Dimensionality-driven metal-insulator transition in spin-orbit-coupled IrO2.

A metal-insulator transition is observed in spin-orbit-coupled IrO2 thin films upon reduction of the film thickness. In the epitaxially grown samples, the critical thickness (t ∼ 1.5-2.2 nm) is found to depend on growth orientation (001), (100) or (110). Interestingly from the applied point of view, the insulating behavior is found even in polycrystalline ultrathin films. By analyzing the experimental electrical response with various theoretical models, we find good fits to the Efros-Shklovskii-VRH and the Arrhenius-type behaviors, which suggests an important role of electron correlations in determining the electrical properties of IrO2. Our magnetic measurements also point to a significant role of magnetic order. Altogether, our results would point to a mixed Slater- and Mott-type of insulator.

[Genetic evolution of in situ follicular neoplasia to t(14;18)-positive aggressive B-cell lymphoma]. / Die genetische Evolution der in situ follikulären Neoplasie zum t(14;18)-positiven aggressiven B­Zell-Lymphom.

BACKGROUND: In situ follicular neoplasia (ISFN) is a t(14;18)(q32;q21)+ precursor lesion of follicular lymphoma (FL), which in turn can transform into diffuse large B­cell lymphoma (DLBCL). For DLBCL that arise de novo, no precursor lesion is known. Given the high frequency of the t(14;18) translocation in de novo DLBCL as well, we investigated whether they can also arise from ISFN without FL as an intermediate step. OBJECTIVES: To investigate the clonal evolution of ISFN to DLBCL - transformed from FL and de novo. MATERIALS AND METHODS: Identification of ISFN lesions in patients with DLBCL was performed by BCL2 staining of reactive lymphoid tissues. ISFN and DLBCL were subsequently analyzed by fluorescence in situ hybridization, clonality analyses, sequencing of the t(14;18) breakpoint, and targeted next-generation sequencing. RESULTS: 10 cases with paired ISFN and DLBCL samples were identified, 6 of which were de novo DLBCL and 4 transformed from FL. 3 DLBCL carried MYC-rearrangements in addition to the t(14;18) and were classified as high-grade B­cell lymphoma (HGBL). The clonal relationship of ISFN and DLBCL/HGBL was confirmed for all cases. CREBBP, KMT2D, EZH2, TNFRSF14, and BCL2 were the genes most frequently mutated, with the distribution of private and shared mutations pointing to 2 different scenarios of clonal evolution. In most cases, DLBCL/HGBL, ISFN, and, if also present, FL had evolved divergently from a common progenitor, whereas linear evolution was less frequent. CONCLUSION: We show for the first time that t(14;18)+ DLBCL/HGBL can arise directly from ISFN without FL as an intermediate step and that during this progression, divergent evolution is common.

Primary cutaneous peripheral T-cell lymphoma, not otherwise specified: results of a multicentre European Organization for Research and Treatment of Cancer (EORTC) cutaneous lymphoma taskforce study on the clinico-pathological and prognostic features.

BACKGROUND: Cutaneous peripheral T-cell lymphoma, not otherwise specified (PTL NOS) is an aggressive, but poorly characterized neoplasm. OBJECTIVES: The European Organization for Research and Treatment of Cancer cutaneous lymphoma taskforce (EORTC CLTF) investigated 33 biopsies of 30 patients with primary cutaneous PTL NOS to analyse their clinical, histological, immunophenotypic features and outcome. METHODS: Retrospective analysis of clinical data and histopathological features by an expert panel. RESULTS: Cutaneous PTL NOS manifested clinically either with solitary or disseminated rapidly grown ulcerated tumours or disseminated papulo-nodular lesions. Histologically, a mostly diffuse or nodular infiltrate in the dermis and often extending into the subcutis was found. Epidermotropism was rarely present and only mild and focal. Unusual phenotypes were frequent, e.g. CD3+ /CD4- /CD8- and CD3+ /CD4+ /CD8+ . Moreover, 18% of the cases exhibited an aberrant expression of the B-cell marker CD20 by the tumour cells. All solitary tumours were located on the limbs and presented a high expression of GATA-3 but this did not correlate with outcome and therefore could not serve as a prognostic factor. The prognosis was shown to be generally poor with 10 of 30 patients (33%) dying of lymphoma within the follow-up of 36 months (mean value; range 3-144). The survival rates were 61% after 3 years (CI, 43-85%) and 54% after 5 years (CI, 36-81%). Small to medium-sized morphology of tumour cells was associated with a better outcome than medium to large or large tumour cells. Age, gender, clinical stage, CD4/CD8 phenotype and GATA-3 expression were not associated with prognosis. Chemotherapy was the most common treatment modality, but surgical excision and/or radiotherapy may represent an appropriate first-line treatment for solitary lesions. CONCLUSIONS: Cutaneous PTL NOS shows an aggressive course in most patients independent of initial presentation, age and phenotype. Cytomorphology was identified as a prognostic factor. The data indicate a need for more effective treatment modalities in PTL NOS.

Advanced-stage mycosis fungoides: role of the signal transducer and activator of transcription 3, nuclear factor-κB and nuclear factor of activated T cells pathways.

BACKGROUND: The malignant mechanisms that control the development of cutaneous T-cell lymphoma (CTCL) are beginning to be identified. Recent evidence suggests that disturbances in specific intracellular signalling pathways, such as RAS-mitogen-activated protein kinase, T-cell receptor (TCR)-phospholipase C gamma 1 (PLCG1)-nuclear factor of activated T cells (NFAT) and Janus kinase (JAK)-signal transducer and activator of transcription (STAT), may play an essential role in the pathogenesis of CTCL. OBJECTIVES: To investigate the mechanisms controlling disease development and progression in mycosis fungoides (MF), the most common form of CTCL. METHODS: We collected 100 samples that were submitted for diagnosis of, or a second opinion regarding, MF between 2001 and 2018, 80% of which were in the early clinical stages of the disease. Formalin-fixed paraffin-embedded tissues were used for histological review and to measure the expression by immunohistochemistry of surrogate markers of activation of the TCR-PLCG1-NFAT, JAK-STAT and NF-κB pathways. Folliculotropism and large-cell transformation were also examined. RESULTS: NFAT and nuclear factor kappa B (NF-κB) markers showed a comparable activation status in early and advanced stages, while STAT3 activation was more frequent in advanced stages and was associated with large-cell transformation. Consistently with this observation, STAT3 activation occurred in parallel with MF progression in two initially MF-negative cases. A significant association of NFAT with NF-κB markers was also found, reflecting a common mechanism of activation in the two pathways. Genomic studies identified nine mutations in seven genes known to play a potential role in tumorigenesis in T-cell leukaemia/lymphoma, including PLCG1, JAK3 and STAT3, which underlies the activation of these key cell-survival pathways. A higher mutational allele frequency was detected in advanced stages. CONCLUSIONS: Our results show that STAT3 is activated in advanced cases and is associated with large-cell transformation, while the activation of NFAT and NF-κB is maintained throughout the disease. These findings could have important diagnostic and therapeutic implications. What's already known about this topic? Mycosis fungoides is characterized by a clonal expansion of T cells in the skin. The mechanisms controlling disease development and progression are not fully understood. What does this study add? An association of the nuclear factor of activated T cells and nuclear factor kappa B pathways was found, which could reflect a common mechanism of activation. These pathways were activated in early and advanced stages at the same level. Signal transducer and activator of transcription 3 activation was associated with large-cell transformation and was more frequent in advanced stages. A genomic analysis of cutaneous T-cell lymphoma-associated genes was performed. Nine mutations were detected. What is the translational message? These results could have important implications for the treatment of MF in the near future.

Concordant bone marrow involvement of diffuse large B-cell lymphoma represents a distinct clinical and biological entity in the era of immunotherapy.

In diffuse large B-cell lymphoma (DLBCL), the clinical and biological significance of concordant and discordant bone marrow (BM) involvement have not been well investigated. We evaluated 712 de novo DLBCL patients with front-line rituximab-containing treatment, including 263 patients with positive and 449 with negative BM status. Compared with negative BM disease, concordant BM adversely impacted overall and progression-free survival, independent of the International Prognostic Index (IPI) and cell-of-origin classification. Once BM is concordantly involved, poor prognosis was not associated with the extent of BM involvement. Conversely, patients with discordant BM showed favorable overall survival similar to stage I-II DLBCL. A BM-adjusted IPI, using three parameters: concordant BM involvement, age >60 years, and performance status >1, improves the risk stratification for DLBCL with positive BM. Intensive immunochemotherapy seemingly rendered survival benefit for patients with concordant BM, as did rituximab maintenance for the discordant BM group. Frequently revealing adverse clinical and molecular characteristics, patients with concordant BM demonstrated gene expression signatures relevant to tumor cell proliferation, migration and immune escape. In conclusion, clinical and biological heterogeneity is seen in DLBCL with positive BM but concordant BM involvement represents a distinct subset with unfavorable gene signatures, high-risk clinicopathologic features and poor prognosis.

On the performance of natural orbital functional approximations in the Hubbard model.

Strongly correlated materials are now under intense development, and natural orbital functional (NOF) methods seem to be able to capture the physics of these systems. We present a benchmark based on the Hubbard model for a class of commonly used NOF approximations (also known as reduced density matrix functional approximations). Our findings highlight the importance of imposing ensemble N-representability conditions in order to obtain consistent results in systems with either weak or strong electronic correlation, such as the Hubbard system with a varying two-particle interaction parameter. Based on the accuracy of the results obtained using PNOF7, which retrieves a large amount of the total strong nondynamic correlation, the Hubbard model points out that N-representability gives solid foundations for NOF development.

Loss of PRDM1/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma.

PRDM1/BLIMP-1, a master regulator of plasma-cell differentiation, is frequently inactivated in activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) patients. Little is known about its genetic aberrations and relevant clinical implications. A large series of patients with de novo DLBCL was effectively evaluated for PRDM1/BLIMP-1 deletion, mutation, and protein expression. BLIMP-1 expression was frequently associated with the ABC phenotype and plasmablastic morphologic subtype of DLBCL, yet 63% of the ABC-DLBCL patients were negative for BLIMP-1 protein expression. In these patients, loss of BLIMP-1 was associated with Myc overexpression and decreased expression of p53 pathway molecules. In addition, homozygous PRDM1 deletions and PRDM1 mutations within exons 1 and 2, which encode for domains crucial for transcriptional repression, were found to show a poor prognostic impact in patients with ABC-DLBCL but not in those with germinal center B-cell-like DLBCL (GCB-DLBCL). Gene expression profiling revealed that loss of PRDM1/BLIMP-1 expression correlated with a decreased plasma-cell differentiation signature and upregulation of genes involved in B-cell receptor signaling and tumor-cell proliferation. In conclusion, these results provide novel clinical and biological insight into the tumor-suppressive role of PRDM1/BLIMP-1 in ABC-DLBCL patients and suggest that loss of PRDM1/BLIMP-1 function contributes to the overall poor prognosis of ABC-DLBCL patients.

Primary testicular diffuse large B-cell lymphoma displays distinct clinical and biological features for treatment failure in rituximab era: a report from the International PTL Consortium.

Primary testicular diffuse large B-cell lymphoma (PT-DLBCL) is a unique subtype of DLBCL. The impact of rituximab on survival and patterns of treatment failure in PT-DLBCL patient remain controversial. We analyzed the clinical and biological feature of 280 PT-DLBCL cases, 64% of which were treated with rituximab-containing regimens. Although most (95%) patients achieved complete remission, a continuous risk of relapse was observed. Rituximab significantly reduced the cumulative risk of relapse (P=0.022) and improved both progression-free survival (PFS, P=0.012) and overall survival (OS, P=0.027) of PT-DLBCL patients (5-year PFS, 56% vs 36%; 5-year OS, 68% vs 48%). Central nervous system and contralateral testis were the most common sites of relapse, but other extranodal and nodal sites of relapse were also observed. Most cases of PT-DLBCL had a non-germinal center B-cell like (84%) immunophenotype and an activated B-cell like (86%) gene expression profile (GEP) subtype. The distinctive GEP signature of primary testicular lymphoma was relevant to tumor cell proliferation, dysregulated expression of adhesion molecules and immune response, likely accounting for the poor outcome. Accordingly, forkhead box P1 transcription factor (FOXP1) and T-cell leukemia/lymphoma 1 (TCL1) oncogenic activation were confirmed and predicted a significant trend of poor survival. This study provides valuable observations for better understanding of both clinical and biological features in PT-DLBCL patients.

Contribution of JAK2 mutations to T-cell lymphoblastic lymphoma development.

The JAK-STAT pathway has a substantial role in lymphoid precursor cell proliferation, survival and differentiation. Nonetheless, the contribution of JAK2 to T-cell lymphoblastic lymphoma (T-LBL) development remains poorly understood. We have identified one activating TEL-JAK2 translocation and four missense mutations accumulated in 2 out of 16 T-LBL samples. Two of them are novel JAK2 mutations and the other two are reported for the first time in T-LBL. Notably, R683G and I682T might have arisen owing to RNA editing. Mutated samples showed different mutated transcripts suggesting sub-clonal heterogeneity. Functional approaches revealed that two JAK2 mutations (H574R and R683G) constitutively activate JAK-STAT signaling in γ2A cells and can drive the proliferation of BaF3-EpoR cytokine-dependent cell line. In addition, aberrant hypermethylation of SOCS3 might contribute to enhance the activation of JAK-STAT signaling. Of utmost interest is that primary T-LBL samples harboring JAK2 mutations exhibited increased expression of LMO2, suggesting a mechanistic link between JAK2 mutations and the expression of LMO2, which was confirmed for the four missense mutations in transfected γ2A cells. We therefore propose that active JAK2 contribute to T-LBL development by two different mechanisms, and that the use of pan-JAK inhibitors in combination with epigenetic drugs should be considered in future treatments.

Low-Lying Isomers of Free-Space Halogen Clusters with Tetrahedral and Octahedral Symmetry in Relation to Stable Molecules Such as SF6.

Motivated by previous work involving one of us (N.H.M.) on some 20 stable tetrahedral (t) and octahedral (o) molecules, including XF(4) (X = C, Si, Ge), the natural orbital functional PNOF6 is here used to study the free-space halogen cluster t-F(4). We consider an extended functional PNOF6(Nc) by coupling Nc orbitals (Nc > 1) to each orbital below the Fermi level, which improves the description of the electron pairs. Similar studies are presented for t-Cl(4). The successful calculation on the stable molecule BrF(5) (Theor. Chem. Acc. 2013, 132, 1298) has prompted a study of the clusters o-F(6) and o-Cl(6) too. The size relation with calculated known stable molecules and the experimental data are finally considered. In the case of the o-SF(6), the geometry optimization with fixed octahedral symmetry has also been performed at the PNOF6(3) level of theory, leading to an equilibrium distance of 2.95 au in perfect agreement with the experiment. Our results confirm the multireferential character of Z(4) and Z(6) compounds (Z = H, F, Cl), in contrast with the single-reference character of the XZ(4) (X = C, Si, Ge) and YZ(6) (Y = S, Se, U) compounds; therefore, despite the clear patterns within a group, it is not possible to extrapolate the results to the case when the atomic number, X or Y, becomes zero.

Interacting pairs in natural orbital functional theory.

An interacting-pair model is considered to attain a new natural orbital functional (NOF). The new approach, which will be termed PNOF6, belongs to the JKL-only family of NOFs known in the literature as PNOFi. Accordingly, the approximated two-particle reduced density matrix (RDM) is reconstructed from the one-particle RDM, considering an explicit form of the two-particle cumulant in terms of the occupation numbers, and enforcing (2,2)-positivity conditions for the N-representability of the 2-RDM. PNOF6 is superior to its predecessor, PNOF5, which is an independent-pair approach. The functional is able to treat both dynamic and static correlations, thereby putting together the advantages of the other members of this series. The theory is applied to the dissociation of selected diatomic molecules. The equilibrium distances, dipole moments, harmonic frequencies, anharmonicity constants, and binding energies of the considered molecules are presented. Comparative potential energy curves for the deformation of benzene are given at the PNOF5 and PNOF6 levels of theory. In benzene, PNOF5 breaks the symmetry by about 1.5°, with an energy lowering of almost 3 kcal/mol, whereas PNOF6 provides the correct D6h symmetry.

FAS system deregulation in T-cell lymphoblastic lymphoma.

The acquisition of resistance towards FAS-mediated apoptosis may be required for tumor formation. Tumors from various histological origins exhibit FAS mutations, the most frequent being hematological malignancies. However, data regarding FAS mutations or FAS signaling alterations are still lacking in precursor T-cell lymphoblastic lymphomas (T-LBLs). The available data on acute lymphoblastic leukemia, of precursor origin as well, indicate a low frequency of FAS mutations but often report a serious reduction in FAS-mediated apoptosis as well as chemoresistance, thus suggesting the occurrence of mechanisms able to deregulate the FAS signaling pathway, different from FAS mutation. Our aim at this study was to determine whether FAS-mediated apoptotic signaling is compromised in human T-LBL samples and the mechanisms involved. This study on 26 T-LBL samples confirms that the FAS system is impaired to a wide extent in these tumors, with 57.7% of the cases presenting any alteration of the pathway. A variety of mechanisms seems to be involved in such alteration, in order of frequency the downregulation of FAS, the deregulation of other members of the pathway and the occurrence of mutations at FAS. Considering these results together, it seems plausible to think of a cumulative effect of several alterations in each T-LBL, which in turn may result in FAS/FASLG system deregulation. Since defective FAS signaling may render the T-LBL tumor cells resistant to apoptotic cell death, the correct prognosis, diagnosis and thus the success of anticancer therapy may require such an in-depth knowledge of the complete scenario of FAS-signaling alterations.

Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a very rare disease that currently lacks genomic and genetic biomarkers to assist in its clinical management. We performed whole-exome sequencing (WES) of three BPDCN cases. Based on these data, we designed a resequencing approach to identify mutations in 38 selected genes in 25 BPDCN samples. WES revealed 37-99 deleterious gene mutations per exome with no common affected genes between patients, but with clear overlap in terms of molecular and disease pathways (hematological and dermatological disease). We identified for the first time deleterious mutations in IKZF3, HOXB9, UBE2G2 and ZEB2 in human leukemia. Target sequencing identified 29 recurring genes, ranging in prevalence from 36% for previously known genes, such as TET2, to 12-16% for newly identified genes, such as IKZF3 or ZEB2. Half of the tumors had mutations affecting either the DNA methylation or chromatin remodeling pathways. The clinical analysis revealed that patients with mutations in DNA methylation pathway had a significantly reduced overall survival (P=0.047). We provide the first mutational profiling of BPDCN. The data support the current WHO classification of the disease as a myeloid disorder and provide a biological rationale for the incorporation of epigenetic therapies for its treatment.

Increasing genomic and epigenomic complexity in the clonal evolution from in situ to manifest t(14;18)-positive follicular lymphoma.

Follicular lymphoma (FL) is characterized besides the t(14;18)(q32;q21), by recurrent chromosomal alterations and somatic mutations. In this study, we analyzed cases of FL in situ (FLIS) without manifest FL (mFL), partial involvement by FL (PFL) and paired cases of FLIS and mFL to detect possible early chromosomal imbalances, mutations, as well as DNA-methylation patterns of genomic regions of selected genes. We demonstrate that all paired FLIS and mFL cases were clonally related, based on IGH rearrangement patterns and BCL2 breakpoint sequences. FLIS and PFL had no or few secondary chromosomal imbalances detectable by array comparative genomic hybridization (FLIS 0.8 copy number alterations (CNA)/case; PFL 2.0 CNA/case; mFL 6.3 CNA/case) and a lower level of DNA methylation of genes recurrently de novo methylated in lymphomas, as compared with mFL. EZH2 Tyr641 mutations were detected in a subset of both FLIS (2/9) and PFL (1/3) cases. In conclusion, these findings provide evidence that FLIS represents a FL precursor lesion of long-lived clonal B cells carrying the t(14;18) with no or few secondary genetic changes. Our data suggest that there may be more than one distinct lesion driving the progression from FLIS to manifest lymphoma.

Whole-exome sequencing in splenic marginal zone lymphoma reveals mutations in genes involved in marginal zone differentiation.

Splenic marginal zone lymphoma (SMZL) is a B-cell neoplasm whose molecular pathogenesis remains fundamentally unexplained, requiring more precise diagnostic markers. Previous molecular studies have revealed 7q loss and mutations of nuclear factor κB (NF-κB), B-cell receptor (BCR) and Notch signalling genes. We performed whole-exome sequencing in a series of SMZL cases. Results confirmed that SMZL is an entity distinct from other low-grade B-cell lymphomas, and identified mutations in multiple genes involved in marginal zone development, and others involved in NF-κB, BCR, chromatin remodelling and the cytoskeleton.

The intrapair electron correlation in natural orbital functional theory.

A previously proposed [M. Piris, X. Lopez, F. Ruipérez, J. M. Matxain, and J. M. Ugalde, J. Chem. Phys. 134, 164102 (2011)] formulation of the two-particle cumulant, based on an orbital-pairing scheme, is extended here for including more than two natural orbitals. This new approximation is used to reconstruct the two-particle reduced density matrix (2-RDM) constrained to the D, Q, and G positivity necessary conditions of the N-representable 2-RDM. In this way, we have derived an extended version of the Piris natural orbital functional 5 (PNOF5e). An antisymmetrized product of strongly orthogonal geminals with the expansion coefficients explicitly expressed by the occupation numbers is also used to generate the PNOF5e. The theory is applied to the homolytic dissociation of selected diatomic molecules: H2, LiH, and Li2. The Bader's theory of atoms in molecules is used to analyze the electron density and the presence of non-nuclear maxima in the case of a set of light atomic clusters: Li2, Li3(+), Li4(2+), and H3(+). The improvement of PNOF5e over PNOF5 was observed by visualizing the electron densities.

Interpair electron correlation by second-order perturbative corrections to PNOF5.

An antisymmetrized product of strongly orthogonal geminals with the expansion coefficients explicitly expressed by the occupation numbers is used to generate the Piris natural orbital functional 5 (PNOF5). Second-order corrections to PNOF5 are derived and implemented using the multiconfigurational perturbation theory size consistent at second-order (SC2-MCPT). A modified version of the SC2-MCPT including only doubly excited determinants from different geminals is proposed to describe the dispersion interaction in the helium dimer, and to avoid the breakdown of curves in homolytic dissociations of FH, CO, and N2. Comparisons of calculated properties to experimental data are included to verify the accuracy of the formulation.

Addition of rituximab to chemotherapy overcomes the negative prognostic impact of cyclin E expression in diffuse large B-cell lymphoma.

BACKGROUND: High levels of cyclin E (CCNE) are accompanied by shorter survival in cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP)-treated diffuse large B-cell lymphomas (DLBCL), independent of the international prognostic index (IPI). Data on the prognostic role of CCNE in the 'rituximab (R)-era' are lacking. METHODS: To test reproducibility and applicability of observations from the 'pre-R era' to the 'R era', we examined the prognostic role of CCNE expression by immunohistochemistry in 1579 DLBCL on tissue microarrays (TMA); 339 patients were treated by CHOP and 635 by R-CHOP. RESULTS: 1209 samples (77%) were evaluable; failures were due to missing TMA punches and fixation artefacts. Mean expression of CCNE was 13% (0-85%); applying a cut-off of >16%, 382 DLBCL (31%) were positive. CCNE did not correlate with any of the known variables (IPI, primary site, cell of origin, proliferation, and BCL2- or C-MYC rearrangements). We were able to reproduce data suggesting an IPI- and response to therapy independent, negative prognostic impact of CCNE in CHOP-treated DLBCL patients: CCNE-positive cases had a median survival of 16 months compared with 57 months in negative ones (p=0.012). In R-CHOP-treated patients the prognostic impact of CCNE was abrogated and only IPI, cell of origin and response to therapy had a prognostic significance. CONCLUSIONS: Addition of R to CHOP overcomes the negative prognostic impact of CCNE in DLBCL. Thus, R not only prolongs survival in DLBCL but also serves a cautionary note that prognostic factors should not be transferred into the 'R era' without proper scientific studies.

Loss of TCR-beta F1 and/or EZRIN expression is associated with unfavorable prognosis in nodal peripheral T-cell lymphomas.

Nodal peripheral T-cell lymphoma (nodal PTCL) has an unfavorable prognosis, and specific pathogenic alterations have not been fully identified. The biological and clinical relevance of the expression of CD30/T-cell receptor (TCR) genes is a topic under active investigation. One-hundred and ninety-three consecutive nodal PTCLs (89 angioimmunoblastic T-cell lymphomas (AITL) and 104 PTCL-unspecified (PTCL-not otherwise specified (NOS)) cases) were analyzed for the immunohistochemical expression of 19 molecules, involving TCR/CD30 pathways and the associations with standard prognostic indices. Mutually exclusive expression was found between CD3 and TCR-beta F1 with CD30 expression. Taking all PTCL cases together, logistic regression identified a biological score (BS) including TCR molecules (TCR-beta F1 and EZRIN) that separates two subgroups of patients with a median survival of 34.57 and 5.20 months (P<0.001). Multivariate analysis identified BS and the prognostic index for PTCL (PIT) score as independent prognostic factors. This BS maintained its significance in multivariate analysis only for the PTCL-NOS subgroup of tumors. In AITL cases, only a high level of ki67 expression was related to prognosis. A BS including molecules involved in the TCR signaling pathway proved to be an independent prognostic factor of poor outcome in a multivariate analysis, specifically in PTCL-NOS patients. Nevertheless, validation in an independent series of homogeneously treated PTCL patients is required to confirm these data.