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Simple Summary: This research aims to identify new protein markers that can help predict the risk of disease progression in patients with follicular lymphoma (FL) at the time of diagnosis. By analyzing a large number of proteins in FL samples, the study found significant differences in protein composition among patients, which may help distinguish those at higher risk of disease progression. These findings could improve our understanding of FL biology and lead to the discovery of new biomarkers or treatment targets, potentially allowing for more personalized and effective treatment strategies for FL patients, improving their outcomes. Background: Follicular lymphoma (FL) is characterized by an indolent nature and generally favorable prognosis, yet poses a particular clinical challenge, since disease progression is observed in a notable subset of patients. Currently, it is not possible to anticipate which patients will be at risk of progression, highlighting the need for reliable predictive biomarkers that can be detected early in the disease. Methods: We applied tandem-mass-tag labelled nano-liquid chromatography tandem mass spectrometry (nLC-MS/MS) on 48 diagnostic formalin-fixed, paraffin-embedded tumor samples from patients with advanced-stage FL. Of these, 17 experienced subsequent progression (subsequently-progressing, sp-FL) while 31 did not (non-progressing, np-FL). Results: We identified 99 proteins that were significantly differentially expressed between sp-FL samples and np-FL samples (p < 0.05; log2-fold changes between 0.2 and −1.3). Based on this subset of proteins, we classified patients into high-risk and low-risk subgroups using unsupervised machine learning techniques. Pathway analyses of the identified proteins revealed aberrancies within the immune system and cellular energy metabolism. In addition, two proteins were selected for immunohistochemical evaluation, namely stimulator of interferon genes 1 (STING1) and isocitrate dehydrogenase 2 (IDH2). Notably, IDH2 retained significantly lower expression levels in sp-FL samples compared with np-FL samples (p = 0.034). Low IDH2 expression correlated with shorter progression-free survival (PFS, p = 0.020). Conclusions: This study provides evidence for some of the biological mechanisms likely to be involved in FL progression and, importantly, identifies potential predictive biomarkers for improvement of risk stratification up-front at time of FL diagnosis. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) is a lymphoid neoplasia characterized by an indolent clinical nature. Despite generally favorable prognoses, early progression and histological transformation (HT) to a more aggressive lymphoma histology remain the leading causes of death among FL patients. To provide a basis for possible novel treatment options, we set out to evaluate the expression levels of indoleamine 2,3-dioxygenase 1 (IDO1), an immunoinhibitory checkpoint molecule, in follicular and transformed follicular biopsies. The expression levels of IDO1 were assessed using immunohistochemical staining and digital image analysis in lymphoma biopsies from 33 FL patients without subsequent HT (non-transforming FL, nt-FL) and 20 patients with subsequent HT (subsequently transforming FL, st-FL) as well as in paired high-grade biopsies from the time of HT (transformed FL, tFL). Despite no statistical difference in IDO1 expression levels seen between the groups, all diagnostic and transformed lymphomas exhibited positive expression, indicating its possible role in novel treatment regimens. In addition, IDO1 expression revealed a positive correlation with another immune checkpoint inhibitor, namely programmed death 1 (PD-1). In summary, we report IDO1 expression in all cases of FL and tFL, which provides the grounds for future investigations of anti-IDO1 therapy as a possible treatment for FL patients. [ABSTRACT FROM AUTHOR]

Purpose: Follicular lymphoma (FL) is an indolent, yet generally incurable neoplasia with a median survival exceeding 10 years. However, a subset of FL patients experiences histological transformation (HT) to a more aggressive lymphoma, in the majority of cases to diffuse large B-cell lymphoma (DLBCL). This affects both the clinical course and the prognostic outcome, resulting in a markedly reduced survival after transformation. Thus, early risk stratification and prediction of patients at risk of HT would be highly valuable in the clinical setting. Here, we investigated the potential of the immune inhibitory programmed death 1 (PD-1) receptor as a biomarker predictive of HT. Patients and Methods: Immunohistochemical staining and quantification by digital image analysis of PD-1 was performed on diagnostic tumor-tissue samples from FL patients with and without subsequent transformation (n=34 and n=46, respectively), and on paired samples from the transformed lymphoma (n=34). Results: At the time of initial FL diagnosis, samples from patients with subsequent HT had significantly higher tumor-tissue expression of PD-1 compared with diagnostic FL samples from patients without subsequent HT (p=0.010). At the time of transformation, PD-1 expression was significantly reduced (p< 0.001). No difference was observed in intra-follicular PD-1 expression at FL diagnosis between samples from patients with or without HT; however, high intra-follicular levels of PD-1 were associated with significantly shorter transformation-free survival times (p< 0.043). Conclusion: Our data suggest that pre-treatment tumor-tissue PD-1 expression already predicts the risk of subsequent transformation to DLBCL, as early as the time of FL diagnosis. [ABSTRACT FROM AUTHOR]

Purpose: The proliferation marker Ki-67 has been used as a prognostic marker to separate low- and high-risk breast cancer subtypes and guide treatment decisions for adjuvant chemotherapy. The association of Ki-67 with response to tamoxifen therapy is unclear. High-throughput automated scoring of Ki-67 might enable standardization of quantification and definition of clinical cut-off values. We hypothesized that digital image analysis (DIA) of Ki-67 can be used to evaluate proliferation in breast cancer tumors, and that Ki-67 may be associated with tamoxifen resistance in early-stage breast cancer. Patients and Methods: Here, we apply DIA technology from Visiopharm using a custom designed algorithm for quantifying the expression of Ki-67, in a case–control study nested in the Danish Breast Cancer Group clinical database, consisting of stages I, II, or III breast cancer patients of 35– 69 years of age, diagnosed during 1985– 2001, in the Jutland peninsula, Denmark. We assessed DIA-Ki-67 score on tissue microarrays (TMAs) from breast cancer patients in a case–control study including 541 ER-positive and 300 ER-negative recurrent cases and their non-recurrent controls, matched on ER-status, cancer stage, menopausal status, year of diagnosis, and county of residence. We used logistic regression to estimate odds ratios and associated 95% confidence intervals to determine the association of Ki-67 expression with recurrence risk, adjusting for matching factors, chemotherapy, type of surgery, receipt of radiation therapy, age category, and comorbidity. Results: Ki-67 was not associated with increased risk of recurrence in tamoxifen-treated patients (ORadj =0.72, 95% CI 0.54, 0.96) or ER-negative patients (ORadj =0.85, 95% CI 0.54, 1.34). Conclusion: Our findings suggest that Ki-67 digital image analysis in TMAs is not associated with increased risk of recurrence among tamoxifen-treated ER-positive breast cancer or ER-negative breast cancer patients. Overall, our findings do not support an increased risk of recurrence associated with Ki-67 expression. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) is an indolent neoplasia comprising approximately 20% of lymphomas. FL is generally considered incurable, with a median survival exceeding 10 years. A subset of FL patients experiences histological transformation (HT) to a more aggressive lymphoma, resulting in markedly poorer clinical outcome, with a reduced median survival after transformation of 1–2 years. Early, reliable prediction of HT would be valuable in the clinical setting, allowing pre-emptive therapeutic intervention. We previously used proteomics to identify the glycolytic enzymes fructose-bisphosphate aldolase A (aldolase A) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as candidate predictors of FL transformation. Now, we use immunohistochemistry to evaluate expression of these enzymes in paired primary FLs from patients with (n = 41) or without subsequent HT (n = 49), to test their value as predictive biomarkers. At initial FL diagnosis, patients with subsequent HT had significantly higher expression of aldolase A and GAPDH (p<0.001 and p<0.01) compared with patients without HT. Furthermore, high expression of aldolase A and GAPDH was associated with significantly shorter transformation free survival (p = 0.018, p = 0.001). These data suggest that high expression of aldolase A and GAPDH, may indicate increased metabolic turnover, and that these enzymes may be useful biomarkers in primary FL for predicting the risk of subsequent lymphoma transformation. [ABSTRACT FROM AUTHOR]

Simple Summary: Histological transformation remains the leading cause of death in patients diagnosed with follicular lymphoma (FL). To date, no clinical nor biological biomarkers have been identified to unequivocally predict patients in high risk of transformation. In this study, we investigated the predictive value of the hyaluronic acid receptors RHAMM and CD44. Expression levels of RHAMM were higher in patients with subsequent transformation and were associated with poorer outcome. Histological transformation (HT) remains the leading cause of mortality in follicular lymphoma (FL), underlining the need to identify reliable transformation predictors. The hyaluronic acid receptors CD44 and the receptor for hyaluronan mediated motility (RHAMM, also known as HMMR and CD168), have been shown to be involved in the pathogeneses of both solid tumors and hematological malignancies. In an attempt to improve risk stratification, expression of RHAMM and CD44 were evaluated by immunohistochemistry and digital image analysis in pre-therapeutic tumor-tissue biopsies from FL patients, either without (nt-FL, n = 34), or with (st-FL, n = 31) subsequent transformation, and in paired biopsies from the transformed lymphomas (tFL, n = 31). At the time of initial diagnosis, samples from st-FL patients had a higher expression of RHAMM compared with samples from nt-FL patients (p < 0.001). RHAMM expression further increased in tFL samples following transformation (p < 0.001). Evaluation of CD44 expression showed no differences in expression comparing nt-FL, st-FL, and tFL samples. Shorter transformation-free survival was associated with high tumoral and intrafollicular RHAMM expression, as well as with low intrafollicular CD44 expression (p = 0.002, p < 0.001, and p = 0.034, respectively). Our data suggest that high tumor-tissue RHAMM expression predicts the risk of shorter transformation-free survival in FL patients already at initial diagnosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients are diagnosed with myeloproliferative neoplasia (MPN) and lymphoma more frequently in the population than expected, which has led to the hypothesis that the two malignancies may, in some cases, be pathogenetically related. In this study, lymphoma patients with and without MPN show subtle but important differences in the protein expression that enables the clustering of the lymphomas, thus indicating the differences at the molecular level between the lymphoma malignancies with and without MPN, and strengthening the hypothesis that the lymphoma and MPN may be biologically related. Myeloproliferative neoplasia (MPN) and lymphoma are regarded as distinct diseases with different pathogeneses. However, patients that are diagnosed with both malignancies occur more frequently in the population than expected. This has led to the hypothesis that the two malignancies may, in some cases, be pathogenetically related. Using a mass spectrometry-based proteomic approach, we show that pre-treatment lymphoma samples from patients with both MPN and lymphoma, either angioimmunoblastic T-cell lymphoma (MPN-AITL) or diffuse large B-cell lymphoma (MPN-DLBCL), show differences in protein expression compared with reference AITL or DLBCL samples from patients without MPN. A distinct clustering of samples from patients with and without MPN was evident for both AITL and DLBCL. Regarding MPN-AITL, a pathway analysis revealed disturbances of cellular respiration as well as oxidative metabolism, and an immunohistochemical evaluation further demonstrated the differential expression of citrate synthase and DNAJA2 protein (p = 0.007 and p = 0.015). Interestingly, IDH2 protein also showed differential expression in the MPN-AITL patients, which contributes to the growing evidence of this protein's role in both myeloid neoplasia and AITL. In MPN-DLBCL, the disturbed pathways included a significant downregulation of protein synthesis as well as a perturbation of signal transduction. These results imply an underlying disturbance of tumor molecular biology, and in turn an alternative pathogenesis for tumors in these patients with both myeloid and lymphoid malignancies. [ABSTRACT FROM AUTHOR]

ABSTRACT Classic Hodgkin lymphoma (CHL) is a highly curable disease, even in advanced stages. Controversy remains over whether bone involvement negatively affects overall and progression‐free survival in patients treated with intensive chemotherapy regimens. Whether cases that present with bone lesions harbor specific tumor microenvironmental features is unknown. We investigated protein expression in diagnostic lymph node biopsies from CHL patients with and without skeletal involvement at diagnosis to identify potential markers of skeletal disease. Protein expression patterns in diagnostic formalin‐fixed paraffin‐embedded lymphoma lymph node samples from CHL patients were analyzed by nano‐liquid chromatography–tandem mass spectrometry. Patients were grouped according to skeletal involvement, which was defined as the presence of one or more FDG‐avid lesions on a diagnostic FDG‐PET/CT scan. Protein profiles identified patients with skeletal disease at diagnosis and showed disrupted cellular pathways, including immune system processes, cell adhesion, and cell growth/survival. Immunohistochemical evaluation also demonstrated differential expressions of angiotensin‐converting enzyme (ACE), intercellular adhesion molecule 3 (ICAM3), integrin alpha‐X (ITGAX), and calreticulin (CALR). In conclusion, proteomics identified altered protein expression profiles in lymph nodes among CHL cases presenting with disease disseminated to the skeletal system, which implies altered disease pathogenesis for these patients. [ABSTRACT FROM AUTHOR]