PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase.

Natural killer (NK)/T-cell lymphomas failing L-asparaginse regimens have no known salvage and are almost invariably fatal. Seven male patients with NK/T-cell lymphoma (median age, 49 years; range, 31-68 years) for whom a median of 2 (range, 1-5) regimens (including l-asparaginase regimens and allogeneic hematopoietic stem-cell transplantation [HSCT] in 2 cases) failed were treated with the anti-programmed death 1 (PD1) antibody pembrolizumab. All patients responded, according to various clinical, radiologic (positron emission tomography), morphologic, and molecular (circulating Epstein-Barr virus [EBV] DNA) criteria. Two patients achieved complete response (CR) in all parameters. Three patients achieved clinical and radiologic CRs, with two having molecular remission (undetectable EBV DNA) but minimal EBV-encoded RNA-positive cells in lesions comprising predominantly CD3+CD4+ and CD3+CD8+ T cells (which ultimately disappeared, suggesting they represented pseudoprogression) and one having detectable EBV DNA despite morphologic CR. Two patients achieved partial response (PR). After a median of 7 (range, 2-13) cycles of pembrolizumab and a follow-up of a median of 6 (range, 2-10) months, all five CR patients were still in remission. The only adverse event was grade 2 skin graft-versus-host disease in one patient with previous allogeneic HSCT. Expression of the PD1 ligand was strong in 4 patients (3 achieving CR) and weak in 1 (achieving PR). PD1 blockade with pembrolizumab was a potent strategy for NK/T-cell lymphomas failing l-asparaginase regimens.

Receptor-type tyrosine-protein phosphatase κ directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma.

Nasal-type natural killer/T-cell lymphoma (NKTCL) is an aggressive disease characterized by frequent deletions on 6q, and constitutive activation of signal transducer and activator of transcription 3 (STAT3). Phosphorylation at Tyr705 activates STAT3, inducing dimerization, nuclear translocation, and DNA binding. In this study, we investigated whether receptor-type tyrosine-protein phosphatase κ (PTPRK), the only protein tyrosine phosphatase at 6q that contains a STAT3-specifying motif, negatively regulates STAT3 activation in NKTCL. PTPRK was highly expressed in normal NK cells but was underexpressed in 4 of 5 (80%) NKTCL cell lines and 15 of 27 (55.6%) primary tumors. Significantly, PTPRK protein expression was inversely correlated with nuclear phospho-STAT3(Tyr705) expression in NKTCL cell lines (P = .025) and tumors (P = .040). PTPRK restoration decreased nuclear phospho-STAT3(Tyr705) levels, whereas knockdown of PTPRK increased such levels in NKTCL cells. Phosphatase substrate-trapping mutant assays demonstrated the binding of PTPRK to STAT3, and phosphatase assays showed that PTPRK directly dephosphorylated phospho-STAT3(Tyr705). Restoration of PTPRK inhibited tumor cell growth and reduced the migration and invasion ability of NKTCL cells. Monoallelic deletion and promoter hypermethylation caused underexpression of PTPRK messenger RNA in NKTCL, and methylation of the PTPRK promoter significantly correlated with inferior overall survival (P = .049) in NKTCL patients treated with the steroid-dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide regimen. Altogether, our findings show that PTPRK underexpression leads to STAT3 activation and contributes to NKTCL pathogenesis.

Successful treatment of intraocular post-transplant lymphoproliferative disorder with intravenous rituximab.

We reported a rare case of intraocular post-transplant lymphoproliferative disorder (PTLD) arising in a 3-year-old liver transplant recipient who had a prior history of systemic PTLD. The first PTLD entered remission after treatment with intravenous rituximab and withdrawal of immunosuppressants. One year after remission, she presented with granulomatous uveitis and iris nodules in the right eye. Iris biopsy confirmed recurrence of intraocular PTLD, which resolved completely after a second course of intravenous rituximab.

Breakthrough invasive fungal diseases during echinocandin treatment in high-risk hospitalized hematologic patients.

The frequency of breakthrough invasive fungal diseases (IFDs) during echinocandin therapy is unclear. We retrospectively analyzed 534 hematologic patients treated with echinocandin (caspofungin, N = 55; micafungin, N = 306; anidulafungin, N = 173). Four proven IFDs were found, caused by Candida parapsilosis (N = 2), C. parapsilosis and Candida glabrata (N = 1), and Fusarium species (N = 1). Four cases of possible IFDs were observed, all showing pulmonary infection. One case showed features suggestive of hepatosplenic candidiasis. Six of these eight cases had previously received the purine analog clofarabine. Breakthrough IFD during echinocandin treatment occurred infrequently (1.5 %), caused predominantly by Candida species. Clofarabine usage was an important risk factor.

Endobronchial ultrasound-guided transbronchial needle aspiration in lung cancer: the first experience in Hong Kong.

OBJECTIVE: To investigate the diagnostic performance and safety of endobronchial ultrasound-guided transbronchial needle aspiration in patients presenting with radiological features of lung cancer. DESIGN: Prospective case series. SETTING: University teaching hospital, Hong Kong. PATIENTS: Consecutive patients with mediastinal or hilar abnormalities suspected of or confirmed as having lung cancer underwent endobronchial ultrasound-guided transbronchial needle aspiration and presented between August 2006 and December 2010. MAIN OUTCOME MEASURES: Diagnostic performance (including sensitivity, specificity, negative predictive value and accuracy), procedural complications, and tissue adequacy for molecular profiling. RESULTS: A total of 269 procedures were performed in 259 patients, with malignancy confirmed in 210 (81%) of them. In the whole cohort with confirmed or suspected lung cancer, the overall sensitivity, specificity, negative predictive value, and accuracy of endobronchial ultrasound-guided transbronchial needle aspiration were 87%, 100%, 74%, and 91%, respectively. Among 42 patients with tumour samples sent for mutation tests (epidermal growth factor receptor and/or anaplastic lymphoma kinase), 40 (95%) were found to be adequate. No complication or mortality ensued from these procedures. CONCLUSION: Endobronchial ultrasound-guided transbronchial needle aspiration is highly effective in determining the diagnosis and lymph node staging in patients with lung cancer. In combination with its excellent safety profile, it should be considered a frontline diagnostic test for patients presenting with mediastinal abnormalities suspicious of lung cancer.

Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is often challenging to diagnose and classify. Gene expression profiling was performed on 144 cases of PTCL and natural killer cell lymphoma and robust molecular classifiers were constructed for angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase-positive (ALK(+)) anaplastic large-cell lymphoma (ALCL), and adult T-cell leukemia/lymphoma. PTCL-unclassifiable was molecularly heterogeneous, but we were able to identify a molecular subgroup with features of cytotoxic T lymphocytes and a poor survival compared with the remaining PTCL-not otherwise specified cases. Many of the pathologic features and substantial components of the molecular signature of AITL are contributed by the follicular dendritic cells, B-cell, and other stromal components. The expression of Th17-associated molecules in ALK(+) ALCL was noted and may represent aberrant activation of Th17-cell differentiation by abnormal cytokine secretion. Adult T-cell leukemia/lymphoma has a homogeneous molecular signature demonstrating high expression of human T-lymphotropic virus type 1-induced genes. These classifiers reflect the biology of the tumor cells as well as their microenvironment. We also constructed a molecular prognosticator for AITL that appears to be largely related to the microenvironmental signature, and the high expression of 2 immunosuppressive signatures are associated with poor outcome. Oncogenic pathways and tumor-host interactions also were identified, and these findings may lead to better therapies and outcome in the future.

CD44 activation in mature B-cell malignancies by a novel recurrent IGH translocation.

Using inverse polymerase chain reaction, we identified CD44, located on chromosome 11p13, as a novel translocation partner of IGH in 9 of 114 cases of gastric, nongastric extranodal, follicular, and nodal diffuse large B-cell lymphoma (DLBCL). Notably, these translocations involving IGHSmu were detected in follicular lymphomas and exclusively in germinal center B cell-ike (GCB)-DLBCLs. CD44 is not expressed in reactive GC B cells. The IGHSmu/CD44 translocations substitute Smu for the CD44 promoter and remove exon 1 of CD44, resulting in the overexpression of Imu-CD44 hybrid mRNA transcripts activated from derivative 11 that encode a new CD44 variant lacking the leader peptide and with a unique C-terminus (CD44DeltaEx1). When overexpressed in vitro in the CD44(-) GCB-DLBCL cell line BJAB, CD44DeltaEx1-green fluorescent protein localized to the cytoplasm and nucleus, whereas CD44s-green fluorescent protein (standard form) localized to the plasma membrane. The ectopic expression of CD44DeltaEx1 in BJAB cells enhanced their proliferation rate and clonogenic ability, indicating a possible pathogenic role of the translocation.

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).

Post-transplant lymphoproliferative diseases in Asian solid organ transplant recipients: late onset and favorable response to treatment.

Nineteen consecutive patients with post-transplant lymphoproliferative disorders (PTLD) in an Asian population were reviewed. The histopathologic diagnoses were monomorphic (CD20-positive diffuse large B-cell lymphoma, n = 14); plasmacytic (n = 1); Burkitt-like (n = 1); natural killer cell lymphoma (n = 1); lymphomatoid papulosis (n = 1); and classical Hodgkin lymphoma (n = 1). Early-onset (

Utility of FDG PET/CT in the assessment of myeloid sarcoma.

OBJECTIVE: Myeloid sarcoma (MS) is a rare extramedullary manifestation of acute myeloid leukemia that often presents during remission or disease relapse. With awareness of this clinical entity and the appropriate clinical history, MS can be detected despite its nonspecific radiologic features. CONCLUSION: This article highlights the utility of (18)F-FDG PET/CT, which has high sensitivity in detecting early MS and provides a systemic overview of tumor burden, and its potential role in monitoring of treatment response.

Serum ceruloplasmin monitoring in a case of silver intoxication due to intravenous silver infusion.

INTRODUCTION: Colloidal silver packaged as a dietary supplement is readily available online and is thought to be safe. Literature describing its toxicity in humans is scarce. CASE REPORT: A 47-year-old man presented to us for sensory and gait problems. He had unremarkable past health except dystrophic nails. He further volunteered a history of receiving chronic oral and intravenous administration of colloidal silver. We confirmed his plasma silver was 1200-fold elevated, measuring 11990 nmol/L (normal < 10 nmol/L). He had deranged liver function tests, and liver biopsy showed distorted acinar architecture, bridging fibrosis and lymphocytic infiltrate with silver particles clustering along the vascular endothelium and portal venules. Brain magnetic resonance imagining showed features of mineralization over bilateral globus pallidi. There was biochemical evidence of central adrenal insufficiency, intracellular iron overload and hypoceruloplasminemia (<0.05 g/L). Gradual clinical and biochemical improvement was noted after silver cessation: his plasma silver dropped to 4800 nmol/L (3 months) and 1650 nmol/L (12 months), and serum ceruloplasmin reverted to 0.13 g/L (10 months) and 0.29 g/L (20 months). CONCLUSIONS: The potential effects of silver to liver and copper metabolism were shown in this case. Serum ceruloplasmin also serves as a surrogate marker in monitoring silver intoxication.

Non-gastric marginal zone B cell lymphoma: clinicopathologic features and treatment results.

The optimal treatment strategy and outcome of non-gastric marginal zone lymphoma (MZL) remains undefined. The role of rituximab and fludarabine in MZL has not been critically appraised and compared with conventional chemotherapy. We retrospectively analyzed 81 consecutive patients with non-gastric MZL (mucosa-associated lymphoid tissue lymphoma, n=66; splenic MZL, n=11; nodal MZL, n=4). As a group, the treatment results were favorable, with an overall response rate of 87% and a complete response (CR) rate of 73%. The CR rate was similar for conventional chemotherapy, and rituximab- and fludarabine-containing regimens. However, the relapse rate was significantly decreased in rituximab- and fludarabine-containing regimens. The use of rituximab and fludarabine was associated with acceptable side effects. For splenic MZL, splenectomy was significantly associated with a superior CR rate. Early stage, good performance status, and low international prognostic index risk scores significantly impacted on CR rate and survivals. Rituximab and fludarabine were safe for non-gastric MZL and resulted in more durable remissions.

Diffuse large B-cell lymphoma associated with chronic inflammation as an incidental finding and new clinical scenarios.

Diffuse large B-cell lymphoma that develops in the setting of long-standing chronic inflammation is typically associated with Epstein-Barr virus, and usually presents as tumor mass involving body cavities, as in pyothorax-associated lymphoma. It is listed as a distinct entity in the latest World Health Organization lymphoma classification. We report four cases that were incidentally discovered on histologic examination, one each in a splenic false cyst, a long-standing hydrocele, an atrial myxoma, and metallic-implant wear debris. Microscopic foci of atypical (neoplastic) large lymphoid cells were found within the contents of the cysts or curettage material, or within the stroma of the atrial myxoma. Despite the diverse clinical scenarios, all cases showed a homogeneous phenotype: positivity for B-lineage markers (CD20+, CD79a+, PAX5+), non-germinal center immunophenotype (CD10-, BCL6-/+, MUM-1+), and positivity for Epstein-Barr virus with type III latency (LMP1+, EBNA2+). The last feature supports the hypothesis that the lymphoma has arisen in a setting of 'local immunodeficiency' as a result of long-standing chronic inflammation in an enclosed space, a characteristic pathogenetic mechanism of diffuse large B-cell lymphoma associated with chronic inflammation. These cases therefore expand the spectrum of this entity to include new clinical scenarios for the development of this lymphoma type.

Coexistence of paternally-inherited ABCC8 mutation and mosaic paternal uniparental disomy 11p hyperinsulinism.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome with variable clinical phenotype and complex molecular aetiology. It is mainly caused by dysregulation of the chromosome 11p15 imprinted region, which results in overgrowth in multiple tissues, often in a mosaic manner. CASE PRESENTATION: A large-for-gestational-age infant without any other somatic features of BWS presented with medically refractory hyperinsulinism (HI) requiring 80% pancreatectomy. Next generation sequencing with congenital HI sequencing panel identified a pathogenic ABCC8:c.1792C > T (p.Arg598Ter) variant of paternal origin, suggestive of focal HI. However, pancreatic histology revealed atypical findings of coalescing nests and trabeculae of adenomatosis scattered with islets with isolated enlarged, hyperchromatic nuclei scattered throughout the pancreas. Methylation analysis, SNP-based chromosomal microarray and short tandem repeat markers analysis revealed mosaic segmental paternal uniparental disomy (UPD) 11p15.5-p15.1 in the pancreatic tissue, but not the peripheral blood, suggestive of BWS/BW-spectrum HI. CONCLUSIONS: This case highlights the importance of integrating the clinical presentation and subsequent clinical course, together with radiological, genetic and histological findings in the definitive diagnosis of this rare yet clinically important entity. In addition, this is the first report that demonstrated the level of paternal inherited c.1792 T pathogenic variant in the pancreatic tissue being directly correlated to the mosaic level of pUPD.