Pre-treatment [18F]FDG PET/CT for assessing bone marrow involvement and prognosis in patients with newly diagnosed peripheral T-cell lymphoma.

PURPOSE: To explore the value of [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in assessing bone marrow involvement (BMI) and prognosis in newly diagnosed peripheral T-cell lymphomas (PTCLs) before treatment. METHODS: This retrospective study included 201 eligible PTCLs who received pre-bone marrow biopsy (BMB) and PET/CT. The status of bone marrow (BM) by PET was assessed using a visual examination and a quantitative index (the maximal standardized uptake value [SUVmax] of BM divided by the SUVmax of the liver [M/L]). RESULTS: Totally 148 patients had no evidence of BMI by PET or BMB; BMI was detected by both methods in 16 patients. The sensitivity and specificity of PET/CT for patients with confirmed BMI by BMB were 43.2% and 90.2%, respectively (κ = 0.353). In addition, 25 patients assessed by PET/CT staging (having stage I to II disease) had no evidence of BMI detected by both PET/CT and BMB. Image-guided biopsy was also recommended when PET/CT showed a focal FDG uptake outside the iliac crest. Survival analysis revealed that BMB was significant for overall survival (OS) (P = 0.020) while M/L for both progression free survival (P = 0.002) and OS (P < 0.001). In multivariate analysis, M/L (HR 1.825, 95% CI 1.071-3.110, P = 0.027) was an independent prognostic factor for OS. There were no statistical differences at the genetic level about BMI confirmed by PET or BMB. CONCLUSION: PET/CT has a complementary role in assessing BMI and an ability to predict prognosis in PTCL patients.

Low T3 syndrome as a predictor of poor prognosis in peripheral T-cell lymphomas

Purpose The purpose of the study was to evaluate the prognostic value of low T3 syndrome in peripheral T-cell lymphomas (PTCLs). Methods One hundred and seventy-four patients of newly diagnosed PTCLs were enrolled in the study. We performed statistical analysis based on the clinical data collected. Results Thirty-Six (20.69%) patients had low T3 syndrome at first admission. Results suggested that the patients with higher score of ECOG PS, International Prognostic Index (IPI) and Prognostic Index for T-cell lymphoma (PIT), bone marrow involvement and lower level of albumin tended to develop low T3 syndrome. The median progression-free survival (PFS) and overall survival (OS) were 10 months and 36 months, respectively, for all patients. Pre-existing low T3 syndrome was in correlation with worse PFS and OS. Patients with low T3 syndrome showed worse PFS (4 months vs 13 months, P = 0.0001) and OS (7 months vs 83 months, P < 0.0001) than patients without low T3 syndrome. IPI and PIT, respectively, combined with low T3 syndrome improved the ability to predict OS and PFS of PTCLs. Conclusions The study indicated that low T3 syndrome may be a good candidate for predicting prognosis of peripheral T-cell lymphomas (AU)

25-Hydroxy vitamin D deficiency is an inferior predictor of peripheral T-cell lymphomas.

The aim of the study was to explore the significance and prognostic value of 25-hydroxy vitamin D (25-(OH) D) deficiency in peripheral T-cell lymphomas (PTCLs). One hundred fifty-six patients of newly diagnosed PTCLs were enrolled in the study. Univariate and multivariate regression analyses were performed to determine independent risk factors for progression-free survival (PFS) and overall survival (OS). Receiver operating characteristic (ROC) curves were plotted, and corresponding areas under the curve (AUC) were calculated to estimate the accuracy of International Prognostic Index (IPI) plus 25-(OH) D deficiency and Prognostic Index for T-cell lymphoma (PIT) plus 25-(OH) D deficiency respectively in PTCL risk stratification. Our results showed that the 25-(OH) D deficiency was an independent inferior prognostic factor for both PFS (P = 0.0019) and OS (P = 0.005) for PTCLs, especially for AITL and PTCL-not otherwise specified (PTCL-NOS). Additionally, adding 25-(OH) D deficiency to PIT indeed has a superior prognostic significance than PIT alone for PFS (P = 0.043) and OS (P = 0.036). Multivariate COX regression analysis revealed that PIT 2‒4, albumin (ALB) ≤ 35 g/L, and 25-(OH) D deficiency were regarded as independent risk factors of PFS and OS. Our results showed that 25-(OH) D deficiency was associated with inferior survival outcome of PTCLs, especially for AITL and PTCL-NOS. PIT plus 25-(OH) D deficiency could better indicate the prognosis for PFS and OS of PTCLs than PIT.

Low T3 syndrome as a predictor of poor prognosis in peripheral T-cell lymphomas.

PURPOSE: The purpose of the study was to evaluate the prognostic value of low T3 syndrome in peripheral T-cell lymphomas (PTCLs). METHODS: One hundred and seventy-four patients of newly diagnosed PTCLs were enrolled in the study. We performed statistical analysis based on the clinical data collected. RESULTS: Thirty-Six (20.69%) patients had low T3 syndrome at first admission. Results suggested that the patients with higher score of ECOG PS, International Prognostic Index (IPI) and Prognostic Index for T-cell lymphoma (PIT), bone marrow involvement and lower level of albumin tended to develop low T3 syndrome. The median progression-free survival (PFS) and overall survival (OS) were 10 months and 36 months, respectively, for all patients. Pre-existing low T3 syndrome was in correlation with worse PFS and OS. Patients with low T3 syndrome showed worse PFS (4 months vs 13 months, P = 0.0001) and OS (7 months vs 83 months, P < 0.0001) than patients without low T3 syndrome. IPI and PIT, respectively, combined with low T3 syndrome improved the ability to predict OS and PFS of PTCLs. CONCLUSIONS: The study indicated that low T3 syndrome may be a good candidate for predicting prognosis of peripheral T-cell lymphomas.

Autologous hematopoietic stem cell transplantation improves survival outcomes in peripheral T-cell lymphomas: a multicenter retrospective real-world study.

The aim of this study is to evaluate the survival benefit of consolidative autologous hematopoietic stem cell transplantation (ASCT) in patients with peripheral T-cell lymphomas (PTCL). In this retrospective study, the ASCT group underwent consolidative ASCT after first-line therapy at 14 transplantation centers in China between January 2001 and December 2019. Data were collected over the same time frame for the non-ASCT group from the database of lymphoma patient records at Peking University Cancer Hospital & Institute. A total of 120 and 317 patients were enrolled in the ASCT and non-ASCT groups, respectively, and their median ages were 43 years and 51 years, respectively. In the ASCT group, 101 patients had achieved complete remission (CR) and 19 patients had achieved partial remission at the time of ASCT. The median follow-up time was 40.2 months and 68 months, and the 3-year overall survival (OS) rate was 80.6% and 48.9% (p < 0.001) for the ASCT and non-ASCT groups, respectively. The beneficial effect of ASCT for OS remained even after propensity score-matched (PSM) analysis (81.6% vs 68.3%, p = 0.001). Among the 203 patients who were aged ≤ 65 years and achieved CR, ASCT conferred a significant survival benefit (3-year progression-free survival [PFS]: 67.4% vs 47.0%, p = 0.004; 3-year OS: 84.0% vs 74.1%, p = 0.010), and this was also maintained after PSM analysis (3-year PFS: 66.6% vs 48.4%, p = 0.042; 3-year OS: 84.8% vs 70.5%, p = 0.011). Consolidative ASCT improved the survival outcome of PTCL patients, even those who achieved CR after first-line therapy.

Phase I dose escalation and expansion study of golidocitinib, a highly selective JAK1 inhibitor, in relapsed or refractory peripheral T-cell lymphomas.

BACKGROUND: Relapsed or refractory peripheral T-cell lymphomas (r/r PTCLs) are a group of rare and aggressive diseases that lack effective therapies. Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is reported to be associated with PTCLs. Golidocitinib is an oral, potent JAK1 selective inhibitor evaluated in a phase I/II multinational study in patients with r/r PTCLs. PATIENTS AND METHODS: Patients with r/r PTCLs were eligible. The primary objectives were to assess safety and tolerability of golidocitinib and to define its recommended phase II dose (RP2D). The secondary objectives were to evaluate its antitumor activity and pharmacokinetics (PK). RESULTS: A total of 51 patients were enrolled and received golidocitinib treatment at 150 or 250 mg once daily (QD). The median prior lines of therapies were 2 (range: 1-8). Golidocitinib was tolerated at both doses tested, while a higher incidence of serious adverse events and dose modifications at 250 mg were observed. The most common grade ≥3 drug-related treatment-emergent adverse events were neutropenia (27.5%) and thrombocytopenia (11.8%). An objective response rate of 39.2% and a complete response rate of 21.6% were observed. With median follow-up time of 14.7 and 15.9 months, the median duration of response (DoR) and progression-free survival were 8.0 and 3.3 months, respectively. Based on these data, 150 mg QD was defined as the RP2D. Golidocitinib demonstrated a favorable PK profile as an oral agent. Biomarker analysis suggested a potential correlation between JAK/STAT pathway aberrations and clinical activity of golidocitinib. CONCLUSIONS: In this phase I study, golidocitinib demonstrated an acceptable safety profile and encouraging antitumor efficacy in heavily pretreated patients with r/r PTCLs. These results support the initiation of the multinational pivotal study in patients with r/r PTCLs.

Peripheral T-cell lymphomas.

The treatment of peripheral T-cell lymphomas is challenging, as they often display a severe prognosis and lack effective treatment strategies. We will try to answer three burning questions: can we differentiate the initial treatment based on the histotype and the clinical presentation of peripheral T-cell lymphoma patients? Do we require an autologous stem cell transplantation in all patients? Is there room for improvement in the setting of relapsed and refractory disease?

Pathologic and molecular insights in nodal T-follicular helper cell lymphomas.

T-follicular helper (TFH) cells are one of the T-cell subsets with a critical role in the regulation of germinal center (GC) reactions. TFH cells contribute to the positive selection of GC B-cells and promote plasma cell differentiation and antibody production. TFH cells express a unique phenotype characterized by PD-1hi, ICOShi, CD40Lhi, CD95hi, CTLAhi, CCR7lo, and CXCR5hi . Three main subtypes of nodal TFH lymphomas have been described: 1) angioimmunoblastic-type, 2) follicular-type, and 3) not otherwise specified (NOS). The diagnosis of these neoplasms can be challenging, and it is rendered based on a combination of clinical, laboratory, histopathologic, immunophenotypic, and molecular findings. The markers most frequently used to identify a TFH immunophenotype in paraffin-embedded tissue sections include PD-1, CXCL13, CXCR5, ICOS, BCL6, and CD10. These neoplasms feature a characteristic and similar, but not identical, mutational landscape with mutations in epigenetic modifiers (TET2, DNMT3A, IDH2), RHOA, and T-cell receptor signaling genes. Here, we briefly review the biology of TFH cells and present a summary of the current pathologic, molecular, and genetic features of nodal lymphomas. We want to highlight the importance of performing a consistent panel of TFH immunostains and mutational studies in TCLs to identify TFH lymphomas.

TET-2 mutations predict poor outcomes and are associated with unfavorable clinical-biological features in PTCL, not otherwise specified and angioimmunoblastic T-cell lymphoma in Brazilian patients.

INTRODUCTION: Nodal peripheral T-cell lymphomas [nPTCL] constitute a heterogeneous group of rare malignancies with aggressive biological behavior and poor prognosis. Epigenetic phenomena involving genes that control DNA-methylation and histone deacetylation play a central role in their pathogenesis. However, the mutational landscape involving epigenetic regulators has never been reported in Latin American patients and their prognostic impact remains controversial. PATIENTS AND METHODS: From 2000 to 2019, 59-Brazilian patients with nPTCL were eligible for screening mutations in the IDH-1, IDH-2, RHOA, TET-2 and DNMT3A genes by Sanger sequencing at Formalin-Fixed Paraffin-Embedded samples [FFPE] of diagnosis. We reported the frequency, distribution and potential prognosis of these mutations. RESULTS: With a median follow-up of 3.70 years, estimate 2-year OS and PFS were 57.1% and 49.2%, respectively. Mutations in the IDH-1 gene were not found, mutations in the IDH-2 occurred in 3.4% (2/59), RHOA in 23.7% (14/59), TET-2 in 50.8% (30/59) and DNMT3A in 62.7% (37/59). RHOA gene mutations were more frequent in PTCL, NOS and AITL (p= 0.06). Almost half of the patients had more than one mutation in concomitance, particularly RHOA-mut and TET-2-mut. Mutations in RHOA (p= 0.030) and TET-2 (p= 0.046) were associated with high-tumor burden. In the non-ALCL subgroup (PTCL, NOS and AITL) TET-2 mutations were associated with decreased 2-year PFS [HR: 2.22, p= 0.048]. Likewise with lower overall response rate [ORR] (p= 0.048) and unfavorable clinical features, as bulky disease (p= 0.012), ECOG ⩾ 2 (p= 0.032), B-symptoms (p= 0.012), ⩾ 2 extranodal sites compromised (p= 0.022) and high-risk Prognostic Index for T-cell lymphoma (p= 0.005). CONCLUSION: Mutations in RHOA, TET-2 and DNMT3A were frequent in Brazilian patients with nPTCL. TET-2 mutations were associated with lower ORR for CHOP-like chemotherapy, decreased PFS and unfavorable clinical-biological characteristics in non-ALCL (PTCL, NOS and AITL). Further studies using a larger cohort may validate our findings.

Diagnostic and prognostic implications of tumor expression of the GATA-3 gene in nodal peripheral T-cell lymphoma (nPTCL): Retrospective data from a Latin American cohort.

BACKGROUND: Nodal peripheral T-cell lymphomas (nPTCL) encompass a heterogeneous group of mature and aggressive lymphoid malignancies, including peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) ALK-positive and ALK-negative. Their differential diagnosis and prognosis are an issue in clinical practice. Accurate biomarkers to define the different subtypes of nPTCL and to stratify their prognosis are essential to improve their treatment approach. The aim of this study was to test the prognostic impact of GATA-3 gene expression, and its capability to discriminate the different subtypes of nPTCL. PATIENTS AND METHODS: We retrospectively assessed GATA-3 gene expression by quantitative real time PCR (qRT-PCR) from neoplastic biopsies in Formalin-Fixed Paraffin-Embedded samples (FFPE) of 80 patients with nPTCL that were admitted in a single cancer treatment center from 2000 to 2017. RESULTS: Median age was 49 years-old (IqR 34-59), 43/80 (53.7%) were male. Median follow-up was 1.72 years, 36.3% were classified as PTCL, NOS, 31.2% as ALK-negative ALCL, 21.2% as ALK-positive ALCL and 11.3% as AITL. The majority of cases had advanced stage cancer (III/IV). Two-year estimated overall survival (OS) and progression-free survival (PFS) were 52.2% and 39.5%, respectively. The median GATA-3 gene expression level was 0.49 (range 0 - 7.07) in all cohort, with 0.11 for ALK-positive ALCL, 0.46 for ALK-negative ALCL, 0.86 for PTCL, NOS and 0.67 for AITL. The difference of GATA-3 gene expression among distinct variants of nPTCL was statistically significant (p < 0.001). GATA-3 gene expression levels ≥ 0.71 discriminate PTCL, NOS from ALK-negative ALCL and AITL with sensitivity of 62.0% and specificity of 80.3%. GATA-3 gene expression level ≥ median was associated with poor 2-year OS for PTCL, NOS (46.7% versus 21.4%, p = 0.04) and ALK-negative ALCL (85.7% versus 54.5%, p = 0.04). In multivariate analysis, GATA-3 expression ≥ median was an independent factor associated with poor OS in nPTCL (HR: 2.34, 95% CI: 1.12-4.39, p = 0.041). CONCLUSION: GATA-3 gene overexpression may be an important biomarker associated with poor prognosis in PTCL, NOS and ALK-negative ALCL. Moreover, it may also discriminate different subtypes of nPTCL. Further studies with larger series of patients should confirm our findings.

T time: Emerging and new therapies for peripheral T-cell lymphoma.

Peripheral T-cell Lymphomas (PTCL) are a heterogenous group of aggressive non-Hodgkin lymphomas that are far less sensitive to chemotherapy than their B-cell counterparts. Despite their poor prognosis, they are treated similarly to most aggressive B-cell lymphomas, heavily relying on CHOP or CHOP-like combination chemotherapy irrespective of their different subtypes or biology. The last decade has seen the emergence of many targeted therapies that include histone deacetylase inhibitors, hypomethylating agents, monoclonal antibodies and PIK3 inhibitors, among others. However, prognosis remains poor especially in the relapsed/refractory setting. Using an extensive pubmed search, the authors will be summarizing the different trials that led to these approved targeted agents as well as novel combination strategies. The fundamental recognition that different subtypes of PTCL have specific biological features that drive not only proliferation, but also responses to different treatment approaches, should be informing the design of future clinical trials.

Linfomas de células T/NK das regiões oral e maxilofacial: um estudo multicêntrico / T/NK cell lymphomas of the oral and maxillofacial regions: a multicenter study

Os linfomas representam um grupo importante, complexo e heterogêneo de distúrbios proliferativos malignos originados a partir das células do tecido linfoide. Os linfomas de células T/NK maduras representam 12,7% a 26,2% dos linfomas não-Hodgkin, são condições relativamente raras, e a incidência da maioria das neoplasias aumenta com a idade. Portanto, o objetivo desse estudo é avaliar as características clinicopatológicas e imunoistoquímicas de uma série de linfomas de células T/NK maduras que acometem as regiões oral e maxilofacial e fornecer uma revisão atualizada da literatura sobre as bases biológicas desse grupo de doenças malignas. Casos diagnosticados como linfomas maduros de células T/NK afetando a região oral e maxilofacial foram recuperados retrospectivamente de seis centros de patologia oral e maxilofacial, e seus diagnósticos foram confirmados por meio de lâminas coradas com hematoxilina e eosina, reações imuno-histoquímicas e hibridização in situ para detecção do vírus Epstein-Barr (EBV). Um total de 22 casos foram incluídos neste estudo. Onze (50%) consistiam em linfomas extranodais de células T/NK, tipo nasal; oito (36,4%) eram linfomas periféricos de células T, sem outra especificação; dois (9,1%) eram leucemia/linfomas de células T, tipo adulto e um (4,5%) era um linfoma anaplásico de grandes células ALK-positivo. No geral, houve predomínio do sexo masculino, com média de idade de 55 anos. O palato foi o local mais acometido (50%), e os tumores geralmente se apresentavam como úlceras destrutivas e dolorosas. O EBV estava presente em todos os casos de linfoma de células T/NK extranodal tipo nasal, mas estava ausente nos outros subtipos.

Lymphomas represent an important, complex, and heterogeneous group of malignant proliferative disorders arising from lymphoid tissue cells. Mature T/NK cell lymphomas represent 12.7% to 26.2% of non-Hodgkin lymphomas, are relatively rare conditions, and the incidence of most neoplasms increases with age. Therefore, the aim of this study is to evaluate the clinicopathological and immunohistochemical characteristics of a series of mature T/NK cell lymphomas that affect the oral and maxillofacial regions and to provide an updated review of the literature on the biological basis of this group of malignancies. Cases diagnosed as mature T/NK cell lymphomas affecting the oral and maxillofacial region were retrospectively retrieved from six oral and maxillofacial pathology centers, and their diagnoses were confirmed by hematoxylin-and-eosinstained slides, immunohistochemical reactions, and in situ hybridization for detection of Epstein-Barr virus (EBV). A total of 22 cases were included in this study. Eleven (50%) consisted of extranodal T/NK cell lymphomas, nasal type; eight (36.4%) were peripheral T-cell lymphomas, not otherwise specified; two (9.1%) were T-cell leukemia/lymphomas, adult type and one (4.5%) was an ALK-positive anaplastic large cell lymphoma. Overall, there was a predominance of males, with a mean age of 55 years. The palate was the most affected site (50%), and the tumors usually presented as destructive and painful ulcers. EBV was present in all cases of nasal type extranodal T/NK cell lymphoma but was absent in the other subtypes.

Updates in the Treatment of Peripheral T-Cell Lymphomas.

Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of rare hematologic malignancies accounting for less than 10% of non-Hodgkin lymphomas. The 2016 classification of World Health Organization recognized 29 different entities of PTCLs. These subgroups are characterized by different molecular and genetic patterns. For nearly 30 years, little improvement in the treatment of PTCLs has been noticed due to the paucity of randomized trials and anthracycline-based chemotherapy remains the mainstay of first-line treatment. In front-line setting, ECHELON-2, the first randomized controlled Phase III clinical trial, recently met its primary endpoint of PFS demonstrating the superiority of BV containing regimen when compared to standard CHOP in patients with CD30 positive PTCLs. The role of therapeutic intensifications such as autologous or allogenic stem cell transplantations remains controversial in first-line setting and in relapsed/refractory disease due to the lack of studies clearly addressing this question and the recently published negative studies. PTCLs are often refractory to first-line chemotherapy and tend to relapse after an initial response. New agents have been approved for relapsed/refractory disease such as Histone deacetylase inhibitors, folate analogue metabolic inhibitor or CD30 antibody drug conjugated. Despite an acceptable response to these agents, progression-free survival remains very poor. New strategies such as combinations of different agents have been evaluated in order to improve outcomes. Innovative drugs in the fields of epigenetics, immunomodulation within the tumor microenvironment, and direct targeting of tumor cells to CD30 and T-cell receptor abnormalities open new perspectives to improve the treatment of PTCLs.

Molecularly targeted therapies for relapsed and refractory peripheral T-cell lymphomas.

The advent of molecularly targeted agents for patients with peripheral T-cell lymphomas (PTCL) has begun to change the therapeutic landscape in these diseases, especially for patients with relapsed or refractory disease. These agents, grounded in targeting numerous pathways or alterations related to disease pathogenesis, have shown promise across many PTCL subhistologies. Aided by significant advances in experimental techniques related to molecular biology, epigenetics, and immunology, more recent studies have begun elucidating mediators of resistance, both intrinsic and acquired, to inform future therapeutic advances. Defining and targeting these escape mechanisms through rational combination approaches will likely be important to continue to build on these promising advances and further improve clinical outcomes for patients facing PTCL.

Correlation of mutational landscape and survival outcome of peripheral T-cell lymphomas.

OBJECTIVE: To explore the correlation of mutation landscape with clinical outcomes in patients with peripheral T-cell lymphoma (PTCL). METHODS: We retrospectively analyzed the clinicopathological and prognosis data of 53 patients with PTCL from November 2011 to December 2017. Targeted next-generation sequencing of a 659-gene panel was performed for tissues from 53 patients with PTCLs. The correlation of mutation landscape with clinical outcomes was analyzed. RESULTS: TET2 was the most frequently mutated gene (64%), followed by RHOA (43%), PCLO (23%), DNMT3A (19%), IDH2 (17%), PIEZO1 (17%) and TP53 (15%). When mutated genes were categorized into functional groups, the most common mutations were those involved in epigenetic/chromatin modification (75%), T-cell activation (74%), and the DNA repair/TP53 pathway (64%). TET2/TP53 mutations were significantly associated with positive B symptoms (P = 0.045), and elevated lactate dehydrogenase (LDH) level (P = 0.011). Moreover, TET2/TP53 mutation was a risk factor for PTCL patient survival (HR 3.574, 95% CI 1.069 - 11.941, P = 0.039). The occurrence of JAK/STAT pathway mutations in angioimmunoblastic T-cell lymphoma (AITL) patients conferred a worse progression-free survival (HR 2.366, 95% CI 0.9130-6.129, P = 0.0334). CONCLUSIONS: Heterogeneous gene mutations occur in PTCL, some of which have a negative impact on the survival outcome.

Prognostic and predictive value of a mRNA signature in peripheral T-cell lymphomas: A mRNA expression analysis.

Current international prognostic index is widely questioned on the risk stratification of peripheral T-cell lymphoma and does not accurately predict the outcome for patients. We postulated that multiple mRNAs could combine into a model to improve risk stratification and helping clinicians make treatment decisions. In this study, the gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was used to screening genes in selected module which most closely related to PTCLs, and then built a mRNA signature using a LASSO Cox regression model and validated the prognostic accuracy of it. Finally, a nomogram was constructed and the performance was assessed. A total of 799 WGCNA-selected mRNAs in black module were identified, and a mRNA signature which based on DOCK2, GSTM1, H2AFY, KCNAB2, LAPTM5 and SYK for PTCLs was developed. Significantly statistical difference can be seen in overall survival of PTCLs between low-risk group and high-risk group (training set:hazard ratio [HR] 4.3, 95% CI 2.4-7.4, P < .0001; internal testing set:hazard ratio [HR] 2.4, 95% CI 1.2-4.8, P < .01; external testing set:hazard ratio [HR] 2.3, 95% CI 1.10-4.7, P = .02). Furthermore, multivariate regression demonstrated that the signature was an independently prognostic factor. Moreover, the nomogram which combined the mRNA signature and multiple clinical factors suggesting that predicted survival probability agreed well with the actual survival probability. The signature is a reliable prognostic tool for patients with PTCLs, and it has the potential for clinicians to implement personalized therapeutic regimen for patients with PTCLs.

Identification of Hub Genes and Key Pathways Associated with Peripheral T-cell Lymphoma.

Peripheral T-cell lymphoma (PTCL) is a very aggressive and heterogeneous hematological malignancy and has no effective targeted therapy. The molecular pathogenesis of PTCL remains unknown. In this study, we chose the gene expression profile of GSE6338 from the Gene Expression Omnibus (GEO) database to identify hub genes and key pathways and explore possible molecular pathogenesis of PTCL by bioinformatic analysis. Differentially expressed genes (DEGs) between PTCL and normal T cells were selected using GEO2R tool. Gene ontology (GO) analysis and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis were performed using Database for Annotation, Visualization and Integrated Discovery (DAVID). Moreover, the Search Tool for the Retrieval of Interacting Genes (STRING) and Molecular Complex Detection (MCODE) were utilized to construct protein-protein interaction (PPI) network and perform module analysis of these DEGs. A total of 518 DEGs were identified, including 413 down-regulated and 105 up-regulated genes. The down-regulated genes were enriched in osteoclast differentiation, Chagas disease and mitogen-activated protein kinase (MAPK) signaling pathway. The up-regulated genes were mainly associated with extracellular matrix (ECM)-receptor interaction, focal adhesion and pertussis. Four important modules were detected from the PPI network by using MCODE software. Fifteen hub genes with a high degree of connectivity were selected. Our study identified DEGs, hub genes and pathways associated with PTCL by bioinformatic analysis. Results provide a basis for further study on the pathogenesis of PTCL.

American Registry of Pathology Expert Opinions: Recommendations for the diagnostic workup of mature T cell neoplasms.

The diagnosis of T-cell lymphomas is highly challenging and requires an integrated approach in which clinical, morphologic, immunophenotypic and molecular data are incorporated into the diagnosis. Under the auspices of the American Registry of Pathology, the authors met to discuss this topic with the goal to provide practical and useful recommendations for pathologists when evaluating T-cell lymphomas. In this review, we discuss the diagnostic findings and workup for the various types of nodal T-cell lymphoma including anaplastic large cell lymphoma, nodal peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), and PTCL with a T follicular helper (TFH) phenotype. We review clinicopathologic and immunophenotypic features (including flow cytometry panels) helpful in the differential diagnosis of mature T-cell lymphomas presenting in the peripheral blood and bone marrow, and we discuss some of the more common extranodal-based T-cell lymphomas including extranodal natural killer/T-cell lymphoma of nasal and non-nasal type, gamma delta T cell lymphomas, and aggressive and indolent T- and NK-lymphoproliferative disorders involving the gastrointestinal tract. Mycosis fungoides and most other cutaneous T-cell lymphomas are not the focus of this review, although the differential diagnosis of Sezary syndrome from mycosis fungoides is covered. We do not intend for these recommendations to be anything other than suggestions that will hopefully spur on additional discussion, and perhaps eventually evolve into a consensus approach for the workup of T-cell lymphomas.

Germinal Center Cells Turning to the Dark Side: Neoplasms of B Cells, Follicular Helper T Cells, and Follicular Dendritic Cells.

Gaining knowledge of the neoplastic side of the three main cells-B cells, Follicular Helper T (Tfh) cells, and follicular dendritic cells (FDCs) -involved in the germinal center (GC) reaction can shed light toward further understanding the microuniverse that is the GC, opening the possibility of better treatments. This paper gives a review of the more complex underlying mechanisms involved in the malignant transformations that take place in the GC. Whilst our understanding of the biology of the GC-related B cell lymphomas has increased-this is not reviewed in detail here-the dark side involving neoplasms of Tfh cells and FDCs are poorly studied, in great part, due to their low incidence. The aggressive behavior of Tfh lymphomas and the metastatic potential of FDCs sarcomas make them clinically relevant, merit further attention and are the main focus of this review. Tfh cells and FDCs malignancies can often be misdiagnosed. The better understanding of these entities linked to their molecular and genetic characterization will lead to prediction of high-risk patients, better diagnosis, prognosis, and treatments based on molecular profiles.