Gene expression profiling and FDG-PET radiomics uncover radiometabolic signatures associated with outcome in DLBCL.

Emerging evidence indicates that chemoresistance is closely related to altered metabolism in cancer. Here, we hypothesized that distinct metabolic gene expression profiling (GEP) signatures might be correlated with outcome and with specific fluorodeoxyglucose positron emission tomography (FDG-PET) radiomic profiles in diffuse large B-cell lymphoma (DLBCL). We retrospectively analyzed a discovery cohort of 48 consecutive patients with DLBCL treated at our center with standard first-line chemoimmunotherapy by performing targeted GEP (T-GEP)- and FDG-PET radiomic analyses on the same target lesions at baseline. T-GEP-based metabolic profiling identified a 6-gene signature independently associated with outcomes in univariate and multivariate analyses. This signature included genes regulating mitochondrial oxidative metabolism (SCL25A1, PDK4, PDPR) that were upregulated and was inversely associated with genes involved in hypoxia and glycolysis (MAP2K1, HIF1A, GBE1) that were downregulated. These data were validated in 2 large publicly available cohorts. By integrating FDG-PET radiomics and T-GEP, we identified a radiometabolic signature (RadSig) including 4 radiomic features (histo kurtosis, histo energy, shape sphericity, and neighboring gray level dependence matrix contrast), significantly associated with the metabolic GEP-based signature (r = 0.43, P = .0027) and with progression-free survival (P = .028). These results were confirmed using different target lesions, an alternative segmentation method, and were validated in an independent cohort of 64 patients. RadSig retained independent prognostic value in relation to the International Prognostic Index score and metabolic tumor volume (MTV). Integration of RadSig and MTV further refined prognostic stratification. This study provides the proof of principle for the use of FDG-PET radiomics as a tool for noninvasive assessment of cancer metabolism and prognostic stratification in DLBCL.

A Rare Case of BIA-ALCL Mass Associated with Mastectomy Skin Flap Erythema After Immunization with COVID-19.

BACKGROUND: The immune response to breast implants after COVID-19 disease or COVID-19 vaccine administration includes acute inflammatory manifestations, capsular contracture and seroma. Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a very rare tumor in which numerous up-regulated pro-inflammatory immunological pathways activate a T cell lymphoproliferative disorder. METHODS: The first reported case of a BIA-ALCL hidden mass clinically manifesting with inflammatory signs after SARS-CoV-2 infection and vaccinations is here described. RESULTS: Complete capsulectomy and adjuvant chemotherapy were performed and immediately after the surgical procedure local inflammatory signs disappeared; no evidence of disease was present 1 year later. CONCLUSIONS: Immunological stimulation by COVID-19 disease and vaccines may highlight some rare clinical manifestations of BIA-ALCL; persistent inflammatory symptomatology over breast implants should be investigated using second-level imaging. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Antimicrobial and Gas Barrier Crustaceans and Fungal Chitin-Based Coatings on Biodegradable Bioplastic Films.

Chitin nanofibrils (CN) can be obtained from crustaceans and fungal sources and can be used for preparing coatings for bioplastic films, that are fundamental for developing a safe and sustainable biodegradable food packaging. Coatings with different concentrations of CN from shrimps were applied on different bioplastic substrates, like Poly (butylene succinate-co-adipate)/Poly(3-hydroxybutyrate-co-3-hydroxyvalerate (PBSA/PHBV) blend, Polybutylene succinate (PBS), and Polybutylene adipate terephthalate/Poly(lactic acid) (PBAT/PLA) blend, but the adhesion to the substrates was scarce. On the contrary, the fungal-based CN showed a better adhesion. Additionally, it was found that the use of an additive based on oligomeric lactic acid was useful to prepare a coating with an improved adhesion to bioplastics. The gas barrier properties to oxygen and water vapour of coated and un-coated films were measured, revealing an improvement of these properties thanks to applied coatings, especially towards the oxygen. Antimicrobial properties and biodegradation capacity were also evaluated revealing an antibacterial effect of the coatings that did not significantly interfere with their biodegradability. The results are discussed and interpreted considering the correlation between composition and macromolecular structures with the observed functional properties.

Dampening of cytotoxic innate lymphoid cells: A new tumour immune escape mechanism in B cell non-Hodgkin's lymphoma.

The role and regulation of innate immune cells is poorly understood in B-cell non-Hodgkin lymphoma (NHL). As natural killer (NK) cells, helper innate lymphoid cells (ILCs) are lymphocytes endowed with either anti- or pro-tumour activity and involved in inflammatory processes. In our ex vivo analysis of NK cells and ILCs from NHL patients, we observed that, in comparison to healthy donors (HD), the frequency of the cytotoxic subset of NK cells, the CD16+ NK, decreased in patients' peripheral blood. In general, circulating NK cells showed a pro-tumorigenic phenotype, while ILCs displayed a more activated/cytotoxic phenotype. Conversely, at the tumour site, in patients' lymph nodes, ILCs showed a low expression of granzyme.In vitromixed lymphocyte-tumour cell cultures with HD PBMCs and NHL cell lines demonstrated that ILC cytotoxic potential was lowered by the presence of tumour cells but, in the absence of T regulatory cells (Tregs), their cytolytic potential was recovered. Our data shed novel light on dysfunctional innate immunity in NHL. We suggest a new mechanism of tumour immuno-escape based on the reduction of cell cytotoxicity involving ILCs and likely controlled by Tregs.

NR1H3 (LXRα) is associated with pro-inflammatory macrophages, predicts survival and suggests potential therapeutic rationales in diffuse large b-cell lymphoma.

The role of macrophages (Mo) and their prognostic impact in diffuse large B-cell lymphomas (DLBCL) remain controversial. By regulating the lipid metabolism, Liver-X-Receptors (LXRs) control Mo polarization/inflammatory response, and their pharmacological modulation is under clinical investigation to treat human cancers, including lymphomas. Herein, we surveyed the role of LXRs in DLBCL for prognostic purposes. Comparing bulk tumors with purified malignant and normal B-cells, we found an intriguing association of NR1H3, encoding for the LXR-α isoform, with the tumor microenvironment (TME). CIBERSORTx-based purification on large DLBCL datasets revealed a high expression of the receptor transcript in M1-like pro-inflammatory Mo. By determining an expression cut-off of NR1H3, we used digital measurement to validate its prognostic capacity on two large independent on-trial and real-world cohorts. Independently of classical prognosticators, NR1H3high patients displayed longer survival compared with NR1H3low cases and a high-resolution Mo GEP dissection suggested a remarkable transcriptional divergence between subgroups. Overall, our findings indicate NR1H3 as a Mo-related biomarker identifying patients at higher risk and prompt future preclinical studies investigating its mouldability for therapeutic purposes.

The identification of TCF1+ progenitor exhausted T cells in THRLBCL may predict a better response to PD-1/PD-L1 blockade.

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare and aggressive variant of diffuse large B-cell lymphoma (DLBCL) that usually affects young to middle-aged patients, with disseminated disease at presentation. The tumor microenvironment (TME) plays a key role in THRLBCL due to its peculiar cellular composition (<10% neoplastic B cells interspersed in a cytotoxic T-cell/histiocyte-rich background). A significant percentage of THRLBCL is refractory to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-based regimens and to chimeric antigen receptor T-cell therapy; thus, the development of a specific therapeutic approach for these patients represents an unmet clinical need. To better understand the interaction of immune cells in THRLBCL TME and identify more promising therapeutic strategies, we compared the immune gene expression profiles of 12 THRLBCL and 10 DLBCL samples, and further corroborated our findings in an extended in silico set. Gene coexpression network analysis identified the predominant role of the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis in the modulation of the immune response. Furthermore, the PD-1/PD-L1 activation was flanked by the overexpression of 48 genes related to the functional exhaustion of T cells. Globally, THRLBCL TME was highly interferon-inflamed and severely exhausted. The immune gene profiling findings strongly suggest that THRLBCL may be responsive to anti-PD-1 therapy but also allowed us to take a step forward in understanding THRLBCL TME. Of therapeutic relevance, we validated our results by immunohistochemistry, identifying a subset of TCF1+ (T cell-specific transcription factor 1, encoded by the TCF7 gene) progenitor exhausted T cells enriched in patients with THRLBCL. This subset of TCF1+ exhausted T cells correlates with good clinical response to immune checkpoint therapy and may improve prediction of anti-PD-1 response in patients with THRLBCL.

A Malignant Lymphoma Growing Inside a Cardiac Mixoma: A Case Report

Abstract Introduction: Lymphomas arising from cardiac myxomas represent a particularly rare pathology, with only few cases reported in the literature. Case presentation: We report a complete excision of a malignant lymphoma arising from a cardiac myxoma in a 44-year-old female patient. The myxoma presented like a floating mass within the left atrium with a maximum diameter of 3.5 cm. The clinical post-operative period was uneventful and the patient was dismissed on the 6th post-operative day. Conclusion: This case reinforces the concept of radical excision of cardiac neoplasms.

Advances in therapeutic strategies for primary CNS B-cell lymphomas.

INTRODUCTION: Primary CNS lymphoma (PCNSL) has traditionally been treated with induction HD-MTX-based chemotherapy, followed by consolidation whole-brain radiotherapy. However, this approach is associated with significant neurocognitive complications, especially in older patients. Therefore, different consolidation protocols have been evaluated. High-dose chemotherapy followed by autologous stem cell transplantation (HD-ASCT) has the best long-term survival outcomes in younger patients. AREAS COVERED: In this review of the literature, we focus on the overall therapeutic strategy and advances in the management of the aggressive primary CNS B-cell lymphomas. EXPERT OPINION: In young and fit PCNSL patients, HD-ASCT is the preferred consolidation strategy to achieve long-term survivals. Older patients with good performance status should also be evaluated for MTX-based induction polychemotherapy followed by ASCT. However, management of PCNSL patients remains challenging, and new avenues with targeted therapies are under investigation. To date, ibrutinib, lenalidomide, and immune checkpoint inhibitors appearto be promising in PCNSL. However, as monotherapy, durable responses are less likely to be achieved. Unfortunately, when combined with chemoimmunotherapy, considerable toxicity and mortality have been reported. Clinical trials on these molecules are aiming to reduce toxicity and maintain responses. CAR-T-cell therapy has recently emerged as a further option. It has shown efficacy in patients with secondary CNS lymphoma, with few but encouraging results in primary CNSL.

A Malignant Lymphoma Growing Inside a Cardiac Mixoma: A Case Report.

INTRODUCTION: Lymphomas arising from cardiac myxomas represent a particularly rare pathology, with only few cases reported in the literature.Case presentation: We report a complete excision of a malignant lymphoma arising from a cardiac myxoma in a 44-year-old female patient. The myxoma presented like a floating mass within the left atrium with a maximum diameter of 3.5 cm. The clinical post-operative period was uneventful and the patient was dismissed on the 6th post-operative day. CONCLUSION: This case reinforces the concept of radical excision of cardiac neoplasms.

Dual targeting of the DNA damage response pathway and BCL-2 in diffuse large B-cell lymphoma.

Standard chemotherapies for diffuse large B-cell lymphoma (DLBCL), based on the induction of exogenous DNA damage and oxidative stress, are often less effective in the presence of increased MYC and BCL-2 levels, especially in the case of double hit (DH) lymphomas harboring rearrangements of the MYC and BCL-2 oncogenes, which enrich for a patient's population characterized by refractoriness to anthracycline-based chemotherapy. Here we hypothesized that adaptive mechanisms to MYC-induced replicative and oxidative stress, consisting in DNA damage response (DDR) activation and BCL-2 overexpression, could represent the biologic basis of the poor prognosis and chemoresistance observed in MYC/BCL-2-positive lymphoma. We first integrated targeted gene expression profiling (T-GEP), fluorescence in situ hybridization (FISH) analysis, and characterization of replicative and oxidative stress biomarkers in two independent DLBCL cohorts. The presence of oxidative DNA damage biomarkers identified a poor prognosis double expresser (DE)-DLBCL subset, characterized by relatively higher BCL-2 gene expression levels and enrichment for DH lymphomas. Based on these findings, we tested therapeutic strategies based on combined DDR and BCL-2 inhibition, confirming efficacy and synergistic interactions in in vitro and in vivo DH-DLBCL models. These data provide the rationale for precision-therapy strategies based on combined DDR and BCL-2 inhibition in DH or DE-DLBCL.

Peripheral T-Cell Lymphoma, Not Otherwise Specified: Clinical Manifestations, Diagnosis, and Future Treatment.

Peripheral T-cell lymphoma, not otherwise specified (PTCL_NOS) corresponds to about one fourth of mature T-cell tumors, which overall represent 10-12% of all lymphoid malignancies. This category comprises all T-cell neoplasms, which do not correspond to any of the distinct entities listed in the WHO (World Health Organization) Classification of Tumours of Haematopoietic and Lymphoid Tissues. In spite of the extreme variability of morphologic features and phenotypic profiles, gene expression profiling (GEP) studies have shown a signature that is distinct from that of all remaining PTCLs. GEP has also allowed the identification of subtypes provided with prognostic relevance. Conversely to GEP, next-generation sequencing (NGS) has so far been applied to a limited number of cases, providing some hints to better understand the pathobiology of PTCL_NOS. Although several pieces of information have emerged from pathological studies, PTCL_NOS still remains a tumor with a dismal prognosis. The usage of CHOEP (cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide) followed by autologous stem cell transplantation may represent the best option, by curing about 50% of the patients whom such an approach can be applied to. Many new drugs have been proposed without achieving the expected results. Thus, the optimal treatment of PTCL_NOS remains unidentified.

Newly-Discovered Neural Features Expand the Pathobiological Knowledge of Blastic Plasmacytoid Dendritic Cell Neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). The microRNA expression profile of BPDCN was compared to that of normal pDCs and the impact of miRNA dysregulation on the BPDCN transcriptional program was assessed. MiRNA and gene expression profiling data were integrated to obtain the BPDCN miRNA-regulatory network. The biological process mainly dysregulated by this network was predicted to be neurogenesis, a phenomenon raising growing interest in solid tumors. Neurogenesis was explored in BPDCN by querying different molecular sources (RNA sequencing, Chromatin immunoprecipitation-sequencing, and immunohistochemistry). It was shown that BPDCN cells upregulated neural mitogen genes possibly critical for tumor dissemination, expressed neuronal progenitor markers involved in cell migration, exchanged acetylcholine neurotransmitter, and overexpressed multiple neural receptors that may stimulate tumor proliferation, migration and cross-talk with the nervous system. Most neural genes upregulated in BPDCN are currently investigated as therapeutic targets.

MRI features of breast implant-associated anaplastic large cell lymphoma.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare and newly recognized subtype of T cell Non-Hodgkin Lymphoma (NHLs) associated with breast implants.The mechanism involved in the development of this kind of lymphoma is still uncertain.BIA-ALCL is generally an indolent disease localized to the breast implant and its capsule and effectively treated with capsulectomy alone without chemotherapy.Clinically, BIA-ALCL may typically present a sudden-onset breast-swelling secondary to periimplant effusion. The minority of BIA-ALCL patients present a more aggressive mass-forming subtype, for which systemic therapy is mandatory.Despite the number of cases has recently increased, BIA-ALCL remains a rare disease described mainly in several case reports and small case series.Breast imaging, including mammography, ultrasound and breast MRI are routinely used in the screening of breast cancer; however, guidelines for the imaging and pathological diagnosis of this disease have only recently been proposed and included in the 2019 National Comprehensive Cancer Network (NCCN) consensus guidelines for BIA-ALCL.The main purpose of this pictorial is to illustrate the MRI signs of BIA-ALCL and correlate them with the corresponding pathology features in order to improve the knowledge of the principals MRI features of this type of lymphoma.

Predictive and Prognostic Molecular Factors in Diffuse Large B-Cell Lymphomas.

Diffuse large B-cell lymphoma (DLBCL) is the commonest form of lymphoid malignancy, with a prevalence of about 40% worldwide. Its classification encompasses a common form, also termed as "not otherwise specified" (NOS), and a series of variants, which are rare and at least in part related to viral agents. Over the last two decades, DLBCL-NOS, which accounts for more than 80% of the neoplasms included in the DLBCL chapter, has been the object of an increasing number of molecular studies which have led to the identification of prognostic/predictive factors that are increasingly entering daily practice. In this review, the main achievements obtained by gene expression profiling (with respect to both neoplastic cells and the microenvironment) and next-generation sequencing will be discussed and compared. Only the amalgamation of molecular attributes will lead to the achievement of the long-term goal of using tailored therapies and possibly chemotherapy-free protocols capable of curing most (if not all) patients with minimal or no toxic effects.

Prognostic Impact of Baseline Immunologic Profile in Aggressive B-cell non-Hodgkin's Lymphomas.

Host immune homeostasis as an independent prognostic indicator has been inadequately evaluated in aggressive non-Hodgkin's lymphomas (NHL). The present study addresses the prognostic significance in aggressive NHLs of the immunologic profile evaluated by pretreatment serum levels of immunoglobulins (Ig) and lymphocyte-monocyte ratio (LMR). In this series of 90 patients with aggressive lymphoma, the median level for IgG was 1,024mg/dl (range 436-2236), and for LMR was 2.2 (range 0.2-13.8). CR rate was higher with IgG levels ≥1,024mg/dL (91% vs 77% p=0.059). LMR ≤ 2.2 was associated with lower 1-year PFS (73% vs. 92%, p 0.016). Patients with good/very good R-IPI showed a reduced PFS if IgG or LMR was low, while patients with poor R-IPI did better if LMR or IgG levels were high. We combined both parameters with the R-IPI and produced a four-risk prognostic score showing one-year PFS of 95% (95% CI 68%-99%), 100% (95% CI 100%-100%), 73% (95% CI 52%-86%), and 59% (95% CI 31%-79%), in patients with zero, one, two and three risk factors, respectively. The results indicate for the first time the value of baseline serum Ig levels in the prognostic assessment of aggressive lymphoma.

HHV8-Negative Effusion-Based Large B Cell Lymphoma Arising in Chronic Myeloid Leukemia Patients under Dasatinib Treatment: A Report of Two Cases.

Tyrosine kinase inhibitors (TKIs) are the treatment of choice for BCR-ABL1-positive chronic myeloid leukemia (CML). Although TKIs have substantially improved prognosis of CML patients, their use is not free of adverse effects. Dasatinib is a second generation TKI frequently associated with pleural effusion in up to 33% of patients. This results in symptoms as dyspnea, cough and chest pain that may require therapy discontinuation. In the present report, we describe two exceptional cases of HHV8-negative large B-cell effusion-based lymphoma (EBL) confined to the pleura, incidentally, diagnosed in patients presenting with dasatinib-related pleural effusion. One patient (case 1) is alive and is in remission at 17 months from large B-cell EBL diagnosis while unfortunately the other patient (case 2) died of progressive disease and COVID-19 pneumonia 16 months from large B-cell EBL diagnosis. These cases raise concern about a possible association between large B-cell EBL and dasatinib, and the different clinical outcome of the two cases poses a challenge in treatment decision. For this reason, we strongly recommend cytological investigation in patients with persistent/relapsing pleural effusion under dasatinib, primarily to validate its possible association with lymphoma development and to improve the knowledge about this entity.

A three-gene signature based on MYC, BCL-2 and NFKBIA improves risk stratification in diffuse large B-cell lymphoma.

Recent randomized trials focused on gene expression-based determination of the cell of origin in diffuse large B-cell lymphoma could not show significant improvements by adding novel agents to standard chemoimmunotherapy. The aim of this study was the identification of a gene signature able to refine current prognostication algorithms and applicable to clinical practice. Here we used a targeted gene expression profiling panel combining the Lymph2Cx signature for cell of origin classification with additional targets including MYC, BCL-2 and NFKBIA, in 186 patients from 2 randomized trials (discovery cohort) (NCT00355199 and NCT00499018). Data were validated in 3 independent series (2 large public datasets and a real-life cohort). By integrating the cell of origin, MYC/BCL-2 double expressor status and NFKBIA expression, we defined a 3-gene signature combining MYC, BCL-2 and NFKBIA (MBN-signature), which outperformed the MYC/BCL-2 double expressor status in multivariate analysis, and allowed further risk stratification within the germinal center B-cell/unclassified subset. The high-risk (MBN Sig-high) subgroup identified the vast majority of double hit cases and a significant fraction of Activated B-Cell-derived diffuse large B-cell lymphomas. These results were validated in 3 independent series including a cohort from the REMoDL-B trial, where, in an exploratory ad hoc analysis, the addition of bortezomib in the MBN Sig-high subgroup provided a progression free survival advantage compared with standard chemoimmunotherapy. These data indicate that a simple 3-gene signature based on MYC, BCL-2 and NFKBIA could refine the prognostic stratification in diffuse large B-cell lymphoma, and might be the basis for future precision-therapy approaches.