Lysyl-Oxidase Dependent Extracellular Matrix Stiffness in Hodgkin Lymphomas: Mechanical and Topographical Evidence

Purpose: The biochemical composition and architecture of the extracellular matrix (ECM) is known to condition development and invasiveness of neoplasms. To clarify this point, we analyzed ECM stiffness, collagen cross-linking and anisotropy in lymph nodes (LN) of Hodgkin lymphomas (HL), follicular lymphomas (FL) and diffuse large B-cell lymphomas (DLBCL), compared with non-neoplastic LN (LDN). Methods and Results: We found increased elastic (Young’s) modulus in HL and advanced FL (grade 3A) over LDN, FL grade 1–2 and DLBCL. Digital imaging evidenced larger stromal areas in HL, where increased collagen cross-linking was found; in turn, architectural modifications were documented in FL3A by scanning electron microscopy and enhanced anisotropy by polarized light microscopy. Interestingly, HL expressed high levels of lysyl oxidase (LOX), an enzyme responsible for collagen cross-linking. Using gelatin scaffolds fabricated with a low elastic modulus, comparable to that of non-neoplastic tissues, we demonstrated that HL LN-derived mesenchymal stromal cells and HL cells increased the Young’s modulus of the extracellular microenvironment through the expression of LOX. Indeed, LOX inhibition by β-aminopropionitrile prevented the gelatin stiffness increase. Conclusions: These data indicate that different mechanical, topographical and/or architectural modifications of ECM are detectable in human lymphomas and are related to their histotype and grading.

Low-Grade Primary Splenic CD10-Positive Small B-Cell Lymphoma/Follicular Lymphoma

Primary splenic lymphoma (PSL) is a rare malignancy representing about 1% of all lymphoproliferative disorders, when using a strict definition that allows only involvement of spleen and hilar lymph nodes. In contrast, secondary low-grade B-cell lymphomas in the spleen, such as follicular lymphomas (FL), lymphoplasmacytic lymphoma and chronic lymphocytic leukemia/ small lymphocytic lymphoma, particularly as part of advanced stage disease, are more common. Indolent B cell lymphomas expressing CD10 almost always represent FL, which in its primary splenic form is the focus of this review. Primary splenic follicular lymphoma (PSFL) is exceedingly infrequent. This type of lymphoproliferative disorder is understudied and, in most cases, clinically characterized by splenomegaly or cytopenias related to hypersplenism. The diagnosis requires correlation of histopathology of spleen, blood and/or bone marrow with the correct immunophenotype (determined by flow cytometry and/or immunohistochemistry) and if necessary, additional molecular profiling. Management of this incurable disease is evolving, and splenectomy remains the mainstream treatment for stage I PSFL.

Radioimmunotherapy in Oncology: Overview of the Last Decade Clinical Trials

The specific irradiation of tumors with selective radiolabeled antibodies constitutes an attractive therapeutic approach. Consequent preclinical research has been conducted by both biologists to identify pertinent targets and to select corresponding antibodies (mAb) and by radiochemists to radiolabel mAbs. These numerous preclinical investigations have ascertained the therapeutic interest of radioimmunotherapy (RIT) protocols in mice models. Here, we summarize the clinical studies that have been performed the last decade, including clinical trials (phases I, II, and III), prospective and retrospective studies, and cases series. We thereby reported 92 clinical studies. Among them, 62 concern the treatment of hematological malignancies, and 30 concern solid tumors. For hematologic diseases, the analysis was complex due to the high discrepancy of therapeutic strategies (first-line therapy, consolidation, stem cell transplantation conditioning) as well as the high variety of malignancies that were treated. The clinical studies from the last decade failed to expand anti-CD20 RIT indications but confirmed that RIT using radiolabeled anti-CD20 remains a pertinent choice for patients with relapse follicular lymphomas. For solid tumors, the positive benefit of RIT is more mitigated, apart for few malignancies that can be treated locally. Clinical trials also demonstrated the potential of some antibody formats, such as F(ab′)2, which has already been approved by the China State FDA under the trend name Licartin®. Despite disparate results, mAb fragments are an interesting prospect for the improvement of RIT efficiency as well as for pretargeted strategies that delay the injection of radioactive treatments from the mAb ones.

Follicular lymphoma subgroups with and without t(14;18) differ in their N-glycosylation pattern and IGHV usage

We previously reported that t(14;18)-negative follicular lymphomas (FL) show a clear reduction of newly acquired N-glycosylation sites (NANGS) in immunoglobulin genes. We therefore aimed to investigate in-depth the occurrence of NANGS in a larger cohort of t(14;18)-positive and t(14;18)-negative FL, including early (I/II) and advanced (III/IV) stage treatment naïve and relapsed tumors. We determined the clonotype using a next generation sequencing approach in a series of 68 FL with fresh frozen material (36 t(14;18)-positive and 32 t(14;18)-negative). The frequency of NANGS differed considerably between t(14;18)-positive and t(14;18)-negative FL III/IV, but no difference was observed among t(14;18)-positive and t(14;18)-negative FL I/II. The introduction of NANGS in all t(14;18)-negative clinical subgroups occurred significantly more often in the FR3 region. Moreover, t(14;18)-negative treatment naïve FL, specifically those with NANGS, showed a strong bias for IGHV4-34 usage compared to t(14;18)-positive treatment naïve cases with NANGS, while IGHV4-34 usage was never found in relapsed FL. In conclusion, subgroups of t(14;18)-negative FL might use different mechanisms of BCR stimulation compared to the lectin-mediated binding described in t(14;18)-positive FL, including responsiveness to autoantigens as indicated by biased IGHV4-34 usage and strong NANGS enrichment in FR3.

Excess mortality by patient’s multimorbidity, socioeconomic, and healthcare factors, among Diffuse Large B–cell and Follicular lymphomas patients in England: A population-based multilevel study

Background Socioeconomic inequalities of survival in patients with non–Hodgkin lymphoma (NHL) persists, which may be explained by patients’ comorbidities. We aimed to assess the association between co/multimorbidity and survival in patients diagnosed with Diffuse Large B-cell (DLBCL) or Follicular lymphoma (FL) in England accounting for other socio-demographic characteristics. Methods Population-based cancer registry data was linked to Hospital Episode Statistics. We used a flexible multilevel excess hazard model to estimate 5–year net survival and excess mortality by patient’s multimorbidity and comorbidity status adjusted for sociodemographic, economic, healthcare factors, and accounting for the patient’s area of residence. Results Overall, 15,516 and 29,898 patients were diagnosed with FL and DLBCL in England between 2005–2013, respectively. Respectively, those with comorbidities and multimorbidities had 1.3 (95% Confidence Interval -CI-: 1.20–1.40) and 1.5 (95% CI 1.27–1.87) times higher excess mortality compared to those without comorbidities. Patients in most deprived areas showed 26% (95% CI 1.20–1.32) excess mortality risk compared to those in least deprived areas. Conclusion Co/multimorbidities are consistently associated with poorer survival among patients diagnosed with DLBCL or FL. Comorbidities and multimorbidity need to be considered when planning public health interventions targeting haematological malignancies in England.

Significance of abnormal 53BP1 expression as a novel molecular pathologic parameter of follicular-shaped B-cell lymphoid lesions in human digestive tract

The digestive tract is a common site of extranodal malignant lymphomas (MLs) and benign lymphoid lesions (BLs). TP53-binding protein 1 (53BP1) expression has been widely investigated in class switch recombination but rarely in human lymphoid tissues with respect to tumorigenesis. We previously reported that immunofluorescence (IF) analysis of 53BP1 nuclear foci (NF), reflecting DNA double strand breaks, is useful for estimating genomic instability in different tumor types. In this study, we evaluated the potential of IF-based analysis of 53BP1 expression in differentiating MLs from BLs. We examined 231 biopsied tissue samples of primary MLs and BLs in the digestive tract. The 53BP1 immunoreactivity pattern was determined by multicolor IF. Compared to BLs, MLs showed a high frequency of abnormal 53BP1 expression (p < 0.0001). Statistically, abnormal 53BP1 expression is an effective test for distinguishing follicular lymphomas from BLs (specificity 98.6%, sensitivity 86.8%) and for distinguishing small B-cell lymphomas from BLs (specificity 98.3%, sensitivity 77.6%). Furthermore, a high frequency of abnormal 53BP1 expression was associated with “high-risk” MALT lymphomas, which exhibited t(11;18)(q21;21) (p = 0.0145). Collectively, these results suggest that IF-based analysis of 53BP1 expression in biopsy samples is a promising technique for diagnosing MLs in the digestive system.