. Good performance status was associated with better OS (P = 0.03), and response to initial treatment led to better OS and PFS (P < 0.001). Am. J. Hematol. 87:663–668, 2012.

Breast Lymphoma: Favorable Prognosis after Treatment with Standard Combination Chemotherapy

Purpose: This paper is to determine the clinicopathological features and outcome of patients with breast lymphoma seen at a single institution. Patients and Methods: We have reviewed data on 14 patients with breast lymphoma seen at our institution from 1990 to 2003. Results: All patients were female, with a median age of 47.6 years. Diffuse large B-cell lymphoma (DLBCL) was observed in 9 cases, while follicular, Burkitt’s, small lymphocytic, MALT and T-cell lymphoma were observed in 1 case each. 5 patients (35.7%) had stage IE disease, 6 patients (42.9%) had stage IIE disease and 3 patients (21.4%) had stage IV disease. Standard CHOP with or without rituximab was given to all patients with aggressive breast lymphoma (n = 10), while 1 patient with Burkitt’s lymphoma received a CHOP-based regimen. The 3-year actuarial survival estimate among all 11 patients with aggressive breast lymphoma was 73%. Among those with localized disease, the estimated 3-year survival was 90%. The actuarial 3-year overall survival (OS) estimate for the entire cohort of 14 patients was 76.9%. Conclusion: Our results indicate that breast lymphoma is not associated with an inferior outcome when treated with standard CHOP-based chemotherapy.

Relevance of the International Prognostic Index in the Rituximab Era

TO THEEDITOR:Wereadwithinterestthismeta-anaylsisbyZiepert etal 1 involving1,062patientswithdiffuselargeB-celllymphomaaccrued fromthreeprospectivephaseII/IIItrials:MinT(Mab-TheraInternational Trial), RICOVER-60 (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab [R-CHOP] for patients older than age 60 years),andMegaCHOEP(dose-escalatedregimenofcyclophosphamide, doxorubicin,vincristine,etoposide,andprednisone)trials. 2-4 Theauthors affirms the prognostic relevance of the International Prognostic Index (IPI)scoreforallthreeendpointsofprogression-freesurvival,event-free survival,andoverallsurvival.Thus,theyconcludedthatIPIshouldremain the major tool for risk stratification for patients with diffuse large B-cell lymphoma in the era of rituximab. WhileweagreewithZiepertetal 1 thattheIPIwillremainanimpor

Multicenter study of comparative outcomes of hematopoietic stem cell transplant for peripheral T cell lymphoma and natural killer/T-cell lymphoma

Department of Haematology, Singapore General Hospital, Singapore, Duke-NUS Graduate Medical School, Singapore, Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, National Cancer Centre, Singapore, Department of Haematology, St George’s Hospital and Medical School, London, UK, Department of Clinical Research, Singapore General Hospital, Singapore, and Singapore Clinical Research Institute, Singapore

An Epstein-Barr virus positive natural killer lymphoma xenograft derived for drug testing

Natural killer (NK) lymphomas occurring more frequently in the Far East and South America respond poorly to anthracycline-based regimens. Here we report an in vivo NK lymphoma xenograft (NK-S1) derived from the testicular metastasis of a patient with an extranodal NK lymphoma (nasal type). The NK-S1 xenograft, established in severe combined immune deficient (SCID) mice retained the same imunophenotypic features as the original tumor. NK-S1 disseminated intra-abdominally to the testis, intestine and liver. Although doxorubicin, rapamycin, bevacizumab, rapamycin-doxorubicin, and bevacizumab-doxorubicin had no effects on the growth of subcutaneous NK-S1 xenografts, intraperitoneal (IP) delivery of cyclophosphamide caused complete tumor regression; this tumor regression was associated with apoptosis, upregulation of activated caspase-3, and cleaved Poly(ADP-ribose) polymerase (PARP). In an IP model of NK lymphoma, cyclophosphamide also prolonged the survival of mice and potently inhibited tumor dissemination and ascites formation. Our data suggest that the NK-S1 xenograft is a useful tool for screening preclinical drugs, and cyclophosphamide may be a useful drug for the treatment of this disease.

EBV-associated primary nodal T/NK-cell lymphoma shows distinct molecular signature and copy number changes.

The molecular biology of primary nodal T- and NK-cell lymphoma and its relationship with extranodal NK/T-cell lymphoma, nasal type is poorly understood. In this study, we assessed the relationship between nodal and extranodal Epstein-Barr virus-positive T/NK-cell lymphomas using gene expression profiling and copy number aberration analyses. We performed gene expression profiling and copy number aberration analysis on 66 cases of Epstein-Barr virus-associated T/NK-cell lymphoma from nodal and extranodal sites, and correlated the molecular signatures with clinicopathological features. Three distinct molecular clusters were identified with one enriched for nodal presentation and loss of 14q11.2 (TCRA loci). T/NK-cell lymphomas with a nodal presentation (nodal-group) were significantly associated with older age, lack of nasal involvement, and T-cell lineage compared to those with an extranodal presentation (extranodal-group). On multivariate analysis, nodal presentation was an independent factor associated with short survival. Comparing the molecular signatures of the nodal and extranodal groups it was seen that the former was characterized by upregulation of PD-L1 and T-cell-related genes, including CD2 and CD8, and downregulation of CD56, consistent with the CD8+/CD56-immunophenotype. PD-L1 and CD2 protein expression levels were validated using multiplexed immunofluorescence. Interestingly, nodal group lymphomas were associated with 14q11.2 loss which correlated with loss of TCR loci and T-cell origin. Overall, our results suggest that T/NK-cell lymphoma with nodal presentation is distinct and deserves to be classified separately from T/NK-cell lymphoma with extranodal presentation. Upregulation of PD-L1 indicates that it may be possible to use anti-PD1 immunotherapy in this distinctive entity. In addition, loss of 14q11.2 may be a potentially useful diagnostic marker of T-cell lineage.

Use of rituximab in combination with high-dose methotrexate in the treatment of primary central nervous system lymphoma in a mycophenolate mofetil treated patient with lupus nephritis

Several studies have suggested that immunosuppression and several autoimmune and chronic infl ammatory conditions such as rheumatoid arthritis (RA), Sj ö gren’s syndrome (SS) and systemic lupus erythematosus (SLE), are associated with an increased risk of developing malignant lymphomas [1]. While NHL developing in patients with rheumatoid arthritis and Sj ö gren’s syndrome has been fairly well described [2 – 5], NHL developing in patients with SLE is much less common and understood. A 20-year-old female with a history of lupus nephritis on MMF presented following a seizure. She was diagnosed with stage 1 PCNSL, and was started on Rituximab, Methotrexate, Vincristine and Procarbazine. She developed status epilepticus and recurrent seizures during the seventh cycle. MRI brain showed disease progression, and treatment was changed to two courses of salvage CYVE chemotherapy (Cytarabine, Etoposide). She attained near complete remission and went on to receive high-dose Thiotepa, Busulfan, and Cyclophosphamide with autologous peripheral stem-cell rescue (APSCR). She experienced numerous infective complications while receiving salvage CYVE chemotherapy. These included grade IV neutropaenic fever, fungaemia ( Candida glabrata) and septicaemia (Methicillinresistant Staphyloccocal aureus , Klebsiella pneumoniae ). On day 1 of APSCR, the patient developed grade IV hypertension and altered mental state. An urgent CT brain showed the classical appearance of posterior

The C-ErbAβ Thyroid Hormone Receptor Expression and cDNA sequence analysis of the hormone-binding domain in human cancer cell lines

The human c-erbAβ protooncogene encodes a thyroid hormone receptor (comprising a hormone-binding domain and a DNA-binding domain) which modulates expression of specific genes, such as cell differentiation genes. Using the reverse transcription and polymerase chain reaction (RT-PCR) assay, significant expression of the c-erbAβ gene was detected in the SiHa, CaSki, HeLa cervical carcinoma; Hep3B, PLC/PRF/5, Mahlavu hepatocellular carcinoma; HT-1080 fibrosarcoma cell lines; as well as in normal MRC-5 embryo lung and FS-4 foreskin fibroblast cell lines. However, the Molt-4 leukaemia and Raji Burkitts lymphoma cell lines exhibited very low levels of c-erbAβ expression. Single-strand conformation polymorphism analysis and direct sequencing of PCR products of the c-erbAβ hormone-binding domain cDNAs of these cell lines revealed identical sequences, but differed from the published human placental c-erbAβ sequence by five single base disparities. Sequencing of an aberrant fragment fortuitously amplified from the ...

Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma

Mature T-cell lymphomas, including peripheral T-cell lymphoma (PTCL) and extranodal NK/T-cell lymphoma (NKTL), represent a heterogeneous group of non-Hodgkin lymphomas with dismal outcomes and limited treatment options. To determine the extent of involvement of the JAK/STAT pathway in this malignancy, we performed targeted capture sequencing of 188 genes in this pathway in 171 PTCL and NKTL cases. A total of 272 nonsynonymous somatic mutations in 101 genes were identified in 73% of the samples, including 258 single-nucleotide variants and 14 insertions or deletions. Recurrent mutations were most frequently located in STAT3 and TP53 (15%), followed by JAK3 and JAK1 (6%) and SOCS1 (4%). A high prevalence of STAT3 mutation (21%) was observed specifically in NKTL. Novel STAT3 mutations (p.D427H, E616G, p.E616K, and p.E696K) were shown to increase STAT3 phosphorylation and transcriptional activity of STAT3 in the absence of cytokine, in which p.E616K induced programmed cell death-ligand 1 (PD-L1) expression by robust binding of activated STAT3 to the PD-L1 gene promoter. Consistent with these findings, PD-L1 was overexpressed in NKTL cell lines harboring hotspot STAT3 mutations, and similar findings were observed by the overexpression of p.E616K and p.E616G in the STAT3 wild-type NKTL cell line. Conversely, STAT3 silencing and inhibition decreased PD-L1 expression in STAT3 mutant NKTL cell lines. In NKTL tumors, STAT3 activation correlated significantly with PD-L1 expression. We demonstrated that STAT3 activation confers high PD-L1 expression, which may promote tumor immune evasion. The combination of PD-1/PD-L1 antibodies and STAT3 inhibitors might be a promising therapeutic approach for NKTL, and possibly PTCL.