Single gene mutations and prognosis in limited-stage follicular lymphoma treated with radiation therapy.

Radiotherapy is routinely used for management of limited-stage follicular lymphoma (FL), yet half of patients ultimately relapse. We hypothesized that the presence of specific gene mutations may predict outcomes. We performed targeted sequencing of a 69-gene panel in 117 limited-stage FL patients treated with radiotherapy and identified recurrently mutated genes. CREBBP was most frequently mutated, and mutated CREBBP was associated with inferior progression-free survival, though not after false discovery rate adjustment. This association failed to validate in an independent cohort. We conclude that recurrent gene mutations do not predict outcomes in this setting. Alternative biomarkers may offer better prognostic insight.

Validation of the RHL30 digital gene expression assay as a prognostic biomarker for relapsed Hodgkin lymphoma.

Despite continuing improvements in the management of classical Hodgkin lymphoma (cHL), relapse remains associated with a risk of lymphoma-related mortality. The biological composition of relapse tumour biopsies shows interpatient variability, which can be leveraged to design prognostic biomarkers. Here, we validated the RHL30 assay, a previously reported gene expression model in an independent cohort of 41 patients with relapsed cHL. Patients classified as high-risk by the RHL30 assay had inferior failure-free survival (FFS) after autologous stem cell transplantation (2-year FFS 41% vs. 92%, P = 0·035). The RHL30 model is a robust biomarker that risk-stratifies patients considered for autologous stem cell transplantation.

How Wide Should Margins Be for Phyllodes Tumors of the Breast?

The surgical management of phyllodes tumors (PTs) is still controversial. Some studies have suggested surgical margins ≥1 cm, but recent studies suggested that negative margins could be appropriate regardless of their width. To evaluate recurrence rates of PTs following surgery according to margins. Retrospective study of women who attended a tertiary breast cancer reference center between 1998 and 2010: 142 patients with a PT diagnosis, either at minimally invasive breast biopsy or at surgery, were identified. Clinical, pathologic and follow-up characteristics were assessed. Among 140 patients who underwent surgery, 64.3% of biopsies accurately predicted the final PT diagnosis at surgery. Forty-two (42/87, 48.3%) PTs had positive margins. Twenty-one (21/42, 50.0%) patients had a surgical revision of margins. Only one (1/42, 2.4%) had margins greater or equal to 1 cm. After a median follow-up of 1.29 years in benign PTs, 4.99 years in borderline PTs, and 5.42 years in malignant PTs, there were five local recurrences, three in originally benign PTs and two in borderline PTs. All were managed with surgery. Four had initial margins ≤1 mm. One patient with borderline PT had a local recurrence and later progressed to regional recurrence and metastasis. Free surgical margins are necessary to treat PT, and margins of at least 1 mm might be sufficient to prevent recurrence. Core needle biopsy might not be the best diagnostic tool for PTs.

Identification of genetic subtypes in follicular lymphoma.

Follicular lymphoma (FL) exhibits considerable variability in biological features and clinical trajectories across patients. To dissect the diversity of FL, we utilized a Bernoulli mixture model to identify genetic subtypes in 713 pre-treatment tumor tissue samples. Our analysis revealed the existence of five subtypes with unique genetic profiles that correlated with clinicopathological characteristics. The clusters were enriched in specific mutations as follows: CS (CREBBP and STAT6), TT (TNFAIP3 and TP53), GM (GNA13 and MEF2B), Q (quiescent, for low mutation burden), and AR (mutations of mTOR pathway-related genes). The subtype Q was enriched for patients with stage I disease and associated with a lower proliferative history than the other subtypes. The AR subtype was unique in its enrichment for IgM-expressing FL cases and was associated with advanced-stage and more than 4 nodal sites. The existence of subtypes was validated in an independent cohort of 418 samples from the GALLIUM trial. Notably, patients assigned to the TT subtype consistently experienced inferior progression-free survival when treated with immunochemotherapy. Our findings offer insight into core pathways distinctly linked with each FL cluster and are expected to be informative in the era of targeted therapies.

Breast implant-associated EBV-positive diffuse large B-cell lymphoma: Two case reports and literature review.

Lymphomas associated with breast implants are mostly of the T-cell type. They are predominantly anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALK-negative ALCL) characterized by CD30 positivity universally. Whilst the majority of primary breast lymphomas occurring in the absence of breast implants are of B-cell origin, there are few cases of implant-associated B-cell lymphomas reported to date in the literature, a subset of which are diffuse large B-cell lymphoma (DLBCL). Given the rarity of this entity, we describe two cases of breast implant-associated DLBCL. Both patients developed Epstein-Barr Virus (EBV)-positive large cell lymphoma of B-cell origin confined to the implant capsule with no evidence of systemic lymphoma. Considering the association with EBV, the activated B-cell phenotype and the presumed chronic inflammatory environment associated with the implant capsule, these might represent forms of DLBCL associated with chronic inflammation (DLBCL-CI) or fibrin-associated DLBCL (FA-DLBCL). Treatment included implant removal with total capsulectomy, and for one of the cases adjuvant systemic chemotherapy. Recognizing this rare type of breast implant-associated B-cell lymphoma could improve our understanding of this entity and hence develop appropriate management strategies.

DNA Methylation-Based Classification of Small B-Cell Lymphomas: A Proof-of-Principle Study.

Although most small B-cell lymphomas (SBCLs) can be diagnosed using routine methods, challenges exist. For example, marginal zone lymphomas (MZLs) can be difficult to rule-in, in large part because no widely-used, sensitive, and specific biomarker is available for the marginal zone cell of origin. In this study, it was hypothesized that DNA methylation array profiling can assist with the classification of SBCLs, including MZLs. Extramedullary SBCLs, including challenging cases, were reviewed internally for pathology consensus and profiled. By combining the resulting array data set with data sets from other groups, a set of 26 informative probes was selected and used to train machine learning models to classify 4 common SBCLs: chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, mantle cell lymphoma, and MZL. Prediction probability cutoff was used to separate classifiable from unclassifiable cases, and show that the trained model was able to classify 95% of independent test cases (n = 264/279). The concordance between model predictions and pathology diagnoses was 99.6% (n = 262/263) among classifiable test cases. One validation reference test case was reclassified based on model prediction. The model was also used to predict the diagnoses of two challenging SBCLs. Although the differential examined and data on difficult cases are limited, these results support accurate methylation-based classification of SBCLs. Furthermore, high specificities of predictions suggest that methylation signatures can be used to rule-in MZLs.

Role of CD47 in Hematological Malignancies.

CD47, or integrin-associated protein, is a cell surface ligand expressed in low levels by nearly all cells of the body. It plays an integral role in various immune responses as well as autoimmunity, by sending a potent "don't eat me" signal to prevent phagocytosis. A growing body of evidence demonstrates that CD47 is overexpressed in various hematological malignancies and its interaction with SIRPα on the phagocytic cells prevents phagocytosis of cancer cells. Additionally, it is expressed by different cell types in the tumor microenvironment and is required for establishing tumor metastasis. Overexpression of CD47 is thus often associated with poor clinical outcomes. CD47 has emerged as a potential therapeutic target and is being investigated in various preclinical studies as well as clinical trials to prove its safety and efficacy in treating hematological neoplasms. This review focuses on different therapeutic mechanisms to target CD47, either alone or in combination with other cell surface markers, and its pivotal role in impairing tumor growth and metastatic spread of various types of hematological malignancies.

Modulating PD-L1 expression in multiple myeloma: an alternative strategy to target the PD-1/PD-L1 pathway.

Even with recent advances in therapy regimen, multiple myeloma patients commonly develop drug resistance and relapse. The relevance of targeting the PD-1/PD-L1 axis has been demonstrated in pre-clinical models. Monotherapy with PD-1 inhibitors produced disappointing results, but combinations with other drugs used in the treatment of multiple myeloma seemed promising, and clinical trials are ongoing. However, there have recently been concerns about the safety of PD-1 and PD-L1 inhibitors combined with immunomodulators in the treatment of multiple myeloma, and several trials have been suspended. There is therefore a need for alternative combinations of drugs or different approaches to target this pathway. Protein expression of PD-L1 on cancer cells, including in multiple myeloma, has been associated with intrinsic aggressive features independent of immune evasion mechanisms, thereby providing a rationale for the adoption of new strategies directly targeting PD-L1 protein expression. Drugs modulating the transcriptional and post-transcriptional regulation of PD-L1 could represent new therapeutic strategies for the treatment of multiple myeloma, help potentiate the action of other drugs or be combined to PD-1/PD-L1 inhibitors in order to avoid the potentially problematic combination with immunomodulators. This review will focus on the pathophysiology of PD-L1 expression in multiple myeloma and drugs that have been shown to modulate this expression.

EZH2 as a therapeutic target for multiple myeloma and other haematological malignancies.

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that is of great interest in human cancer. It has been shown to have a dual nature, as it can act as a gene repressor or activator. Studies have highlighted the various roles of EZH2 in the pathophysiology of multiple myeloma (MM). It was also shown to have a role in the development of drug resistance in MM. There are several ongoing clinical trials of EZH2 inhibitors in haematological malignancies. Pre-clinical studies have provided a rationale for the therapeutic relevance of EZH2 inhibitors in MM. This paper reviews the evidence supporting the role of EZH2 in MM pathophysiology and drug resistance, with an emphasis on interactions between EZH2 and microRNAs, as well as the prognostic significance of EZH2 expression in MM. Furthermore, results from the pre-clinical studies of EZH2 inhibition in MM and currently available interim results from clinical trials of EZH2 inhibitors in haematological malignancies are presented. Preliminary data exploring anticipated mechanisms of resistance to EZH2 inhibitors are also reviewed. There is therefore strong evidence to support the relevance of targeting EZH2 for the treatment of MM.

Alcohol and HER2 polymorphisms as risk factor for cardiotoxicity in breast cancer treated with trastuzumab.

BACKGROUND: Trastuzumab has no major side-effects except the potential for cardiac toxicity. The main objective of this study was to evaluate the association between trastuzumab-associated cardiac toxicity and two potential risk factors: alcohol intake and HER2 polymorphisms. PATIENTS AND METHODS: In a retrospective cohort study of 237 women with non-metastatic HER2-positive breast cancer treated with trastuzumab, traditional risk factors were assessed by review of medical records, alcohol use by an administered questionnaire to women (n=132), and HER2 polymorphisms (Ile655Val and Ala1170Pro) using TaqMan assays (n=73). RESULTS: Association was observed between alcohol intake (10 drinks and more per week) during the trastuzumab treatment and cardiac toxicity (p=0.04). For polymorphisms, compared to Ile/Ile carriers, HER2 Ile/Val was associated with a higher risk of cardiac toxicity (p=0.02). CONCLUSION: Heavy alcohol use during the course of trastuzumab treatment and the HER2 Ile/Val genotype may constitute risk factors for cardiac toxicity.