Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients

Sequential therapy with inotuzumab ozogamicin, CD19 CAR T cells, and blinatumomab in an elderly patient with relapsed acute lymphoblastic leukemia

Cancer patients frequently require central venous catheters for therapy and parenteral nutrition and are at high risk of central venous catheter-related infections (CRIs). Moreover, CRIs prolong hospitalization, cause an excess in resource utilization and treatment cost, often delay anti-cancer treatment, and are associated with a significant increase in mortality in cancer patients. We therefore summoned a panel of experts by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) and updated our previous guideline on CRIs in cancer patients. After conducting systematic literature searches on PubMed, Medline, and Cochrane databases, video- and meeting-based consensus discussions were held. In the presented guideline, we summarize recommendations on definition, diagnosis, management, and prevention of CRIs in cancer patients including the grading of strength of recommendations and the respective levels of evidence. This guideline supports clinicians and researchers alike in the evidence-based decision-making in the management of CRIs in cancer patients

The role of autologous stem cell transplantation (ASCT) in aggressive B-cell lymphomas: real-world data from a retrospective single-center analysis

Patients with high-risk or relapsed aggressive B-cell lymphomas are characterized by poor prognosis. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) can induce durable remissions in these patients and is potentially curative. Two hundred forty-seven patients with aggressive B-cell lymphomas treated with high-dose chemotherapy and ASCT, either as consolidation after first-line therapy or after salvage therapy for relapsed disease, between 2002 and 2019 at the University Hospital Muenster, were analyzed. The median follow-up of surviving patients was 36 months (range 0-163). Progression-free survival (PFS) and overall survival (OS) after 3 years was 63% and 68%, respectively. After ASCT, 28% of all patients experienced a relapse. The cumulative incidence of non-relapse mortality at day 100 after ASCT was 4%. Multivariate analysis identified remission status at ASCT, age at ASCT, and the numbers of infused CD3

Long-term survival and polyclonal immunoglobulin reconstitution after allogeneic stem cell transplantation in multiple myeloma

Despite significant progress made in the treatment of patients with multiple myeloma (MM) in the last decade, for patients with early relapse or rapidly progressing high-risk disease, allogeneic hematopoietic stem cell transplantation (SCT) might be an option leading to long-term survival. Here, we retrospectively analyzed the outcomes of 90 MM patients who received allogeneic SCT in our center between 1999 and 2017. We specifically assessed the association of impaired humoral immune reconstitution, referred to as immunoparesis, and post-transplant survival. Sixty-four patients received allogeneic SCT in relapse following 2-7 lines of therapy; 26 patients received upfront tandem autologous-allogeneic SCT. With a median follow-up of 76 months, OS and PFS were 52.6% (95% CI 42.9-64.3) and 36.4% (95% CI 27.6-47.9) at 2 years and 38.6% (95% CI 29.2-51.1) and 25.3% (95% CI 17.5-36.4) at 5 years, respectively. Receiving more than two therapy lines prior to transplantation was an independent risk factor for OS (HR 3.68, 95% CI 2.02-6.70) and PFS (HR 3.69, 95% CI 2.09-6.50). In a landmark analysis at day 200, prolonged immunoparesis was associated with reduced OS (HR 3.22, 95% CI 1.14-9.11). Allogeneic stem cell transplantation offers an additional treatment element that may lead to long-term remission in selected patients with poor prognosis, probably exploiting graft-versus-myeloma effects. Immunoparesis could potentially serve as an indicator for impaired survival following allogeneic transplantation, an observation to be further studied prospectively

A combinatorial strategy for treating KRAS mutant lung cancer

Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proven difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents. Here we take a systematic approach towards identifying combination targets for trametinib, an FDA-approved MEK inhibitor that acts downstream of KRAS to suppress signaling through the mitogen-activated protein kinase (MAPK) cascade. Informed by a short-hairpin RNA (shRNA) screen, we show that trametinib provokes a compensatory response involving the fibroblast growth factor receptor 1 (FGFR1) that leads to signaling rebound and adaptive drug resistance. As a consequence, genetic or pharmacologic inhibition of FGFR1 in combination with trametinib enhances tumor cell death in vitro and in vivo. This compensatory response shows distinct specificities – it is dominated by FGFR1 in KRAS mutant lung and pancreatic cancer cells, but is not activated or involves other mechanisms in KRAS wild-type lung and KRAS-mutant colon cancer cells. Importantly, KRAS-mutant lung cancer cells and patient tumors treated with trametinib show an increase in FRS2 phosphorylation, a biomarker of FGFR activation; this increase is abolished by FGFR1 inhibition and correlates with sensitivity to trametinib and FGFR inhibitor combinations. These results demonstrate that FGFR1 can mediate adaptive resistance to trametinib and validate a combinatorial approach for treating KRAS-mutant lung cancer

The dark matter of the cancer genome: aberrations in regulatory elements, untranslated regions, splice sites, non-coding RNA and synonymous mutations

Cancer is a disease of the genome caused by oncogene activation and tumor suppressor gene inhibition. Deep sequencing studies including large consortia such as TCGA and ICGC identified numerous tumor‐specific mutations not only in protein‐coding sequences but also in non‐coding sequences. Although 98% of the genome is not translated into proteins, most studies have neglected the information hidden in this “dark matter” of the genome. Malignancy‐driving mutations can occur in all genetic elements outside the coding region, namely in enhancer, silencer, insulator, and promoter as well as in 5′‐UTR and 3′‐UTR. Intron or splice site mutations can alter the splicing pattern. Moreover, cancer genomes contain mutations within non‐coding RNA, such as microRNA, lncRNA, and lincRNA. A synonymous mutation changes the coding region in the DNA and RNA but not the protein sequence. Importantly, oncogenes such as TERT or miR‐21 as well as tumor suppressor genes such as TP53/p53,APC,BRCA1, or RB1 can be affected by these alterations. In summary, coding‐independent mutations can affect gene regulation from transcription, splicing, mRNA stability to translation, and hence, this largely neglected area needs functional studies to elucidate the mechanisms underlying tumorigenesis. This review will focus on the important role and novel mechanisms of these non‐coding or allegedly silent mutations in tumorigenesis

The dark matter of the cancer genome: aberrations in regulatory elements, untranslated regions, splice sites, non-coding RNA and synonymous mutations

This paper deals with the use of reported speech (RS) in Spanish criminal lawsuits (querellas) and police reports (denuncias) and argues about the most suitable strategies to translate such RS into Italian. In line of principle, the written record of the statements made by the individual(s) who filed the complaint is often the result of an oral cooperation between the plaintiff and the police officer and/or their attorney, whose subjectivity is reflected on the texts in a quite different fashion in the two legal cultures. The so-called ‘verbatim assumption’ of quotations in direct speech (DS) turns out to be a fallacy in the discussed genres, insofar as the locutor (i.e. the police officer or the attorney responsible for the drafting of the document) often normalizes the original utterances of the enunciator (i.e. the plaintiff whose point of view is represented in the report) in terms of cohesion, register and sentence length. Usually, these texts are translated following a strictly ‘interlinear approach’, so much so as to result almost illegible. An adequate command  of genre conventions – both in the source and in the target language – and the abidance by the translation universals of simplification and explicitation may help the translator produce a more efficient and readable target text, consistent with the expectations of a jurist in the target culture