Search

Gray-zone lymphoma (GZL) reflects an aggressive B-cell neoplasm with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). The International Prognostic Index (IPI) and its derivatives (R-IPI, NCCN-IPI, and the Hasenclever IPS) have been established for DLBCL or cHL while the most suitable scoring system for GZL remains undetermined. In an exploratory multi-centric cohort of GZL (n = 61), we performed a comparative analysis of prognostic indices with regard to model fit and mutual concordance. The calculation of the corrected Akaike's information criterion (cAIC) and Harrel's concordance index (c-index) for each scoring system identified the NCCN-IPI to harbor the most convincing prognostic capabilities regarding both overall survival (OS) and progression-free survival (PFS) compared to its enhanced derivatives. The current results affirm the clinical utility of the NCCN-IPI and suggest its preferential use in clinical practice in GZL-patients. [ABSTRACT FROM AUTHOR]

Summary: Burkitt lymphoma (BL) is an aggressive B‐cell‐malignancy derived from germinal‐centre B‐cells. Curative therapy traditionally requires intensive immunochemotherapy. Recently, immuno‐oncological approaches, modulating the T‐cell tumour response, were approved for the treatment of a variety of malignancies. The architecture of the tumour‐infiltrating T‐cell receptor (TCR) repertoire in BL remains insufficiently characterized. We therefore performed a large‐scale, next‐generation sequencing study of the complimentary‐determining region (CDR)‐3 region of the TCRβ chain repertoire in a large cohort of all epidemiological subtypes of BL (n = 82) and diffuse large B‐cell lymphoma (DLBCL; n = 34). Molecular data were subsequently assessed for correlation with clinical outcome. Our investigations revealed an age‐dependent immunoprofile in BL as in DLBCL. Moreover, we found several public clonotypes in numerous patients suggestive of shared tumour neoantigen selection exclusive to BL and distinct from DLBCL regardless of Epstein–Barr virus and/or human immunodeficiency virus status. Compared with baseline, longitudinal analysis unveiled significant repertoire restrictions upon relapse (P = 0·0437) while productive TCR repertoire clonality proved to be a useful indicator of both overall and progression‐free‐survival [OS: P = 0·0001; hazard ratio (HR): 6·220; confidence interval (CI): 2·263–11·78; PFS: P = 0·0025; HR: 3·086; CI: 1·555–7·030]. Multivariate analysis confirmed its independence from established prognosticators, including age at diagnosis and comorbidities. Our findings establish the clinical relevance of the architecture and clonality of the TCR repertoire and its age‐determined dynamics in BL. [ABSTRACT FROM AUTHOR]

The article presents a study on investigation of the prognostic capabilities of Glasgow Prognostic Score (GPS)advanced stage classical Hodgkin lymphoma (cHL) as a complementary resource for risk stratification. Topics include treatment of patients with a chemotherapy regimen along with Clinicopathological characteristics; multivariate analysis along GPS incorporating Positron emission tomography (PET) and limitations of the study which include its sample size and retrospective design.

The article focuses on a study related to exploring whether single nucleotide polymorphism (SNP) will be clinical outcome predictive in multiple myeloma (MM) or not, using autologous stem cell support and high-dose melphalan. Topics discussed include assumption of polygenic phenomenon for MM risk; treatment of patients with thalidomide monotherapy; and use of SNP in TP53 is predictive of clinical outcome in MM.

A letter to the editor is presented regarding the study on the prognostic impact of RAS mutations on clinical outcome of patients with multiple myeloma who were treated with high-dose melphalan and autologous stem cell transplantation.

Epstein-Barr virus (EBV)-associated diffuse large B-cell lymphoma (DLBCL) of the elderly constitutes a provisional clinicopathological entity in the current World Health Organization (WHO) classification and its genomic features remain sparsely characterized. We investigated a cohort of 26 cases of untreated de novo EBV-positive DLBCL of the elderly by high-resolution array-based comparative genomic profiling and fluorescence in situ hybridization (FISH). Moreover, we screened for activating mutations affecting nuclear factor (NF)-κB pathway signaling and chromatin remodeling (EZH2, CD79B, CARD11 and MYD88) due to their impact of gene expression signatures and postulated upcoming therapeutic targetability. We identified an overlap between genomic aberrations previously described to be exclusive features of plasmablastic lymphoma (PL), post-transplant lymphoproliferative disorder (PTLD) and DLBCL, respectively, indicating a close cytogenetic relationship between these entities. Few mutations affecting CD79B and CARD11 and no MYD88 mutations were detectable, hinting at EBV-mediated activation of NF-κB as an alternative to pathologically enforced B-cell receptor signaling in this rare entity. [ABSTRACT FROM AUTHOR]

Double-hit lymphomas (DHL) with MYC and either BCL2 or BCL6 rearrangements are rare neoplasms with an aggressive clinical presentation and grim prognosis. Moreover, molecular characterization of DHL remains insufficient, and especially the role of TP53 pathway disruption is unknown. We employed a next-generation sequencing approach to investigate the mutational status of TP53 in DHL and correlated genomic data with immunohistochemical reactivity for p53. We identified TP53 mutations in MYC+/BCL2+ lymphomas at a frequency intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. Remarkably, TP53 mutations were particularly scarce in MYC+/BCL6+ lymphomas. Our findings indicate a significant difference between these two types of DHL at a molecular level with pathogenetic implications, as arguably, TP53 mutations inhibiting p53 mediated promotion of apoptosis pose a synergistic advantage in clonal evolution of cells with malignantly enforced overexpression of BCL2. Immunohistochemical staining appears to be a sensitive surrogate of TP53 mutation status with moderate specificity. [ABSTRACT FROM AUTHOR]

We report a case of a long-term surviving patient with EML4/ALK translocated non-small cell adenocarcinoma of the lung in UICC8 stage IVA. During recurrence under continuous crizotinib therapy, a hitherto insufficiently characterized missense mutation in the ALK gene (Arg1181His) was identified through targeted sequencing. The aforementioned EML4/ALK translocation could still be detected in this situation. Employing a 3D reconstruction of the ALK tertiary structure, considering its interaction with various ALK inhibitors at the molecular binding site, our analysis indicated the presence of a mutation associated with crizotinib resistance. To validate the biological relevance of this previously unknown mutation, we carried out an in vitro validation approach in cell culture in addition to the molecular diagnostics accompanied by the molecular tumor board. The tumor scenario was mimicked through retroviral transfection. Our comparative in vitro treatment regimen paired with the clinical trajectory of the patient, corroborated our initial clinical and biochemical suspicions. Our approach demonstrates preclinical, in silico, and clinical evidence of a novel crizotinib resistance mutation in ALK as well as sensitivity toward brigatinib and potentially lorlatinib. In future cases, this procedure represents an important contribution to functional diagnostics in the context of molecular tumor boards., (© The Author(s) 2024. Published by Oxford University Press.)

High-grade B-cell lymphoma accompanied with double/triple-hit MYC and BCL2 and/or BCL6 rearrangements (HGBLDH/ TH) poses a cytogenetically-defined provisional entity among aggressive B-cell lymphomas that is traditionally associated with unfavorable prognosis. In order to better understand the mutational and molecular landscape of HGBLDH/ TH we here performed whole-exome sequencing and deep panel next-generation sequencing of 47 clinically annotated cases. Oncogenic drivers, mutational signatures and perturbed pathways were compared with data from follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). We find an accumulation of oncogenic mutations in NOTCH, IL6/JAK/STAT and NFκB signaling pathways and delineate the mutational relationship within the continuum between FL/DLBCL, HGBL-DH/TH and BL. Further, we provide evidence of a molecular divergence between BCL2 and BCL6 rearranged HGBL-DH. Beyond a significant congruency with the C3/EZB DLBCL cluster in BCL2 rearranged cases on an exome-wide level, we observe an enrichment of the SBS6 mutation signature in BCL6 rearranged cases. Differential gene set enrichment and subsequent network propagation analysis according to cytogenetically defined subgroups revealed an impairment of TP53 and MYC pathway signaling in BCL2 rearranged cases, whereas BCL6 rearranged cases lacked this enrichment, but instead showed impairment of E2F targets. Intriguingly, HGBL-TH displayed intermediate mutational features considering all three aspects. This study elucidates a recurrent pattern of mutational events driving FL into MYC-driven BCL2-rearranged HGBL, unveiling the mutational pathogenesis of this provisional entity. Through this refinement of the molecular taxonomy for aggressive, germinal center-derived B-cell lymphomas, this calls into question the current World Health Organization classification system, especially regarding the status of MYC/BCL6- rearranged HGBL.

Aim: To design a tool to predict the probability of new cerebral lesions after stereotactic radiosurgery/radiotherapy for patients with 1-3 brain metastases from colorectal cancer., Patients and Methods: In 21 patients, nine factors were evaluated for freedom from new brain metastases, namely age, gender, Karnofsky performance score (KPS), tumor type, number, maximum total diameter of all lesions and sites of cerebral lesions, extra-cranial metastases, and time from cancer diagnosis to irradiation., Results: Freedom from new lesions was positively associated with KPS of 90-100 (p=0.013); maximum total diameter ≤15 mm showed a trend for positive association (p=0.09). Points were assigned as: KPS 70-80=1 point, KPS 90-100=2 points, maximum diameter ≤15 mm=2 points and maximum diameter >15 mm=1 point. Six-month rates of freedom from new lesions were 29%, 45% and 100% for those with total scores of 2, 3 and 4 points, respectively, with corresponding 12-month rates of 0%, 45% and 100% (p=0.027)., Conclusion: This study identified three risk groups regarding new brain metastases after stereotactic irradiation. Patients with 2 points could benefit from additional whole-brain radiotherapy., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: To create an instrument for estimating the risk of new brain metastases after stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) alone in patients with renal cell carcinoma (RCC)., Patients and Methods: In 45 patients with 1-3 brain metastases, seven characteristics were analyzed for association with freedom from new brain metastases (age, gender, performance score, number and sites of brain metastases, extra-cerebral metastasis, interval from RCC diagnosis to SRS/FSRT)., Results: Lower risk of subsequent brain lesions after RT was associated with single metastasis (p=0.043) and supratentorial involvement only (p=0.018). Scoring points were: One metastasis=1, 2-3 metastases=0, supratentorial alone=1, infratentorial with/without supratentorial=0. Scores of 0, 1 and 2 points were associated with 6-month rates of freedom from subsequent brain lesions of 25%, 74% and 92% (p=0.008). After combining groups with 1 and 2 points, 6-month rates were 25% for those with 0 points and 83% for those with 1-2 points (p=0.002)., Conclusion: Two groups were identified with different risks of new brain metastases after SRS or FSRT alone. High-risk patients may benefit from additional whole-brain irradiation., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Patients with brain metastases from thyroid cancer are extremely rare. This study evaluated clinical factors for survival following whole-brain radiotherapy (WBRT) alone., Patients and Methods: In six patients, the following factors were analyzed for survival: Regimen of WBRT (5×4 Gy vs. 10×3 Gy), gender, age (≤55 vs. ≥56 years), Karnofsky performance score (KPS) (60% vs. 70-80%), number of brain lesions (2-3 vs. ≥4) and number of extra-cranial metastatic sites (one vs. more than one)., Results: KPS 70-80% (p=0.036) and involvement of only one extra-cranial site (p=0.018) were associated with better survival on univariate analysis. On Cox regression analysis, KPS (p=0.14) and number of extra-cranial sites (p=0.14) showed trends for association with survival. In patients with KPS 70-80% and only one extra-cranial site, 6-month survival was 100%, no patient with KPS 60% and more than one extra-cranial site survived to 6 months., Conclusion: KPS and number of involved extra-cranial metastatic sites were associated with survival and may be helpful for individualizing therapy in patients with brain metastases from thyroid cancer., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: To identify predictors of local control and survival after whole-brain irradiation (WBI) for cerebral metastases from cancer of unknown primary (CUP)., Patients and Methods: In 140 patients receiving WBI alone or following resection, seven factors were investigated including treatment approach, WBI-regimen, age, gender, Eastern Cooperative Oncology Group (ECOG) performance score, number of cerebral lesions and extra-cerebral metastases., Results: On univariate analysis, resection plus WBI and boost (p=0.002), ECOG 0-1 (p<0.001) and a single lesion (p<0.001) were positively associated with local control. On Cox regression, ECOG-score remained significant (p=0.002). On univariate analysis of survival, surgery plus WBI and boost (p=0.009), ECOG 0-1 (p<0.001), a single lesion (p=0.024) and no extra-cerebral metastases (p<0.001) were associated with better outcomes. On Cox regression, ECOG-score (p<0.001) and extra-cerebral lesions (p<0.001) were significant., Conclusion: Significant predictors of local control and survival were identified that contribute to treatment personalization and design of prospective trials in patients with cerebral metastases from CUP., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: This study was performed to investigate the prognostic impact of the myeloma subtype on the survival prognosis of patients with spinal cord compression (SCC) from myeloma., Patients and Methods: In 238 patients irradiated for SCC from myeloma, the myeloma subtype and 10 additional characteristics were evaluated for survival. These characteristics were fractionation of radiotherapy, age, time from myeloma diagnosis to SCC, presence of extra-osseous lesions, additional osseous lesions, gender, time to developing motor weakness, ability to walk, number of vertebrae affected by SCC and performance status., Results: Immunoglobulin G subtype was associated with significantly better survival than other subtypes both at 1 year (80% vs. 50%) and at 2 years (56% vs. 30%) following radiotherapy of SCC (p<0.001). In the subsequent Cox regression analysis, myeloma subtype maintained significance (risk ratio=2.44; 95% confidence interval=1.56-3.85; p<0.001)., Conclusion: This study identified myeloma subtype as being an independent prognostic factor of survival in patients with SCC from myeloma., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aim: This is the first study to investigate patients with metastatic spinal cord compression (MSCC) from hepatocellular carcinoma (HCC)., Patients and Methods: Eight patients were analyzed with regard to survival and motor dysfunction., Results: Out of seven factors (age, affected vertebrae, ambulatory status, bone lesions, other distant metastases, time developing motor dysfunction, performance score) ambulatory status (p=0.005) and distant metastases (p=0.032) had a significant influence on survival. Both factors were used as a predictive tool (points: not ambulatory 0, ambulatory 1, distant metastases 0, no distant metastases 1). Total scores were 0, 1 or 2 points. Three-month survival rates were 0%, 67% and 100%, six-month survival rates 0%, 0% and 100%. Progression of motor dysfunction was prevented in 63% of patients; time developing motor deficits showed a trend (p=0.08)., Conclusion: Many patients with MSCC from HCC have a short survival, which can be predicted with a new tool. Radiation therapy can stop progression of motor dysfunction., (Copyright © 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aim: To develop a predictive tool for survival after stereotactic radiosurgery of brain metastases from colorectal cancer., Patients and Methods: Out of nine factors analyzed for survival, those showing significance (p<0.05) or a trend (p≤0.06) were included. For each factor, 0 (worse survival) or 1 (better survival) point was assigned. Total scores represented the sum of the factor scores., Results: Performance status (p=0.010) and interval from diagnosis of colorectal cancer until radiosurgery (p=0.026) achieved significance, extracranial metastases showed a trend (p=0.06). These factors were included in the tool. Total scores were 0-3 points. Six-month survival rates were 17% for patients with 0, 25% for those with 1, 67% for those with 2 and 100% for those with 3 points; 12-month rates were 0%, 0%, 33% and 67%, respectively. Two groups were created: 0-1 and 2-3 points. Six- and 12-month survival rates were 20% vs. 78% and 0% vs. 44% (p=0.002), respectively., Conclusion: This tool helps optimize the treatment of patients after stereotactic radiosurgery for brain metastases from colorectal cancer., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aim: Renal cell carcinoma (RCC) is a relatively radioresistant tumor and may require for higher radiation doses than other tumor types., Patients and Methods: Nineteen patients treated with 20 Gy of stereotactic radiosurgery (SRS) alone for one to three cerebral metastases were compared to nine patients treated with 16-18 Gy., Results: SRS with 20 Gy led to significantly better local control than did 16-18 Gy (81% vs. 50% at 12 months; p<0.001). Results were also significant on multivariate analysis (risk ratio: 6.30; p=0.033). SRS dose did not associate with freedom from new cerebral metastases (75% vs. 62% at 12 months; p=0.42) or survival (16% vs. 56% at 12 months; p=0.46). On multivariate analyses, better survival was associated with higher Karnofsky performance score (p<0.001) and absence of extracranial metastatic disease (p=0.006)., Conclusion: In patients treated with SRS alone, local control of cerebral metastases from RCC was better after 20 Gy than after 16-18 Gy., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Angioimmunoblastic T-cell lymphomas (AITLs) are the second most frequent peripheral T-cell lymphomas in humans worldwide and histomorphologically well characterized. MicroRNAs are a group of small non-coding RNAs that can negatively regulate gene expression on a posttranscriptional level. Their dysregulation has been shown to be of importance in numerous tumour entities., Materials and Methods: As a first step towards understanding the possible influence of microRNA-dysregulation in AITL, we analyzed the expression signatures of 760 microRNAs in 30 nodal AITLs in comparison to reactive lymphadenitis with T-zone hyperplasia., Results: We found miR-34a, miR-146a and miR-193b to be up-regulated, as well as miR-140-3p, let-7g, miR-30b and miR-664 to be down-regulated in AITL to a significant level., Conclusion: The microRNA-signatures of AITL reveal some overlap to autoimmune diseases, virus-triggered lymphomas and angiogenic factors that, coupled with future studies, will potentially provide better understanding of this disease., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Primary mediastinal large B-cell lymphoma (PMBL) is a distinct subtype of diffuse large B-cell lymphoma (DLBCL) frequently observed in young patients. High-dose immunochemotherapy constitutes the current therapeutic gold-standard, despite significant toxicity and serious late effects. Several hotspots harboring oncogenic gain-of-function mutations were recently shown to pose vital hallmarks in activated B-cell like (ABC-) (CD79B, CARD11 and MYD88) and germinal center like (GCB-) DLBCL (EZH2), respectively. Several promising targeted-therapy approaches, derived from these findings, are currently under development., Materials and Methods: We thoroughly characterized a cohort of 25 untreated patients with de novo PMBL by immunohistochemical and cytogenetic means and assessed the prevalence of activating mutations affecting EZH2, CD79B and CARD11 utilizing a polymerase chain reaction (PCR)-based capillary sequencing approach. Moreover, the MYD88 p. L265P status was assessed by employing a pyrosequencing approach., Results: PMBLs included in this study did not harbor any of the reported hotspot mutations activating the nuclear factor (NF)-kappa B signaling cascade or the EZH2-mediated epigenetic deregulation of gene expression. Immunohistochemical characterization revealed an ABC phenotype in 44% (n=11) of cases., Conclusion: We report that genetic alterations of these genes are rare events in PMBL unlike other subtypes of DLBCL. Our findings suggest that a substantial subset of PMBL patients may benefit from treatment approaches targeting BCR-mediated activation of NF-kappa B., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Pancreatic neuroendocrine neoplasms (pNEN) are rare tumors with a poor prognosis. Although increasing data have accumulated on the molecular pathology of pNEN, very scarce data exist on microRNAs in pNEN and no data are published on microRNAs as potential biomarkers of pNEN in serum. This study aimed to identify microRNA signatures of pNEN in tissue and serum., Materials and Methods: We included tissue samples from 37 patients with pNEN, 9 patients with non-neoplastic pancreatic pathology, seven samples of micro-dissected pancreatic islets and serum samples of 27 patients with pNEN, as well as of 15 healthy volunteers. MicroRNA expression profiles were established using real-time quantitative Polymerase Chain reaction (PCR) for 754 microRNAs., Results: MicroRNA signatures differed between pNEN, pancreatic islets and total pancreas, with virtually no overlap between the groups of de-regulated microRNAs. Expression of miR-642 correlated with Ki67 (MiB1) score and miR-210 correlated with metastatic disease. When comparing microRNA levels in serum from patients with pNEN and healthy volunteers, 13 microRNAs were more abundant in the serum of patients. MiR-193b was also up-regulated in pNEN tissue when compared to pancreatic islets and remained significantly increased in serum even when corrected for multiple testing., Conclusion: Evaluation of microRNAs appears to be promising in the assessment of pNEN. In particular, miR-193b, which is also increased in serum, may be a potential new biomarker of pNEN.